The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation
© The Author(s). 2017
Received: 15 January 2017
Accepted: 28 March 2017
Published: 12 April 2017
P73 antisense RNA 1 T (non-protein coding), also known as TP73-AS1, is a long non-coding RNA (lncRNA) which is involved in cell proliferation and the development of tumors. However, the exact effects and molecular mechanisms of TP73-AS1 in hepatocellular carcinoma (HCC) progression are still unknown. The present study is aimed to investigate the detailed functions and the mechanism of TP73-AS1 in regulation of HCC cell proliferation.
TP73-AS1 expression in HCC tissues and cell lines was determined using real-time PCR assays; the correlation of TP73-AS1 expression with clinicopathological features of HCC was analyzed. The functions of TP73-AS1 in regulation of HCC cell proliferation was evaluated using MTT and BrdU assays. The candidate upstream miRNAs of HMGB1 were screened using miRcode, miRWalk, miRanda and Target scan, verified using real-time PCR assays. The interaction between TP73-AS1 and miR-200a was confirmed using Luciferase report gene assays. The proten levels of HMGB1 signaling-related factors in response to co-processing TP73-AS1 knockdown and miR-200a inhibition were determined using Western blot assays and ELISA. Further, miR-200a, HMGB1 mRNA and RAGE mRNA and their correlations in HCC tissues were determined.
TP73-AS1 was upregulated in HCC tissues and cell lines. High TP73-AS1 expression was correlated with worse clinicopathological features, poorer prognosis and shorter survival. Knockdown of TP73-AS1 inhibited the HCC proliferation and the expression levels of HMGB1, RAGE and NF-κB in HCC cells. By using online tools, we screened out several candidate upstream miRNAs of HMGB1, among which miR-200a overexpression inhibited HMGB1 mRNA expression the most significantly. By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3’UTR of HMGB1; TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1. In HCC tissues, miR-200a was down-regulated while HMGB1 and RAGE were up-regulated; TP73-AS1 was inversely correlated with miR-200a, while positively correlated with HMGB1 and RAGE, respectively.
Our data indicated that TP73-AS1 might be an oncogenic lncRNA that promoted proliferation of HCC and could be regarded as a therapeutic target in human HCC.
KeywordslncRNA TP73-AS1 miR-200a HCC HMGB1 Proliferation
Liver cancer is the sixth most common cancer in the world, with 782,000 new cases diagnosed in 2012 alone. Hepatocellular carcinoma (HCC) is the dominant histological type of liver cancer, and accounts for about 80% of primary liver cancer occurrences . In China specifically, HCC is a common type of cancer, and is the second highest cause of mortality in the country. More than 110,000 people die from liver cancer each year, accounting for 45% of all HCC deaths worldwide [2–4]. Despite therapeutic advances, the five-year survival rate of HCC is still below 5% [5–8]. HCC is the result of a multistep process which involves the accumulation of several structural and genomic alterations, gene expression profile and intracellular signal pathway alterations [9, 10]. Hence, it is critical to clearly understand these alterations and develop novel strategies for the early diagnosis, prognosis prediction and therapeutic target of patients with HCC.
Human genome sequence data indicates that more than 90% of the DNA sequences actively transcribed but only 2% of it encodes proteins, thus the majority of transcripts are referred to as non-coding RNAs (ncRNAs) [11, 12]. Small non-coding RNAs such as microRNAs have been studied extensively and their roles in gene regulation and cell function have been elucidated innumerous cancers . Recent studies have shown that lncRNAs play important roles in both normal development and diseases including cancer . LncRNAs have emerged as new players in cancer research and several studies have shown that some lncRNAs function as oncogenes, tumor suppressor genes or both, depending on the circumstance .
Several lncRNAs have been reported to be involved in cancers. Urothelial cancer-associated 1 (UCA1) lncRNA has been revealed significantly elevated in tongue squamous cell carcinoma tissues (P < .0001) and was statistically correlated with lymph node metastasis (P = .0371). Over-expression of UCA1 lncRNA could promote metastatic but not proliferation ability of TSCC cells . LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of HCC via the miR-200a-3p/ZEB1 signaling pathway . LncRNA BANCR expression was remarkably increased in HCC tissues, BANCR downregulation in Hep3B cells impaired cell proliferation, promoted cell apoptosis, reduced cell invasion and migration, led to downregulated vimentin, and upregulated E-cadherin protein levels .
TP73-AS1, a lncRNA transcribed from chromosome 1p36, has been reported to be associated with cell proliferation and tumor progress . Previous study predicted that TP73-AS1 might be up-regulated in HCC cells through Bioinformatics database . Although emerging evidence has suggested that TP73-AS1 associated with cancer progression and prognosis, the detailed role of TP73-AS1 in HCC and the underlying mechanism still remains unclear.
