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Noncoding RNAs regulate alternative splicing in Cancer

Abstract

AS (alternative splicing) is a fundamental process by which a gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in AS influence the occurrence and development of many diseases, including cancers, and are frequently found to participate in various aspects of cancer biology, such as promoting invasion, metastasis, apoptosis resistance and drug resistance. NcRNAs (noncoding RNAs) are an abundant class of RNAs that do not encode proteins. NcRNAs include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular RNAs) and snRNAs (small nuclear RNAs) and have been proven to act as regulatory molecules that mediate cancer processes through AS. NcRNAs can directly or indirectly influence a plethora of molecular targets to regulate cis-acting elements, trans-acting factors, or pre-mRNA transcription at multiple levels, affecting the AS process and generating alternatively spliced isoforms. Consequently, ncRNA-mediated AS outcomes affect multiple cellular signaling pathways that promote or suppress cancer progression. In this review, we summarize the current mechanisms by which ncRNAs regulate AS in cancers and discuss their potential clinical applications as biomarkers and therapeutic targets.

Background

AS (alternative splicing) of RNA involves the way in which pre-mRNA (pre-messenger RNA) undergoes splicing at different splice sites, and introns are selectively removed while exons are retained to produce two or more kinds of mRNA splicing isoforms. AS progression has been discovered in over 95% of human multiexon genes and has profound consequences at the protein level, increasing the diversity of gene phenotypes and protein functions in eukaryotes [1, 2]. AS allows pointed splicing isoforms expressed at a given time to participate in various cellular activities, while AS defects are related to various diseases. In recent decades, it has been observed that many AS changes play vital roles in cancer progression. Cancer cells subvert normal AS events to produce special splicing isoforms that affect cellular functions and potentially control cell proliferation and tumorigenesis. Gaining an understanding of AS mechanisms may reveal new opportunities to develop targeted cancer treatment strategies [3,4,5].

AS is a highly controlled process, and with the use of high-throughput sequencing and RNA-seq technologies, thousands of ncRNAs (noncoding RNAs) have been identified crucial to regulate AS at multiple levels in cancers [6]. Here, we review our current knowledge of ncRNAs as AS regulators, their mechanisms of action in cancer, and their contributions to the diagnosis and treatment of cancer.

Alternative splicing in cancer

AS relies mainly on the spliceosome, splice site, cis-acting element and trans-acting factor. The spliceosome is assembled from five snRNPs (small nuclear ribonucleoproteins), namely, U1, U2, U4, U5, U6 and over 300 non-snRNP proteins. In AS, spliceosomes recognize splice sites located at the borders between introns and exons, including 5′ splice sites, 3′ splice sites and branch points of pre-mRNA. Through recognition, spliceosomes convene and function as ribozymes to catalyze the removal of introns [7]. Then, retained exons link together to eventually generate the mRNA, forming five different types of AS: ES (exon skipping), IR (intron retention), MXE (mutually exclusive exon), A5SS (alternative 5′ splice site) and A3SS (alternative 3′ splice site) (Fig. 1). During the AS process, the spliceosome cannot interact with the splice site independently to determine the gene sequences of the pre-mRNA that are retained or skipped. Cis-acting elements and trans-acting factors are needed in the recognition and selection of splice sites and in the aggregation of spliceosomes [8].

Fig. 1
figure1

Different types of AS. a. ES (exon skipping); b. IR (intron retention); c. MXE (mutually exclusive exon); d. A5SS (alternative 5′ splice site); and e. A3SS (alternative 3′ splice site)

Cis-acting elements, categorized as ISEs (intron splicing enhancers) and ISSs (silencers), as well as ESEs (exon splicing enhancers) and ESSs (silencers), are the only positions beside variable exons and side-by-side introns to provide gene sites of binding with trans-acting factors [9] (Fig. 2).

Fig. 2
figure2

A schematic representation of AS regulated by cis-acting elements and trans-acting factors. The cis-acting elements ESEs and ESSs represent exonic splicing enhancers and silencers, respectively. ISEs and ISSs represent intronic splicing enhancers and silencers, respectively. SR proteins, hnRNPs, or other trans-acting factors bind to cis-acting elements for positive or negative AS regulation by affecting the recruitment or recognition of spliceosome components to splice sites; for example, U1 binds to the 5′ splice site, while U2AF and U2 bind to the 3′ splice site

Trans-acting factors in AS are mainly SFs (splicing factors), which include three common types [10]: SR (serine/arginine-rich) proteins, hnRNPs (heterogeneous nuclear ribonucleoproteins) and tissue-specific SFs. SR proteins, composed of 12 members (serine/arginine-rich splicing factor 1–12, SRSF1–12), generally bind ESE sequences and promote the recognition of exons by recruiting U1 to the 5′ splice site and U2AF (U2 auxiliary factor) and U2 to the 3′ splice site [11, 12]. HnRNPs mainly bind ESS or ISS sequences and inhibit the recognition of exons by hindering contact between spliceosomes and splice sites [13]. Tissue-specific SFs, such as RBM5 (RNA binding motif protein 5), RBM24, QKI (quaking), and Nova1 (NOVA alternative splicing regulator 1), exist in special tissues and allow more specific controls of splice site selection for cell specification and organ function. For example, RBM24 binds an ISE to promote muscle-specific exon inclusion in cardiac and skeletal muscles [14]. In addition to the above three classical SFs, some other regulatory proteins, such as U2AF65, SF3B3 (splicing factor 3b subunit 3), and SF1, have also been classified as SFs by binding directly to pre-mRNAs.

In addition to cis-elements and trans-acting factors, as the excision of most introns occurs cotranscriptionally, AS is coupled with pre-mRNA transcription [15, 16]. Factors or chromatin modifications related to pre-mRNA transcription are able to affect AS. For instance, a fast rate of Pol II (RNA polymerase II) elongation, which contributes to transcription elongation, induces spliceosome aggregation at the stronger alternative 3′ splice site (A3SS), which is located downstream of the weaker A3SS, leading to exon skipping [10]. Moreover, the chromatin modification H3K36me3 (trimethylation on histone H3 thirty-sixth lysine), which can promote transcriptional activation, results in the recruitment of the SF SRSF1 to pre-mRNA to regulate AS [17].

In cancers, AS defects have been repeatedly observed and result from mutations in genes that encode cis-acting elements [18] or SFs [19] or from misregulations in the AS machinery [5, 20]. For example, in hematologic malignancies, a gene mutation in the SF SRSF2, which regulates the AS of the EZH2 pre-mRNA, triggers a reduction in EZH2 isoform expression [21]. In CRC (colorectal cancer) samples, overexpression of the SF SRSF6, which binds to the ZO-1 motif in exon 23, can contribute to the expression of an alternative isoform of ZO-1 due to exon 23 skipping [22].

The outcome of aberrant AS brings numerous special splicing isoforms at the protein level and gives rise to the initiation and progression of cancer. In PCa (prostate cancer), abnormal splicing of the androgen receptor pre-mRNA produces splicing isoforms that promote drug resistance and cancer aggression [23]. In human skin cancer, a splicing alteration in the protein TNC (tenascin C) pre-mRNA increases the number of tumor-promoting TNC-FL isoforms, resulting in cancer cell invasion and metastasis [24].

Noncoding RNAs in alternative splicing

NcRNAs, which occupy almost 60% of the transcriptional output in human cells [25], are RNAs that do not encode proteins. With the development of sequencing technologies, a multitude of ncRNAs have been discovered and classified based on their size or function into many kinds, including miRNAs (microRNAs), siRNAs (small interfering RNAs), piRNAs (piwi-interacting RNAs), rRNAs (ribosomal RNAs), snRNAs (small nuclear RNAs), lncRNAs (long noncoding RNAs), or circRNAs (circular RNAs).

