ChrXq27.3 miRNA cluster functions in cancer development

MicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer. The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial–mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888–892 group are considered to be cell type- or tissue-specific. In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.


Background
MicroRNAs (miRNAs), which are small noncoding RNA molecules (~22 nucleotides in length), regulate gene expression by interacting with the 3′-untranslated regions of genes [1,2]. Numerous studies have revealed the functions of miRNAs in various cancers [2]. Some miRNA-encoding genes are located in narrow regions on the genome, which are so-called miRNA clusters; there are 159 miRNA clusters in the human genome [3]. In an miRNA cluster, miRNA-encoding genes can be under the control of a common regulatory unit and are coexpressed [3,4]. Moreover, members of an miRNA cluster have the same targets or target different genes belonging to specific pathways [3]. One of the most well-known miRNA clusters is the miR-17-92 cluster, which is located on chromosome 13q31.3. This region is amplified in lung cancer and B-cell lymphomas, and the expression of the miRNAs derived from the miR-17-92 cluster is substantially increased in these conditions [5,6]. Functionally, the miR-17-92 cluster is considered an oncogene and acts with c-myc to promote tumor development [5]. An miRNA cluster located in the chrXq27.3 region (the chrXq27.3 miRNA cluster) has received much attention recently, and the oncogenic or tumorsuppressive functions of this cluster have been elucidated through studies on various cancers.
In this review, we provide an overview of the chrXq27.3 miRNA cluster in cancer progression.

chrXq27.3 miRNA cluster
The chrXq27.3 miRNA cluster contains 30 mature miR-NAs synthesized from 22 miRNA-encoding genes in añ 1.3-Mb region (Fig. 1). The miRNA-encoding genes are not uniformly distributed in the region and are separated by a noncoding region of~1.2-Mb. There are 15 miRNA-encoding genes downstream of the noncoding region, and they are named the miR-506-514 group. Similarly, the rest of seven genes are located on the upstream of the noncoding region, and named the miR-888-892 groups. Evolutionarily, mammalian species have an miRNA cluster located between the FMR1 and SLITRK2 genes on the X chromosome, and this miRNA cluster is well conserved among primate species [7][8][9]. Moreover, mature forms of miRNAs with close loci tend to have similar sequences, and hence, these miRNAs can have common target genes [7,8].
Many miRNA genes are located inside or close to fragile sites. The chrXq27.3 region is well-known as a key spot for fragile-X syndrome, the most common form of hereditary intellectual disability. This syndrome is responsible for increased CGG repeats in the FMR1 gene [10]. However, it remains unclear whether the chrXq27.3 Fig. 1 Schema of the chrXq27.3 miRNA cluster and sequence similarity of the miRNAs in the clusterThere are 22 miRNA-encoding genes in the chrXq27.3 cluster, and they are divided into two groups according to their location. Mature forms of the miRNAs with close loci tend to have similar sequences cluster is involved in this syndrome even though some of the miRNAs can target the adjacent gene, FMR1 [9]. Conversely, the expression of these miRNAs is usually negligible in normal tissues except for in the male reproductive system [8,9,11]. Thus, this cluster is thought to be involved in testis development and spermatogenesis, and its alteration might be associated with male infertility [8,9,11,12]. Additionally, according to Pinheiro's hypothesis, X-linked miRNAs might contribute to the immunological advantage of females as the X chromosome contains 10% of all human miRNAs whereas the Y chromosome has no miRNAs, and several X-linked miR-NAs have important functions in immunity and cancer [13]. Therefore, the chrXq27.3 miRNA cluster may be important from the aspect of gender differences.
Conversely, the miR-888-892 group has both oncogenic and tumor-suppressive functions depending on the miRNAs. miR-888-5p and miR-892a are upregulated in colorectal and hepatocellular carcinoma, and higher miR-888-5p or miR-892a expressions are associated with poor survival (Table 1) [63][64][65][66]. However, miR-890 and miR-892b are downregulated in breast cancer, and lower miR-892b expression is associated with a poor prognosis [67,68]. Moreover, miR-892b is downregulated in pancreatic and nasopharyngeal cancer tissues, and lower miR-891b expression is associated with shorter survival in pancreatic cancer [69][70][71]. Favorable, the expression is associated with favorable prognosis; Poor, the expression is associated with poor prognosis Therefore, the alteration of the miRNAs in this cluster is frequently observed in various cancers. Moreover, their roles are usually common across cancer types and are considered critical for cancer development.
miR-510-3p and miR-510-5p As described previously, miR-510-3p and miR-510-5p are upregulated in clinical cancer samples, but their  Tumor-promotive roles of the chrXq27.3 miRNA clusterSome miRNAs in the cluster also act in an oncogenic manner by targeting various genes. Previously validated interactions between the miRNAs and genes or non-cording RNAs are described impact on patient prognosis remains uncertain. Functionally, miR-510-3p promotes cancer proliferation and suppresses apoptosis by targeting PTEN in non-small cell lung cancer (Fig. 4) [61]. Moreover, miR-510-5p, which can be regulated by lncRNA SNHG15, promotes proliferation, migration, and invasion via targeting SRCI N1 and PRDX1 in several cancer cells [60,62,96]. Therefore, it is interesting that the two miRNAs are oncogenic even though they have similar sequences to other neighboring miRNAs.
Based on their genome location, the miR-888-892 group can be coexpressed although each miRNA can act both oncogenic and tumor-suppressive. Therefore, the functions of the miR-888-892 group are more cell typeor tissue-specific than those of the miR-506-514 group.

Future perspectives
The members of the chrXq27.3 miRNA cluster may coordinately regulate cancer-related pathways. The miR-NAs in the miR-506-514 group are particularly strong tumor suppressors, and their downregulation plays important roles in cancer progression. Hence, the regulatory mechanisms of this cluster must be elucidated. According to previous reports, miR-506-3p and miR-507 expressions are reduced due to hypermethylation of their promoter region [16,50]. Conversely, p53 contributes to the increased expressions of miR-506-3p and miR-509-5p [44,106]. Considering the features of miRNA clusters, other miRNAs in this cluster could be regulated by these factors, and the re-activation of tumor-suppressive miRNAs might be a potent therapeutic strategy. Moreover, the location of the cluster makes itself more interesting because the number of X chromosomes differs between men and women, and it might be responsible for the difference in cancer incidence and immunity between males and females [13].
Additionally, miRNA replacement therapy has been developed, and a phase 1 study about miR-16-based mimic miRNA in malignant pleural mesothelioma was performed [107]. To achieve miRNA replacement therapy in various cancers, a suitable delivery system with a high specificity for targeting cancer cells must be developed. Thus, optimal miRNAs should be selected depending on the cancer types. We believe that the tumorsuppressive miRNAs in this cluster may be suitable because their anti-cancer effect is universal regardless of the cancer. However, the rest of the oncogenic miRNAs in the cluster are also attractive therapeutic targets. Inhibiting the miRNAs may potentially have fewer adverse effects because most of the normal tissues show negligible expression of the miRNAs. Therefore, further studies about this cluster are highly anticipated.

Conclusion
In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression in various types of cancer. Among the 30 mature miRNAs in this cluster, miR-506-3p is the most well-known tumor suppressor, but there are many miRNAs with unknown functions. Therefore, this cluster is worth evaluating in the future and is a promising therapeutic target.