LncRNAs exert their functions through different mechanisms, a major one of them is the interaction with miRNAs . In addition, miRNAs themselves have been regarded as essential regulators in pathology of cancers [21, 22]. The miR-200 family consisting of 5 members (miR-200a, −200b, −200c, −141, −429) is an emerging miRNA family that has been shown to play crucial roles in cancer initiation and metastasis, and potentially be important for the diagnosis and treatment of cancer . It was found that forced expression of miR-200a in meningioma cells reduced xenograft tumor growth when injected into the flanks of SCID . Additionally, miR-200a has also been shown to directly target the pro-angiogenic ligands IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1) to regulate angiogenesis in ovarian cancer . Whether miR-200a is involved in HCC? Can TP73-AS1 interact with miR-200a to modulate HCC progression? These remain to be investigated.
In this study, we report an interaction between TP73-AS1 and miR-200a which regulates HCC cell growth through directly targeting HMGB1. Our findings provide a novel understanding of the role of TP73-AS1 and miR-200a in HCC cell proliferation and the mechanism involved.
The human HCC cells, HCCLM3, MHCC97L, SMMC7722, Hep3B and HepG2, and normal hepatocyte THLE-3 were purchased from American Type Culture Collection (ATCC).
Eighty-four paired HCC specimens and corresponding adjacent non-tumor tissues were collected from tumor surgical resection in the Xiangya Hospital (the Central South University, Changsha, China). And all the human tissues were obtained with informed consent and this study was approved by the Medical Ethics Committee of Xiangya hospital at Central South University.
All the miRNA mimics, inhibitor and siRNAs were synthesized by Genepharma Company (Shanghai, China). Oligonucleotide and plasmid transfection were conducted by using the Lipofectamine™ 2000 transfection reagent (Invitrogen, USA), followed by the protocol recommended by the manufacturer. After 48 h transfection, the cells were collected and used for further investigations.
Following transfection, cell proliferation was assessed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay (Promega Corporation, Madison, WI, USA), according to the manufacturer’s instructions. Cells were seeded into 96-well plates at a density of 5000 cells per well. After 24 h, cells were transfected with si-NC or si-TP73-AS1. After an additional 24 h, 20 μl of 5 mg/mL MTT was added into each well and incubated for 4 h in a humidified incubator. The supernatant was then discarded, and 200 μL of DMSO was added to each well to dissolve the formazan. The optical density (OD) was measured at 490 nm. The viability of the cells without any treatment was defined as 100%, and the viability of other groups was calculated separately from that of the sham cells.
BrdU cell proliferation assay
By measuring 5-Bromo-2-deoxyUridine (BrdU) incorporation, the DNA synthesis in proliferating cells was determined. BrdU assays were conducted at 48 h after HCC cells were transfected with si-NC or si-TP73-AS1. Cells were seeded in 96-well culture plates at a density of 2 × 103 cells/well, cultured for 48 h, then incubated with a final concentration of 10 μM BrdU (BD Pharmingen, San Diego, CA, USA) for 2 h. When the incubation period ended, the medium was removed, the cells were fixed for 30 min at RT, incubated with peroxidase-coupled anti-BrdU-antibody (Sigma-Aldrich) for 60 min at RT, washed three times with PBS, incubated with peroxidase substrate (tetramethylbenzidine) for 30 min, and the 450 nm absorbance values were measured for each well. Background BrdU immunofluorescence was determined in cells not exposed to BrdU but stained with the BrdU antibody.
Cell clone formation assay
HCC cells were seeded and transfected with si-NC or si-TP73-AS1. Cells were suspended in RPMI-1640 containing 0.35% low-melting agarose and plated onto 0.6% agarose in six-well culture plates at a density of 1 × 105 cells per dish. The plates were incubated for two weeks at 37 °C in a 5% CO2 incubator, and the number of colonies was counted microscopically after staining with 0.1% crystal violet solution. Colonies with more than 50 cells were manually counted.
RNA extraction and real-time PCR
Total RNA was isolated by TRIZOL Reagent (Invitrogen, USA) following the manufacturer’s instructions. After RNA extraction, RNA samples were reversely transcribed by High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, USA). The Fast Start Universal SYBR Green Master (Roche, USA) was applied for the quantitative RT-PCR. The relative fold changes of candidate genes were analyzed by using 2−ΔΔCT method. Primers were shown in Additional file 1: Table S1.