MiRNAs are small ncRNAs that are approximately 19–25 nucleotides in length with highly conserved properties [26]. MiRNA is commonly assembled into the RISC (RNA-induced silencing complex), which is guided to degrade mRNA or simply inhibit mRNA translation without changing mRNA levels, depending on the complete or partial complementation of miRNA. The miRNA-mediated action occurs mainly in the 3′ UTR (untranslated region) and sometimes in the 5’UTR of the target mRNA [27,28,29,30]. Moreover, some miRNAs are able to stabilize mRNAs or promote translation by binding to the mRNA 5’UTRs [31].

LncRNAs are more than 200 nucleotides in length with poorly conserved properties, and their functions include acting as molecular scaffolds in various biological processes, disturbing nearby pre-mRNA transcription, forming RNA–RNA duplexes with pre-mRNA molecules or miRNAs as posttranscriptional regulators, promoting specific protein activities, and recruiting or inhibiting regulatory proteins in multifarious transcriptional, posttranscriptional or posttranslational manners. Additionally, several lncRNAs encode peptides or generate small RNA molecules that exert biological effects [6, 32,33,34].

CircRNAs are closed endogenous ncRNAs that are more stable than linear RNAs due to their structures, which are covalently closed continuous loops without a 5′ cap structure and 3′ polyadenylated tail [35]. CircRNAs can sponge miRNAs through base pairing to protect their target mRNAs. Moreover, circRNAs are able to inhibit or recruit specific proteins to function in the regulation of various biological processes, to enhance particular protein functions to facilitate gene transcription, and to serve as protein scaffolds to promote the reaction of enzymes and substrates. Additionally, some circRNAs may have coding potential to produce peptides under certain conditions [36, 37].

SnRNAs (U1 ~ U7) average approximately 150 nucleotides in length with highly conserved properties and participate in various aspects of RNA biogenesis as core components of functional snRNPs [38, 39]. On the one hand, snRNAs associate with proteins to form snRNPs and play snRNP-mediated regulatory roles. On the other hand, snRNAs can form dynamic base pairing interactions between snRNAs and between snRNAs and the pre-mRNA, ensuring the coordination of pre-mRNA processing [38, 40].

According to current studies, ncRNAs, especially miRNAs, lncRNAs and circRNAs, play crucial roles in regulating AS. Recently, snRNAs (U1, U2, U4, U5, and U6) have also been shown to act as regulators of AS in cancer, in addition to basal factors of the spliceosome [41, 42]. In the following sections, we further discuss the specific regulatory relationships between ncRNAs and AS in cancers.

Regulation of alternative splicing through cis-acting elements

Some endogenous ncRNAs that act as NATs (natural antisense transcripts), which are RNAs that contain sequences complementary to other endogenous RNAs, can specifically interact with cis-acting elements in pre-mRNAs by RNA–RNA base pairing. The interaction between ncRNAs and cis-acting elements can affect the selection of splice sites and/or the recruitment of SFs, thus regulating the expression of alternatively spliced isoforms in cancers. According to the origin of ncRNAs, their interaction with cis-acting elements has a cis-NAT form and a trans-NAT form.

A cis-NAT is transcribed from the opposite strand of a DNA strand at the same locus and usually has long perfect complementary sequences with the opposite transcript [43]. One example of a cis-NAT is the lncRNA Saf, which is transcribed from the opposite strand of the genomic DNA sequence of the Fas protein. Saf directly binds to the cis-acting element in the Fas pre-mRNA, and they form a specific double-stranded RNA intermediate located within or surrounded by the alternatively spliced exon 6, consequently recruiting the SF SPF45 to the Fas pre-mRNA. The interaction of Fas pre-mRNA, Saf, and SPF45 stimulates the exon skipping of Fas exon 6, resulting in the expression of the sFas (soluble Fas) isoform [44], which contributes to cancer survival by inhibiting Fas-mediated apoptosis in multiple cancers [45] (Fig. 3a). Another example of a cis-NAT is the lncRNA EGOT, which is transcribed from the opposite strand of the ITPR1 (inositol 1,4,5-trisphosphate receptor type 1) genomic sequence. EGOT can directly bind to the cis-acting element in ITPR1 pre-mRNA, resulting in the recruitment of the SF hnRNPH1 to promote hnRNPH1-mediated AS, contributing to the expression of the ITPR1 protein, which sensitizes cells to paclitaxel cytotoxicity in cancer therapy [46]. Additionally, the lncRNA Zeb2 is a NAT and is transcribed from the opposite strand of the Zeb2 protein genomic sequence, binds to the cis-acting element in Zeb2 pre-mRNA and overlaps the splice site in the 5’UTR intron, preventing recognition of the spliceosome. The interaction between the Zeb2 NAT and Zeb2 pre-mRNA promotes the inclusion of the 5’UTR intron, thus increasing the levels of the Zeb2 protein, which can activate EMT (epithelial–mesenchymal transition) in breast cancer cells [47].

Fig. 3
figure3

NcRNAs regulate AS through cis-acting elements. a One example of a cis-NAT: the lncRNA Saf binds specifically to the Ex 6 (exon 6) region of the Fas pre-mRNA and recruits SPF45, resulting in the expression of the sFas isoform, which consequently inhibits apoptosis. b One example of a trans-NAT: the lncRNA BC200 binds to Bcl-x pre-mRNA Ex 3 (exon 3) and recruits hnRNPA1/B2 to form the BC200-Bcl-x-hnRNPA2/B1 complex. This complex contributes to Bcl-xL expression and apoptosis resistance in breast tumor cells

In contrast, ncRNAs can also interact with cis-acting elements through the trans-NAT form to regulate AS. A trans-NAT is transcribed from different genomic loci and usually has short and imperfect complementarity with the target pre-mRNA [43]. For example, the lncRNA BC200, derived from the BC200 gene, can directly bind the cis-acting element in the Bcl-x pre-mRNA derived from the Bcl-x gene [48, 49]. The lncRNA BC200 forms a specific double-stranded RNA intermediate with Bcl-x pre-mRNA exon 3, promoting the recruitment of the SF hnRNPA2/B1 to Bcl-x pre-mRNA. The interaction among BC200, hnRNPA2/B1 and Bcl-x pre-mRNA produces the Bcl-xL isoform and suppresses the expression of the Bcl-xS isoform [50], contributing to the apoptosis resistance of breast tumor cells [51] (Fig. 3b). Additionally, the lncRNA CCAT2, which is transcribed from genomic loci that is different from GLS (glutaminase), binds to an intron 14 fragment of GLS pre-mRNA and recruits the CFIm (cleavage factor I) complex to GLS pre-mRNA by direct binding. The CCAT2-CFIm-GLS interaction results in the expression of the GAC (glutaminase C) splicing isoform, promoting metastases and cell proliferation in CRC [52]. Moreover, the snRNA U1, which recognizes transcriptome-wide 5′ splice sites through base pairing [53], can bind to extensive U1-targeted pre-mRNAs to promote intron exclusion. Aberrant U1-mediated AS events generate many kinds of splicing isoforms and have a close association with characteristic breast cancer subtypes [41].

Therefore, some ncRNAs are able to interact with cis-acting elements through the cis-NAT or trans-NAT form, impacting AS outcomes in cancers.

Regulation of alternative splicing through trans-acting factors

Posttranscriptional regulation of splicing factors

NcRNAs have been observed as posttranscriptional regulators that participate in the regulation of the mRNA expression of SFs, thereby affecting splicing isoform outcomes.