Cell lysates were lysed by RIPA buffer (Sigma-Aldrich, USA) with Complete Protease Inhibitor Cocktail (Roche, USA). Cell lysates were transferred to 1.5 mL tube and kept at −20 °C before use. SDS-PAGE was conducted to separate the cellular proteins. And all the cellular proteins within this study were separated by 5% stacking gel and 10% running gel. The molecular weight of candidate proteins was referred to the information of the Pre-stained SeeBlue rainbow marker (Invitrogen, USA) loaded in parallel. The membranes were probed with the following antibodies: HMGB1 (Abcam, MA, USA), RAGE (Abcam, MA, USA), NF-κB (Abcam, MA, USA) and β-actin (Sigma, USA). The blots were detected on Kodak film developer (Fujifilm, Japan). The gradation analysis of the films was performed using Image J software (National Institutes of Health, Bethesda, MD, USA).
Cells (1 × 104 cells per well) cultured in 96-well plates and transfected with miR-200a inhibitor or si-TP73-AS1 for 48 h. Then the culture media from each group was collected and stored at −80 °C until use. The levels of TNF-αNF-e levels of r in the media were measured using the Human TNF-α, IL-6, IL-1β/IL-1 F2 Quantikine ELISA kits, respectively (R&D systems, lnc., USA) according to the manufacturer’s instructions.
Luciferase reporter assay
By using of the Lipofectamine™ 2000 transfection reagent, HepG2 cells cultured in 24 well plates were co-transfected with luciferase reporter plasmids (wt-HMGB1, mut-HMGB1 containing miR-200a binding site, wt-TP73-AS1, mut-TP73-AS1 containing miR-200a binding site1 or site2) and miRNA mimics or inhibitor as well as the internal control pRSV-β-Galactosidase vector. After 48 h post-transfection, HepG2 cells were lysed by lysis buffer (25 mMTris-phosphate, 1% Triton X-100, 1 mM DTT, 2 mM EDTA, 10% Glycerol, pH = 27.8). After centrifugation at 14,000 rpm for 3 min, the supernatant was transferred to a new 1.5 mL tube. The luciferase activity was monitored by mixing 50 μL supernatant with 50 μl luciferase assay buffer (265 μM ATP, 2.70 mM MgSO4, 1.07 mM MgCl2, 135 μM Coenzyme A, 20 mM Tricine, 0.1 mM EDTA, 33.3 mM DTT, 235 μM D-Luciferin) by using the Gloxmax 20/20 Luminometer (Promega). The β-Galactosidase activity from the pRSV-β-Galactosidase vector was used for the normalization of the luminescence levels. O-nitrophenyl- β-galactoside (ONPG) colorimetric assays were performed to measure the β-Galactosidase activity. The β-Galactosidase activity was evaluated by the measurement of o-nitrophenol by using the ELISA plate reader (Bio-Rad, USA) at the wavelength of 490 nm.
Experiments were done in triplicate. Experimental results are presented as Mean ± SD. Comparisons between two groups were conducted using two-tail Student’s T-test and differences were considered to be statistically significant when P value is less than 0.05.
High lncRNA-TP73-AS1 expression in HCC was correlated with poorer prognosis
The Correlations of TP73-AS1 with Clinicopathological Features of HCC
Tumor size (cm)
Tumor nodule number
I + II
III + IV
Univariate and Multivariate Analysis of Factors Associated with Overall Survival
HR (95% CI)
HR (95% CI)
Tumor size (cm)
Tumor nodule number
I + II
III + IV
TP73-AS1 knockdown inhibited HCC cell proliferation and downregulated HMGB1 signal pathway
High-mobility group box 1 protein (HMGB1) is an evolutionarily ancient and critical regulator of cell death and survival. According to previous studies, the ability of proliferation, migration and invasion of HCC cells was strengthened when the expression endogenous HMGB1 was enhanced using HMGB1 DNA . HMGB1 activates RAGE signaling pathways and induces NF-кB activation to promote cellular proliferation, invasion, and metastasis, in HCC cell lines . Here we monitored the protein levels of HMGB1, RAGE and NF-кB in response to TP73-AS1 knockdown in HepG2 and HCCLM3 cell lines by using Western blot assays. Results showed that in both HepG2 and HCCLM3 cell lines, the protein levels of HMGB1, RAGE and NF-кB were significantly downregulated after TP73-AS1 knockdown by si-TP73-AS1 transfection (Fig. 1f and g). Taken together, these data revealed that TP73-AS1 was specifically upregulated in HCC tissues and cell lines; TP73-AS1 knockdown inhibited HCC cell proliferation and downregulated HMGB1/RAGE signal pathway.
MiR-200a could negatively regulate HMGB1 expression
TP73-AS1 competed with HMGB1 for miR-200a binding
TP73-AS1 regulated HMGB1/RAGE expression and NF-кB targets cytokines levels through miR-200a
Expression of miR-200a, HMGB1 and RAGE and the correlation of TP73-AS1 with miR-200a, HMGB1 and RAGE in HCC tissues
The non-coding portion of the genome accounts for greater than 90% of the total mammalian genome. Studies have demonstrated that among these ncRNAs, ~18% of lncRNAs are associated with human tumors, compared with only 9% of human protein-coding genes , suggesting that lncRNAs could act as major contributors to carcinogenesis and cancer progression. The roles of dysregulated lncRNAs in the proliferation, invasion and migration of many kinds of cancers have garnered increased scientific interest in recent years [32–34].