MiRNAs can inhibit SF expression through complete or partial complementation with the target mRNA of an SF, degradation of the mRNA or the downregulation of mRNA translation as a result [54, 55] (Fig. 4a). For example, in neuroblastoma, both miR-10a and miR-10b degrade SRSF1 mRNA through complete complementation with its 3’UTR and downregulate the translation of SRSF1 as a result of decreasing SRSF1-mediated AS, thus inhibiting the migration, invasion, and metastasis of neuroblastoma cells [56]. Additionally, miR-30c in PCa cells degrades SRSF1 mRNA through complete complementation with its 3’UTR and downregulates its translation to decrease SRSF1-mediated AS, thus suppressing PCa cell survival [57]. Moreover, in HCC (hepatocellular carcinoma), miRNA-133b inhibits the translation of SF3B4 (splicing factor 3b subunit 4) mRNA through partial complementation with its 3’UTR to decrease SF3B4-mediated AS, repressing cell proliferation and metastasis [58]. In HeLa cells, miR-7 inhibits the mRNA translation of the SF SRSF1 through partial complementation with its 3’UTR to downregulate SRSF1-mediated AS, suppressing cancer cell survival [59]. Here, we summarize the current miRNAs that regulate SFs at the posttranscriptional level Table 1.

Fig. 4
figure4

NcRNAs regulate AS through the posttranscriptional regulation of SFs. a MiRNAs silence SFs by directly binding to the SF mRNA. b CircRNAs and lncRNAs can sponge miRNA functions by directly binding to block their function with SF mRNAs, promoting SF expression

Table 1 MiRNAs that regulate SFs at the posttranscriptional level

Some miRNAs and SFs form modulatory feedback circuits to maintain the coordination and relationship between miRNA-mediated SF gene repression and miRNA expression in AS regulatory networks. For instance, miR-7 prevents the translation of SRSF1 mRNA and decreases SRSF1-mediated AS, repressing cancer cell survival. In turn, SRSF1 directly binds to the long primary transcript of miR-7 called pri-miR-7, and SRSF1-independent splicing promotes pri-miR-7 processing into miR-7 by facilitating cleavage by Drosha [59]. Additionally, miR-181a-5p directly decreases both SRSF7 mRNA and protein levels, downregulating SRSF7-mediated AS, which reduces renal cancer cell proliferation. Conversely, SRSF7 contributes to miR-181a-5p expression through a possible mechanism that directly facilitates maturation of the miR-181a-5 primary transcript [62].

In addition, circRNAs and lncRNAs have been observed to promote SF expression by binding and sponging miRNAs as ceRNAs (competing endogenous RNAs), thus regulating AS in cancers (Fig. 4b). For example, in non-small cell lung cancer, the circRNA 100,146 can bind and sponge miR-361-3p and miR-615-5p, which both directly inhibit the expression of the SF SF3B3, thus increasing SF3B3-mediated AS to promote the proliferation and invasion of cancer cells [78]. Similarly, the lncRNA UCA1 can bind and sponge miR-184, which directly decreases the expression of SF1, resulting in the upregulation of SF1-mediated AS to accelerate the proliferation and cisplatin resistance of oral squamous cell carcinoma [77]. The lncRNA CCAT1 binds and sponges miR-490, which directly inhibits the expression of the SF hnRNPA1, consequently increasing hnRNPA1-mediated AS to promote gastric cancer cell migration [64].

Posttranslational regulation of splicing factors

Acting as posttranslational regulators of SFs, ncRNAs can control the posttranslational chemical modifications (e.g., phosphorylation) of SFs or decoy SFs, remodel chromatin, or encode peptides to interact with SFs, thus altering splicing outcomes in cancers.

Posttranslational chemical modifications

NcRNAs are able to control SF phosphorylation, which enhances SF activity to promote AS. In CRC cells, the lncRNA MALAT1 has been found to form a complex with both SRSF1 and SRPK1 (serine/arginine protein kinase 1) in nuclear speckles [79]. MALAT1 can increase both the expression and activity of SRPK1 [80], which functions to catalyze SRSF1 phosphorylation by binding to the RS domain of unphosphorylated SRSF1 [81]. MALAT1-mediated SRSF1 phosphorylation can affect the subcellular localization of SRSF1 and promote splice site selection in AKAP-9 (A-kinase anchor protein 9) pre-mRNA [82,83,84], thus contributing to the expression of the AKAP-9 isoform, which exacerbates cellular proliferation, migration and invasion in CRC [80] (Fig. 5a).

Fig. 5
figure5

NcRNAs regulate AS through the posttranslational regulation of SFs. a Posttranslational chemical modifications. The lncRNA MALAT1 contributes to SRSF1 phosphorylation by stimulating both the expression and activity of SRPK1, thereby promoting SRSF1-mediated AS of the AKAP-9 pre-mRNA and enhancing the expression of the AKAP-9 isoform, which exacerbates CRC. b Decoy SFs. For example, the lncRNA TPM1-AS can directly block the binding between the SF RBM4 and TPM1 pre-mRNA and regulate AS, inhibiting the progression of cancer. c Chromatin remodeling. The lncRNA asFGFR2 recruits PRC2 and KDM2a to chromatin to form a chromatin environment that disrupts the binding of MRG15-PTB. This disruption alters the location of the SF PTB, promoting FGFR2 mRNA with exon IIIb inclusion and consequently repressing HCC progression. d Encoding functional peptides. The lncRNA HOXB-AS3 encodes the peptide HOXB-AS3, which targets hnRNPA1 and blocks it from binding to PKM pre-mRNA flanking exon 9, decreasing the expression of the PKM2 isoform and consequently repressing the growth of colon cancer

Decoy splicing factors

Some ncRNAs can act as “decoys” to inhibit SFs binding to targeted pre-mRNAs through direct interactions, thus regulating AS in cancers [85,86,87]. For example, the lncRNA TPM1-AS binds to the SF RBM4 and blocks the targeting of TPM1 pre-mRNA, leading to the inhibiting of TPM1 exon 2a inclusion and a decrease in the two tumorigenic splicing isoforms V2 and V7 and thus inhibiting migration and filopodium formation in esophageal cancer cells [88] (Fig. 5b). Additionally, the lncRNA PNCTR can recruit at least 6 of the SF PTBP1 (polypyrimidine tract binding protein 1) molecules and sequester them in a nuclear body called the PNC (perinucleolar compartment), hindering PTBP1 from acting on CHEK2 (checkpoint kinase 2) pre-mRNA and contributing to the expression of a CHEK2 isoform that includes exon 8. The lncRNA PNCTR-mediated splicing isoform promotes cell survival in many kinds of cancers [89]. Moreover, the circRNA circSMARCA5 binds and decoys the SF SRSF1 away from VEGF-Axxxa pre-mRNA to decrease the expression of the proangiogenic splicing isoform VEGF-Axxxa, repressing cancer progression in glioblastoma multiforme [90]. Additionally, the circRNA circ-UBR5 can recruit the SFs QKI and NOVA1 and block their splicing functions to change the AS outcome, affecting tumor differentiation in non-small cell lung cancer [91]. It should be noted that a series of studies on the decoy roles by which ncRNAs inhibit SF-mediated AS in cancers have been conducted Table 2. In addition to the inhibitory function described above, ncRNAs can also act as “decoys” to promote the binding of SFs to targeted pre-mRNAs. For example, the lncRNA PCGEM1 can bind and enhance the binding capacity of the SF U2AF65 to AR pre-mRNA and promote the expression of the AR3 splicing isoform by exonization, contributing to the development of PCa [87, 100].

Table 2 NcRNAs as SF decoys to inhibit SF-mediated AS in cancer

Chromatin remodeling

NcRNAs can fine-tune the chromatin structure, which controls the recruitment of SFs to affect their interaction with pre-mRNAs in the AS process, changing splicing outcomes. The lncRNA asFGFR2 has been verified to function through the recruitment of PRC2 (polycomb repressive complex 2, one of the two classes of polycomb-group proteins) and the histone demethylase KDM2a (lysine-specific demethylase 2A) to chromatin to form a special chromatin environment that disrupts the binding between MRG15 (MORF4-related gene on chromosome 15) with PTB (polypyrimidine tract binding protein). The disruption of the MRG15-PTB interaction alters the location of the SF PTB and decreases the recruitment of the SF PTB to exon IIIb, promoting exon IIIb inclusion in the course of FGFR2 (fibroblast growth factor receptor 2) splicing [101] and consequently producing the FGFR2-IIIb isoform, which decreases the proliferation and migratory potential of HCC [102] (Fig. 5c).

Encoding functional peptides

NcRNAs, especially lncRNAs, are able to regulate SFs at the posttranslational level through limited coding potential. For example, the lncRNA HOXB-AS3 encodes a conserved HOXB-AS3 peptide, and the HOXB-AS3 peptide competitively targets arginine residues in an RNA-binding area (called an RGG box) of hnRNPA1, which blocks the binding of hnRNPA1 to certain sequences of the PKM (pyruvate kinase M) pre-mRNA flanking exon 9, thereby inhibiting hnRNPA1-mediated AS, decreasing the expression of the PKM2 isoform and consequently repressing the growth of colon cancer [103] (Fig. 5d).

Regulation of alternative splicing through pre-mRNA transcription

AS is not an independent posttranscriptional regulation but is intimately coupled with transcription, and factors that regulate pre-mRNA transcription can have an impact on AS [10]. Emerging roles of ncRNAs have been found to directly participate in transcription [31, 104, 105] and may therefore impact the AS outcome. For example, the lncRNA EZR-AS1 can form a complex with Pol II and recruit the histone H3-lysine 4-specific methyltransferase SMYD3 (SET and MYND domain containing protein 3) to a site downstream of the transcription promoter. The interaction of EZR-AS1 with Pol II and SMYD3 promotes the histone modification H3K4me3 (trimethylation of lysine 4 on histone H3) in transcription sites and facilitates pre-mRNA transcription [106, 107]. H3K4me3 is also able to recruit spliceosome components to promote the exclusion of exon 2 from the MCL1 (myeloid cell leukemia 1) pre-mRNA, resulting in the expression of the MCL1S isoform, which induces cancer cell apoptosis [107,108,109,110]. In addition, the lncRNA HOTAIR decreases the recruitment of multiple promoting molecules of SETD2 (SET domain-containing 2, the specific methyltransferase of H3K36) to downregulate SETD2 expression and phosphorylation, thus reducing SETD2-mediated H3K36me3, which can activate pre-mRNA transcription [111, 112]. The reduction in H3K36me3 promotes the expression of the CDH1 (cadherin 1) isoform with exon 8, acting as a biological marker in gastric cancer occurrence [113]. Furthermore, the lncRNA DACOR1 in colon cancer cells promotes genome-wide DNA methylation [114, 115]. Interestingly, not correlating with the negative regulation of transcription, DNA methylation at Oct4A gene enhancers can facilitate the expression of the Oct4A splicing isoform by affecting the AS of Oct4A pre-mRNA, inhibiting cell aging in embryonal carcinoma [115, 116].

In conclusion, ncRNAs may regulate AS by affecting transcription, mainly by interacting with Pol II and regulating histone modification and DNA methylation.

Diagnostic and therapeutic value of ncRNA-regulated alternative splicing in cancer

High-throughput sequencing technology has allowed the measurement of an AS event in terms of an overall ratio, and the final results make it possible to provide diagnostic information in this manner. An increasing number of studies have indicated that ncRNAs can serve as biomarkers for diagnosis or drug resistance in many types of cancers due to their participation in AS events [61, 64, 117,118,119,120,121]. For example, the lncRNA HOXA11-AS can regulate SF SRSF1-mediated AS, contributing to GC (gastric cancer) cell proliferation and invasion. Expression of the lncRNA HOXA11-AS was found to be increased in GC tissues and serum samples. Clinical data indicate that GC patients with a high HOXA11-AS level have a poor prognosis and that HOXA11-AS may function as a potential diagnostic biomarker in GC [117]. Additionally, the lncRNA 91H has been verified to regulate hnRNPK-mediated AS, affecting cancer processes such as metastasis in CRC. Expression of the lncRNA 91H in the serum was found to be increased in CRC patients and is considered an early clinical marker for CRC recurrence and metastasis [119]. Additionally, the lncRNA LINC01133 can block the splicing function of SRSF6 [92], which contributes to the EMT process by promoting the expression of the tumorigenic splicing isoform [22]. Analyses of clinical CRC tissues have shown that patients with high LINC01133 expression always have better survival outcomes than those with low expression and that LINC01133 may act as a prognostic biomarker due to its antimetastatic function. In addition, miR-193a-3p can downregulate AS events mediated by the SF SRSF2, thereby contributing to cisplatin resistance. Analyses of clinical GC tissues have suggested that some patients with high miR-193a-3p expression may have a high level of resistance to cisplatin and that miR-193a-3p may act as a clinical biomarker of cisplatin resistance in GC patients after surgery [122]. Moreover, the lncRNA EGOT participates in the AS of ITPR1 pre-mRNA, sensitizing cancer cells to paclitaxel treatment. Analyses of clinical breast cancer samples have shown that patients with low EGOT expression have a high level of paclitaxel resistance and that EGOT may be utilized as a diagnostic biomarker of paclitaxel treatment for breast cancer patients after surgery [46].

In view of the important regulatory roles in AS, ncRNAs have rapidly emerged as promising targets for pharmaceutical development in cancers [67, 68, 92, 123,124,125,126,127,128,129,130,131]. For example, the lncRNA FAS-AS1 promotes the expression of the splicing isoform sFas by directly binding with the SF RBM5, thus increasing resistance to apoptosis in B-cell lymphomas [93]. Ibrutinib has been proven to repress the splicing isoform mediated by RBM5 for cell-killing effects by downregulating FAS-AS1 expression, and it has been applied to target B-cell malignancies as an anticancer drug [93, 132, 133]. Additionally, miR-424 and miR-503 can regulate AS events mediated by the SF hnRNPA1, decreasing breast cancer cell proliferation [134]. Resveratrol, a polyphenolic phytoalexin with multiple functions, such as antitumorigenic and anti-inflammatory effects [135, 136], is a popular health care product on the market. It has been found that resveratrol is able to promote the expression of the tumor-suppressive miRNAs miR-424 and miR-503, and it has been regarded as a promising application for cancer prevention and treatment [134]. Furthermore, with high expression in all GBM (glioblastoma) subtypes, oncogenic miR-10b possesses strong therapeutic potential due to its regulatory function in AS by interacting with multiple SFs, including MBNL1 (muscleblind-like splicing regulator 1), MBNL2 and DGCR14 (DiGeorge syndrome critical region gene 14) [71, 137]. Various formulations of miR-10b ASO (antisense oligonucleotide) inhibitors delayed GBM progression in mouse models through three routes (direct intratumoral injection, continuous osmotic delivery, and systemic intravenous injection) without significant systemic toxicity, indicating that a miR-10b inhibitor can be used as a drug against all GBM subtypes [71]. Moreover, in HCC, miR-374b can play an AS regulatory role in the miR-374b/hnRNPA1/PKM2 axis, addressing the problem of sorafenib resistance. MiR-374b mimic was transfected by lipofectamine, which was injected into SCID mice sensitized HCC cells to sorafenib toxicity, indicating that miR-374b is an effective treatment for sorafenib resistance [66]. In addition, in prostate cancer, PCGEM1 inhibits HnRNPA1-mediated AS in androgen receptor pre-mRNA, promoting castration resistance (including drug resistance to enzalutamide and abiraterone) [87, 138]. PCGEM1-shRNA, through lentiviral packaging and injection into castrated male SCID mice, restrains tumor growth, suggesting that PCGEM1 can act as a likely drug target of castration resistance [87] (Fig. 6).

Fig. 6
figure6

A schematic representation: the diagnostic and therapeutic value of ncRNA-regulated AS in cancer. Multiple ncRNAs can act as diagnostic biomarkers and promising targets for pharmaceutical development in various types of cancers due to their participation in AS events

Conclusions

We summarize the recent ncRNAs, mainly miRNAs (Table 1) and lncRNAs (Table 3), that regulate AS at multiple levels in cancer. Notably, current related observations focus mainly on regulation through cis-acting elements or trans-acting factors based on the posttranscription of nascent pre-mRNAs. Considering that a pre-mRNA indicates simply an immature and temporary state (as a presumptive primary transcript) and that the process of transcription is accompanied by splicing, ncRNA-regulated transcription could have a comprehensive and complex impact on AS, including the maturation and selection of cis-acting elements and the recruitment of trans-acting factors. The direct observation of the functions of ncRNAs in transcription and AS is a potential research direction in the AS domain of cancers.

Table 3 LncRNAs that regulate AS in cancer

The number of current studies on the association of ncRNAs with the regulation of AS in cancer is limited. In view of the use of new technologies represented by high-throughput sequencing and further experiments with innovative designs, it is predictable that many AS-associated ncRNAs, splicing isoforms and new regulatory mechanisms of cancer progression will be found and may provide potential targets for cancer diagnosis and therapy. Additionally, questions remain in the field of small molecules against ncRNA targets. One key consideration is how to classify and evaluate ncRNA targets, as ncRNA targets usually do not have “active sites” [139]. In addition, ncRNA therapeutics may need solutions for drug delivery, toxic side effects, and drug resistance [140, 141].

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

AS:

Alternative splicing

ncRNA:

Noncoding RNA

pre-mRNA:

Pre-messenger RNA

snRNPs:

Small nuclear ribonucleoprotein

ISE:

Intron splicing enhancer

ISS:

Intron splicing silencer

ESE:

Exon splicing enhancer

ESS:

Exon splicing silencer

ES:

Exon skipping

IR:

Intron retention

MXE:

Mutually exclusive exon

A5SS:

Alternative 5′ splice site

A3SS:

Alternative 3′ splice site

SF:

Splicing factor

SR:

Serine/arginine-rich

hnRNP:

Ribonucleoprotein

RBM5:

RNA binding motif protein 5

RBM24:

RNA binding motif protein 24

QKI:

Quaking

Nova1:

NOVA alternative splicing regulator 1

SRSF1–12:

Serine/arginine-rich splicing factor 1–12

U2AF:

U2 auxiliary factor

SF3B3:

Splicing factor 3b subunit 3

Pol II:

RNA polymerase II

H3K36me3:

Trimethylation on histone H3 thirty-sixth lysine

CRC:

Colorectal cancer

PCa:

Prostate cancer

TNC:

Tenascin C

miRNA:

MicroRNA

siRNA:

Small interfering RNA

piRNA:

Piwi-interacting RNA

rRNA:

Ribosomal RNA

snRNA:

Small nuclear RNA

lncRNA:

Long noncoding RNA

circRNA:

Circular RNA

RISC:

RNA-induced silencing complex

UTR:

Untranslated region

NAT:

Natural antisense transcript

sFas:

Soluble Fas

ITPR1:

Inositol 1,4,5-trisphosphate receptor type 1

EMT:

Epithelial–mesenchymal transition

GLS:

Glutaminase

CFIm:

Cleavage factor I

GAC:

Glutaminase C

Ex:

Exon

HCC:

Hepatocellular carcinoma

SF3B4:

Splicing factor 3b subunit 4

ceRNA:

Competing endogenous RNA

SRPK1:

Serine/arginine protein kinase 1

AKAP-9:

A-kinase anchor protein 9

PTBP1:

Polypyrimidine tract binding protein 1

PNC:

Perinucleolar compartment

CHEK2:

Checkpoint kinase 2

PRC2:

Polycomb repressive complex 2

KDM2a:

Lysine-specific demethylase 2A

MRG15:

MORF4-related gene on chromosome 15

PTB:

Polypyrimidine tract binding protein

FGFR2:

Fibroblast growth factor receptor 2

PKM:

Pyruvate kinase M

SMYD3:

SET and MYND domain containing protein 3

H3K4me3:

Trimethylation of lysine 4 on histone H3

MCL1:

Myeloid cell leukemia 1

SETD2:

SET domain-containing 2

CDH1:

Cadherin 1

GC:

Gastric cancer

GBM:

Glioblastoma

MBNL1:

Muscleblind like splicing regulator 1

DGCR14:

DiGeorge syndrome critical region gene 14

ASO:

Antisense oligonucleotide

References

  1. 1.

    Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet. 2010;11(5):345–55.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Yang X, Coulombe-Huntington J, Kang S, Sheynkman GM, Hao T, Richardson A, et al. Widespread expansion of protein interaction capabilities by alternative splicing. Cell. 2016;164(4):805–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X, Bauer TM, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–9.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Climente-Gonzalez H, Porta-Pardo E, Godzik A, Eyras E. The functional impact of alternative splicing in Cancer. Cell Rep. 2017;20(9):2215–26.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Urbanski LM, Leclair N, Anczukow O. Alternative-splicing defects in cancer: splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA. 2018;9(4):e1476.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Romero-Barrios N, Legascue MF, Benhamed M, Ariel F, Crespi M. Splicing regulation by long noncoding RNAs. Nucleic Acids Res. 2018;46(5):2169–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Martinez-Montiel N, Rosas-Murrieta NH, Anaya Ruiz M, Monjaraz-Guzman E, Martinez-Contreras R. Alternative Splicing as a Target for CancerTreatment. Int J Mol Sc. 2018;19(2):504.

    Article  CAS  Google Scholar 

  8. 8.

    Lee Y, Rio DC. Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem. 2015;84:291–323.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Song X, Zeng Z, Wei H, Wang Z. Alternative splicing in cancers: from aberrant regulation to new therapeutics. Semin Cell Dev Biol. 2018;75:13–22.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Kornblihtt AR, Schor IE, Allo M, Dujardin G, Petrillo E, Munoz MJ. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol. 2013;14(3):153–65.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Busch A, Hertel KJ. Evolution of SR protein and hnRNP splicing regulatory factors. Wiley Interdiscip Rev RNA. 2012;3(1):1–12.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Long JC, Caceres JF. The SR protein family of splicing factors: master regulators of gene expression. Biochem J. 2009;417(1):15–27.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Han SP, Tang YH, Smith R. Functional diversity of the hnRNPs: past, present and perspectives. Biochem J. 2010;430(3):379–92.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Yang J, Hung LH, Licht T, Kostin S, Looso M, Khrameeva E, et al. RBM24 is a major regulator of muscle-specific alternative splicing. Dev Cell. 2014;31(1):87–99.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, et al. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 2012;22(9):1616–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Pandya-Jones A, Black DL. Co-transcriptional splicing of constitutive and alternative exons. RNA (New York, NY). 2009;15(10):1896–908.

    CAS  Article  Google Scholar 

  17. 17.

    Pradeepa MM, Sutherland HG, Ule J, Grimes GR, Bickmore WA. Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet. 2012;8(5):e1002717.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Simon JM, Hacker KE, Singh D, Brannon AR, Parker JS, Weiser M, et al. Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res. 2014;24(2):241–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Yoshida K, Ogawa S. Splicing factor mutations and cancer. Wiley Interdiscip Rev RNA. 2014;5(4):445–59.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Bonnal SC, Lopez-Oreja I, Valcarcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol. 2020;17(8):457–74.

    PubMed  Article  Google Scholar 

  21. 21.

    Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, et al. SRSF2 mutations contribute to Myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27(5):617–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Wan L, Yu W, Shen E, Sun W, Liu Y, Kong J, et al. SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer. Gut. 2019;68(1):118–29.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kawamura N, Nimura K, Saga K, Ishibashi A, Kitamura K, Nagano H, et al. SF3B2-mediated RNA splicing drives human prostate Cancer progression. Cancer Res. 2019;79(20):5204–17.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Jensen MA, Wilkinson JE, Krainer AR. Splicing factor SRSF6 promotes hyperplasia of sensitized skin. Nat Struct Mol Biol. 2014;21(2):189–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489(7414):101–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Lu TX, Rothenberg ME. MicroRNA. J Allergy Clin Immunol. 2018;141(4):1202–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Mohr AM, Mott JL. Overview of microRNA biology. Semin Liver Dis. 2015;35(1):3–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Hombach S, Kretz M. Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol. 2016;937:3–17.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5′-untranslated regions of eukaryotic mRNAs. Science (New York, NY). 2016;352(6292):1413–6.

    CAS  Article  Google Scholar 

  31. 31.

    Pu M, Chen J, Tao Z, Miao L, Qi X, Wang Y, et al. Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cell Mol Life Sci. 2019;76(3):441–51.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Chen LL. Linking Long Noncoding RNA localization and function. Trends Biochem Sci. 2016;41(9):761–72.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Akhade VS, Pal D, Kanduri C. Long Noncoding RNA: Genome organization and mechanism of action. Adv Exp Med Biol. 2017;1008:47–74.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Ruiz-Orera J, Messeguer X, Subirana JA, Alba MM. Long non-coding RNAs as a source of new peptides. eLife. 2014;3:e03523.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, et al. Translation of CircRNAs. Mol Cell. 2017;66(1):9–21.e7.

  36. 36.

    Yu CY, Kuo HC. The emerging roles and functions of circular RNAs and their generation. J Biomed Sci. 2019;26(1):29.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20(11):675–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Valadkhan S, Gunawardane LS. Role of small nuclear RNAs in eukaryotic gene expression. Essays Biochem. 2013;54:79–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Yoshino Y, Dwivedi Y. Non-coding RNAs in psychiatric disorders and suicidal behavior. Front Psychiatry. 2020;11:543893.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Bohnsack MT, Sloan KE. Modifications in small nuclear RNAs and their roles in spliceosome assembly and function. Biol Chem. 2018;399(11):1265–76.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Dvinge H, Guenthoer J, Porter PL, Bradley RK. RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing. Genome Res. 2019;29(10):1591–604.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Dong X, Ding S, Yu M, Niu L, Xue L, Zhao Y, et al. Small nuclear RNAs (U1, U2, U5) in tumor-educated platelets are Downregulated and act as promising biomarkers in lung Cancer. Front Oncol. 2020;10:1627.

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Lavorgna G, Dahary D, Lehner B, Sorek R, Sanderson CM, Casari G. In search of antisense. Trends Biochem Sci. 2004;29(2):88–94.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Villamizar O, Chambers CB, Riberdy JM, Persons DA, Wilber A. Long noncoding RNA Saf and splicing factor 45 increase soluble Fas and resistance to apoptosis. Oncotarget. 2016;7(12):13810–26.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Kim R, Emi M, Tanabe K, Uchida Y, Toge T. The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy. Cancer. 2004;100(11):2281–91.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Xu S, Wang P, Zhang J, Wu H, Sui S, Zhang J, et al. Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer. Mol Cancer. 2019;18(1):89.

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R, et al. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 2008;22(6):756–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Skryabin BV, Kremerskothen J, Vassilacopoulou D, Disotell TR, Kapitonov VV, Jurka J, et al. The BC200 RNA gene and its neural expression are conserved in Anthropoidea (primates). J Mol Evol. 1998;47(6):677–85.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Lee EF, Fairlie WD. The Structural Biology of Bcl-xL. Int J Mol Sci. 2019;20(9):2234.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  50. 50.

    Singh R, Gupta SC, Peng WX, Zhou N, Pochampally R, Atfi A, et al. Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis. 2016;7(6):e2262.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Hossini AM, Eberle J, Fecker LF, Orfanos CE, Geilen CC. Conditional expression of exogenous Bcl-X(S) triggers apoptosis in human melanoma cells in vitro and delays growth of melanoma xenografts. FEBS Lett. 2003;553(3):250–6.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, et al. Allele-specific reprogramming of Cancer metabolism by the Long non-coding RNA CCAT2. Mol Cell. 2016;61(4):520–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Singh RN, Singh NN. A novel role of U1 snRNP: splice site selection from a distance. Biochim Biophys Acta Gene Regul Mech. 2019;1862(6):634–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet. 2015;16(7):421–33.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17(5):272–83.

    CAS  Article  Google Scholar 

  56. 56.

    Meseguer S, Mudduluru G, Escamilla JM, Allgayer H, Barettino D. MicroRNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). J Biol Chem. 2011;286(6):4150–64.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Huang YQ, Ling XH, Yuan RQ, Chen ZY, Yang SB, Huang HX, et al. miR30c suppresses prostate cancer survival by targeting the ASF/SF2 splicing factor oncoprotein. Mol Med Rep. 2017;16(3):2431–8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Liu Z, Li W, Pang Y, Zhou Z, Liu S, Cheng K, et al. SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma. EBioMedicine. 2018;38:57–68.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Wu H, Sun S, Tu K, Gao Y, Xie B, Krainer AR, et al. A splicing-independent function of SF2/ASF in microRNA processing. Mol Cell. 2010;38(1):67–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Sokol E, Kedzierska H, Czubaty A, Rybicka B, Rodzik K, Tanski Z, et al. microRNA-mediated regulation of splicing factors SRSF1, SRSF2 and hnRNP A1 in context of their alternatively spliced 3'UTRs. Exp Cell Res. 2018;363(2):208–17.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Li M, Wu P, Yang Z, Deng S, Ni L, Zhang Y, et al. miR-193a-5p promotes pancreatic cancer cell metastasis through SRSF6-mediated alternative splicing of OGDHL and ECM1. Am J Cancer Res. 2020;10(1):38–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Boguslawska J, Sokol E, Rybicka B, Czubaty A, Rodzik K, Piekielko-Witkowska A. microRNAs target SRSF7 splicing factor to modulate the expression of osteopontin splice variants in renal cancer cells. Gene. 2016;595(2):142–9.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Yoshino H, Enokida H, Chiyomaru T, Tatarano S, Hidaka H, Yamasaki T, et al. Tumor suppressive microRNA-1 mediated novel apoptosis pathways through direct inhibition of splicing factor serine/arginine-rich 9 (SRSF9/SRp30c) in bladder cancer. Biochem Biophys Res Commun. 2012;417(1):588–93.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Zhou B, Wang Y, Jiang J, Jiang H, Song J, Han T, et al. The long noncoding RNA colon cancer-associated transcript-1/miR-490 axis regulates gastric cancer cell migration by targeting hnRNPA1. IUBMB Life. 2016;68(3):201–10.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Sun Y, Zhao X, Zhou Y, Hu Y. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncol Rep. 2012;28(4):1346–52.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Zhang M, Zhang H, Hong H, Zhang Z. MiR-374b re-sensitizes hepatocellular carcinoma cells to sorafenib therapy by antagonizing PKM2-mediated glycolysis pathway. Am J Cancer Res. 2019;9(4):765–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Liu J, Bian T, Feng J, Qian L, Zhang J, Jiang D, et al. miR-335 inhibited cell proliferation of lung cancer cells by target Tra2beta. Cancer Sci. 2018;109(2):289–96.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Qian T, Shi S, Xie L, Zhu Y. miR-938 promotes cell proliferation by regulating RBM5 in lung adenocarcinoma cells. Cell biology international. 2019.

  69. 69.

    Dou XQ, Chen XJ, Zhou Q, Wen MX, Zhang SZ, Zhang SQ. miR-335 modulates numb alternative splicing via targeting RBM10 in endometrial cancer. Kaohsiung J Med Sci. 2020;36(3):171–7.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Sugiyama T, Taniguchi K, Matsuhashi N, Tajirika T, Futamura M, Takai T, et al. MiR-133b inhibits growth of human gastric cancer cells by silencing pyruvate kinase muscle-splicer polypyrimidine tract-binding protein 1. Cancer Sci. 2016;107(12):1767–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Teplyuk NM, Uhlmann EJ, Gabriely G, Volfovsky N, Wang Y, Teng J, et al. Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic. EMBO Mol Med. 2016;8(3):268–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Kim EJ, Kim JS, Lee S, Lee H, Yoon JS, Hong JH, et al. QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth. Int J Cancer. 2019;145(6):1585–95.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Pillman KA, Phillips CA, Roslan S, Toubia J, Dredge BK, Bert AG, et al. miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking. EMBO J. 2018;37(13):e99016.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, et al. miR-221 targets QKI to enhance the tumorigenic capacity of human colorectal Cancer stem cells. Cancer Res. 2019;79(20):5151–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Li K, Zhu X, Chen X, Wang X. MicroRNA-27a-3p promotes epithelial-mesenchymal transition by targeting NOVA alternative splicing regulator 1 in gastric cancer. Mol Med Rep. 2020;21(3):1615–22.

    CAS  PubMed  Google Scholar 

  76. 76.

    Puppo M, Bucci G, Rossi M, Giovarelli M, Bordo D, Moshiri A, et al. miRNA-mediated KHSRP silencing rewires distinct post-transcriptional programs during TGF-beta-induced epithelial-to-Mesenchymal transition. Cell Rep. 2016;16(4):967–78.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Fang Z, Zhao J, Xie W, Sun Q, Wang H, Qiao B. LncRNA UCA1 promotes proliferation and cisplatin resistance of oral squamous cell carcinoma by sunppressing miR-184 expression. Cancer Med. 2017;6(12):2897–908.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Chen L, Nan A, Zhang N, Jia Y, Li X, Ling Y, et al. Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer. Mol Cancer. 2019;18(1):13.

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39(6):925–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Hu ZY, Wang XY, Guo WB, Xie LY, Huang YQ, Liu YP, et al. Long non-coding RNA MALAT1 increases AKAP-9 expression by promoting SRPK1-catalyzed SRSF1 phosphorylation in colorectal cancer cells. Oncotarget. 2016;7(10):11733–43.

    PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Koizumi J, Okamoto Y, Onogi H, Mayeda A, Krainer AR, Hagiwara M. The subcellular localization of SF2/ASF is regulated by direct interaction with SR protein kinases (SRPKs). J Biol Chem. 1999;274(16):11125–31.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Stamm S. Regulation of alternative splicing by reversible protein phosphorylation. J Biol Chem. 2008;283(3):1223–7.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Xiao SH, Manley JL. Phosphorylation of the ASF/SF2 RS domain affects both protein-protein and protein-RNA interactions and is necessary for splicing. Genes Dev. 1997;11(3):334–44.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Misteli T, Caceres JF, Clement JQ, Krainer AR, Wilkinson MF, Spector DL. Serine phosphorylation of SR proteins is required for their recruitment to sites of transcription in vivo. J Cell Biol. 1998;143(2):297–307.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Huang A, Zheng H, Wu Z, Chen M, Huang Y. Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics. 2020;10(8):3503–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Zhu LY, Zhu YR, Dai DJ, Wang X, Jin HC. Epigenetic regulation of alternative splicing. Am J Cancer Res. 2018;8(12):2346–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Zhang Z, Zhou N, Huang J, Ho TT, Zhu Z, Qiu Z, et al. Regulation of androgen receptor splice variant AR3 by PCGEM1. Oncotarget. 2016;7(13):15481–91.

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Huang GW, Zhang YL, Liao LD, Li EM, Xu LY. Natural antisense transcript TPM1-AS regulates the alternative splicing of tropomyosin I through an interaction with RNA-binding motif protein 4. Int J Biochem Cell Biol. 2017;90:59–67.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Yap K, Mukhina S, Zhang G, Tan JSC, Ong HS, Makeyev EV. A Short Tandem Repeat-Enriched RNA Assembles a Nuclear Compartment to Control Alternative Splicing and Promote Cell Survival. Mol Cell. 2018;72(3):525–540.e13.

  90. 90.

    Barbagallo D, Caponnetto A, Brex D, Mirabella F, Barbagallo C, Lauretta G, et al. CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1. Cancers (Basel). 2019;11(2):194.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  91. 91.

    Qin M, Wei G, Sun X. Circ-UBR5: An exonic circular RNA and novel small nuclear RNA involved in RNA splicing. Biochem Biophys Res Commun. 2018;503(2):1027–34.

    CAS  Article  Google Scholar 

  92. 92.

    Kong J, Sun W, Li C, Wan L, Wang S, Wu Y, et al. Long non-coding RNA LINC01133 inhibits epithelial-mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. Cancer Lett. 2016;380(2):476–84.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Sehgal L, Mathur R, Braun FK, Wise JF, Berkova Z, Neelapu S, et al. FAS-antisense 1 lncRNA and production of soluble versus membrane FAS in B-cell lymphoma. Leukemia. 2014;28(12):2376–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Pospiech N, Cibis H, Dietrich L, Muller F, Bange T, Hennig S. Identification of novel PANDAR protein interaction partners involved in splicing regulation. Sci Rep. 2018;8(1):2798.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Huan L, Guo T, Wu Y, Xu L, Huang S, Xu Y, et al. Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response. Mol Cancer. 2020;19(1):11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Ji Q, Zhang L, Liu X, Zhou L, Wang W, Han Z, et al. Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. Br J Cancer. 2014;111(4):736–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Ishizuka A, Hasegawa Y, Ishida K, Yanaka K, Nakagawa S. Formation of nuclear bodies by the lncRNA Gomafu-associating proteins Celf3 and SF1. Genes Cells. 2014;19(9):704–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Rodriguez-Mateo C, Torres B, Gutierrez G, Pintor-Toro JA. Downregulation of Lnc-Spry1 mediates TGF-beta-induced epithelial-mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms. Cell Death Differ. 2017;24(5):785–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    De Troyer L, Zhao P, Pastor T, Baietti MF, Barra J, Vendramin R, et al. Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3. Nucleic Acids Res. 2020;48(5):2502–17.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100.

    Sun F, Chen HG, Li W, Yang X, Wang X, Jiang R, et al. Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem. 2014;289(3):1529–39.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Gonzalez I, Munita R, Agirre E, Dittmer TA, Gysling K, Misteli T, et al. A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature. Nat Struct Mol Biol. 2015;22(5):370–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Amann T, Bataille F, Spruss T, Dettmer K, Wild P, Liedtke C, et al. Reduced expression of fibroblast growth factor receptor 2IIIb in hepatocellular carcinoma induces a more aggressive growth. Am J Pathol. 2010;176(3):1433–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Huang JZ, Chen M, Gao XC, Zhu S, Huang H, et al. A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth. Mol Cell. 2017;68(1):171–184.e6.

  104. 104.

    Long Y, Wang X, Youmans DT, Cech TR. How do lncRNAs regulate transcription? Sci Adv. 2017;3(9):eaao2110.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Tang Y, Cheung BB, Atmadibrata B, Marshall GM, Dinger ME, Liu PY, et al. The regulatory role of long noncoding RNAs in cancer. Cancer Lett. 2017;391:12–9.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Zhang XD, Huang GW, Xie YH, He JZ, Guo JC, Xu XE, et al. The interaction of lncRNA EZR-AS1 with SMYD3 maintains overexpression of EZR in ESCC cells. Nucleic Acids Res. 2018;46(4):1793–809.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Sims RJ 3rd, Millhouse S, Chen CF, Lewis BA, Erdjument-Bromage H, Tempst P, et al. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol Cell. 2007;28(4):665–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Khan DH, Gonzalez C, Tailor N, Hamedani MK, Leygue E, Davie JR. Dynamic histone acetylation of H3K4me3 nucleosome regulates MCL1 pre-mRNA splicing. J Cell Physiol. 2016;231(10):2196–204.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Bae J, Leo CP, Hsu SY, Hsueh AJ. MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem. 2000;275(33):25255–61.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    He R, Kidder BL. H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells. Nucleic Acids Res. 2017;45(11):6427–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Li H, An J, Wu M, Zheng Q, Gui X, Li T, et al. LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Oncotarget. 2015;6(29):27847–64.

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Skucha A, Ebner J, Grebien F. Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond. Int J Mol Sci. 2019;20(5):1029.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  113. 113.

    Li XW, Shi BY, Yang QL, Wu J, Wu HM, Wang YF, et al. Epigenetic regulation of CDH1 exon 8 alternative splicing in gastric cancer. BMC Cancer. 2015;15:954.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Somasundaram S, Forrest ME, Moinova H, Cohen A, Varadan V, LaFramboise T, et al. The DNMT1-associated lincRNA DACOR1 reprograms genome-wide DNA methylation in colon cancer. Clin Epigenetics. 2018;10(1):127.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Dor Y, Cedar H. Principles of DNA methylation and their implications for biology and medicine. Lancet (London, England). 2018;392(10149):777–86.

    CAS  Article  Google Scholar 

  116. 116.

    Baryshev M, Inashkina I, Salmina K, Huna A, Jackson TR, Erenpreisa J. DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells. Cell Cycle (Georgetown, Tex). 2018;17(3):362–6.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  117. 117.

    Liu Y, Zhang YM, Ma FB, Pan SR, Liu BZ. Long noncoding RNA HOXA11-AS promotes gastric cancer cell proliferation and invasion via SRSF1 and functions as a biomarker in gastric cancer. World J Gastroenterol. 2019;25(22):2763–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Teplyuk NM, Mollenhauer B, Gabriely G, Giese A, Kim E, Smolsky M, et al. MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro-oncology. 2012;14(6):689–700.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Gao T, Liu X, He B, Nie Z, Zhu C, Zhang P, et al. Exosomal lncRNA 91H is associated with poor development in colorectal cancer by modifying HNRNPK expression. Cancer Cell Int. 2018;18:11.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Wu ZH, Liu CC, Zhou YQ, Hu LN, Guo WJ. OnclncRNA-626 promotes malignancy of gastric cancer via inactivated the p53 pathway through interacting with SRSF1. Am J Cancer Res. 2019;9(10):2249–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Montero-Conde C, Grana-Castro O, Martin-Serrano G, Martinez-Montes AM, Zarzuela E, Munoz J, et al. Hsa-miR-139-5p is a prognostic thyroid cancer marker involved in HNRNPF-mediated alternative splicing. Int J Cancer. 2020;146(2):521–30.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Lee SD, Yu D, Lee DY, Shin HS, Jo JH, Lee YC. Upregulated microRNA-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells. Cancer Sci. 2019;110(2):662–73.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Li D, Wang X, Mei H, Fang E, Ye L, Song H, et al. Long Noncoding RNA pancEts-1 promotes neuroblastoma progression through hnRNPK-mediated beta-catenin stabilization. Cancer Res. 2018;78(5):1169–83.

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Guo LY, Qin CF, Zou HX, Song MY, Gong ML, Chen C. LncRNA AB073614 promotes the proliferation and inhibits apoptosis of cervical cancer cells by repressing RBM5. Eur Rev Med Pharmacol Sci. 2019;23(6):2374–9.

    PubMed  Google Scholar 

  125. 125.

    Sun BZ, Ji DG, Feng ZX, Wang Y. Long noncoding RNA SNHG7 represses the expression of RBM5 to strengthen metastasis of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2019;23(13):5699–704.

    PubMed  Google Scholar 

  126. 126.

    Yang ZT, An F, Hu JD, Zhao WH. Long noncoding RNA AFAP1-AS1 accelerates the proliferation and metastasis of prostate cancer via inhibiting RBM5 expression. Eur Rev Med Pharmacol Sci. 2019;23(8):3284–90.

    PubMed  Google Scholar 

  127. 127.

    Jiang D, Zhang Y, Yang L, Lu W, Mai L, Guo H, et al. Long noncoding RNA HCG22 suppresses proliferation and metastasis of bladder cancer cells by regulation of PTBP1. J Cell Physiol. 2020;235(2):1711–22.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Inamoto T, Taniguchi K, Takahara K, Iwatsuki A, Takai T, Komura K, et al. Intravesical administration of exogenous microRNA-145 as a therapy for mouse orthotopic human bladder cancer xenograft. Oncotarget. 2015;6(25):21628–35.

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Minami K, Taniguchi K, Sugito N, Kuranaga Y, Inamoto T, Takahara K, et al. MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells. Oncotarget. 2017;8(20):33064–77.

    PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Takai T, Yoshikawa Y, Inamoto T, Minami K, Taniguchi K, Sugito N, et al. A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells. Int J Mol Sci. 2017;18(1).

  131. 131.

    Lv L, Deng H, Li Y, Zhang C, Liu X, Liu Q, et al. The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. Cell Death Dis. 2014;5:e1402.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107(29):13075–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood. 2008;112(10):4202–12.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Otsuka K, Yamamoto Y, Ochiya T. Regulatory role of resveratrol, a microRNA-controlling compound, in HNRNPA1 expression, which is associated with poor prognosis in breast cancer. Oncotarget. 2018;9(37):24718–30.

    PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Kumar A, Rimando AM, Levenson AS. Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer. Ann N Y Acad Sci. 2017;1403(1):15–26.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Rauf A, Imran M, Butt MS, Nadeem M, Peters DG, Mubarak MS. Resveratrol as an anti-cancer agent: a review. Crit Rev Food Sci Nutr. 2018;58(9):1428–47.

    PubMed  Article  Google Scholar 

  137. 137.

    Gabriely G, Yi M, Narayan RS, Niers JM, Wurdinger T, Imitola J, et al. Human glioma growth is controlled by microRNA-10b. Cancer Res. 2011;71(10):3563–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Mullard A. Small molecules against RNA targets attract big backers. Nat Rev Drug Discov. 2017;16(12):813–5.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Bonetta L. RNA-based therapeutics: ready for delivery? Cell. 2009;136(4):581–4.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575(7782):299–309.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

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Funding

This research was supported in part by the National Natural Science Foundation of China (Nos. 81702435; Nos. 82072729), the Natural Science Foundation of Jiangsu (BK20170264) and Xuzhou Key R&D Program (KC20064).

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YZ, CWL and YZL designed the research. YZL drafted the manuscript. XL improved the structure of this manuscript and completed the diagrams. YZ, JS, XHJ and HMZ discussed and revised the manuscript. JS put forward some constructive suggestions. All authors read and approved the final manuscript.

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Correspondence to Jun Song or Yi Zhang.

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Liu, Y., Liu, X., Lin, C. et al. Noncoding RNAs regulate alternative splicing in Cancer. J Exp Clin Cancer Res 40, 11 (2021). https://doi.org/10.1186/s13046-020-01798-2

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Keywords

  • Alternative splicing
  • Cancer
  • Noncoding RNA
  • miRNA
  • lncRNA
  • circRNA
  • snRNA