LncRNA TP73-AS1 has been reported to be up-regulated in esophageal squamous cell carcinoma . LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway . In this study, we initially monitored TP73-AS1 expression in a large panel of 84 paired HCC tissues and adjacent normal tissues. A significant higher expression level of TP73-AS1 in HCC tissues was observed compared to the adjacent normal tissues. Consistently, the expression level of TP73-AS1 was obviously higher in HCC cell lines compared to that of the normal cell lines. According to the clinical information in 84 cases of patients with HCC, we found that TP73-AS1 expression was correlated with poor clinicopathological characteristics and was one of independent risk factors of overall survival. Moreover, TP73-AS1 might accelerate the HCC progress through promoting the proliferation of HCC cells. However, the mechanism by which TP73-AS1 affects the progression of HCC still remains to be validated.
HMGB1 and its receptor RAGE are pivotal factors in the development and progression of many types of tumor, including HCC . Emerging evidences have demonstrated that chronic infection of HBV or HCV can induce the translocation of HMGB1 from nuclei to cytoplasm and extracellular release of HMGB1 [35, 36]. Serum HMGB1 levels were found significantly higher in HCC patients and overexpression of HMGB1 was associated with their clinico-pathological features and outcomes . HMGB1 and RAGE can modulate the proliferation and cell cycle of HCC cells . These findings show that HMGB1-RAGE axis may play an important role in the development of HCC, such as the proliferation of HCC cells. We revealed the promotive of TP73-AS1 on HCC proliferation, here we further validated whether TP73-AS1 could act on HMGB1/RAGE to affect HCC cell proliferation. In fact, we observed significantly reduced protein levels of HMGB1, RAGE and NF-κB in TP73-AS1-knocked down HCC cells.
MiRNAs expression dysfunctions are involved in almost all fields of cancer biology, including cell proliferation, invasion and migration. They can play the role of either tumor suppressors or oncogenes . The mechanisms by which miRNAs exert their functions vary in different kinds of cancers, among which binding to the downstream target genes to inhibit their expression is a major one. Several miRNAs were reported to inhibit different downstream genes to delay the progress of HCC, including miR-636 (inhibiting Ras-PI3K/AKT pathway) , miR-16 (inhibiting COX-2) , miR-497 (inhibiting CHEK1) , and so on. Here, online tools were used to screen out the candidate upstream miRNAs for HMGB1. Among nine promising candidate miRNAs, we focused on miR-200a because of its essential regulator roles in breast cancer, skin tumor and ovarian tumorigenesis through targeting different downstream genes. MiR-200a suppresses cell growth and migration by targeting MACC1 in hepatocellular carcinoma . In neuroblastoma cells, miR-200a inhibits tumor proliferation by targeting AP-2gamma . Here, we found that miR-200a significantly down-regulated HMGB1 expression in HCC cells, which inspired us to hypothesize miR-200a might play some functional roles in HCC through regulation of HMGB1. More interestingly, a negative dual-regulation between miR-200a and TP73-AS1 was observed. As predicted by online tools, TP73-AS1 shared a similar binding site of miR-200a with HMGB1. By using luciferase assays, we confirmed miR-200a could directly bind to TP73-AS1 and the 3’UTR of HMGB1 on the predicted binding site(s). Given the consistency of the binding site(s), TP73-AS1 might compete with HMGB1 for miR-200a binding, so that to attenuate the inhibitory effect of miR-200a on HMGB1 expression.
To confirm that miR-200a regulated HMGB1 pathway in HCC cell lines, we monitored the protein levels of HMGB1, RAGE and NF-κB in response to the combined effect of miR-200a inhibition and TP73-AS1 knockdown. After miR-200a inhibited, the protein levels of HMGB1, RAGE and NF-κB were significantly upregulated. When TP73-AS1 was knocked out by si-TP73-AS1 in miR-200a inhibitor-transfected HCC cell lines, the promotive effect of miR-200a inhibitor on the protein levels of HMGB1, RAGE and NF-κB could be partially abolished. Moreover, as a transcription factor, NF-кB could promote the transcription of inflammatory cytokines . Therefore, NF-κB targets cytokines TNF-α, IL-6 and IL-1β’s levels were also showed consistent change trends with NF-κB expression. These data indicated that in HCC cell lines, TP73-AS1 affected cell proliferation through miR-200a-dependent HMGB1/RAGE regulation. Moreover, in HCC tissues, miR-200a expression was downregulated, while HMGB1 and RAGE expression was upregulated. TP73-AS1 was inversely correlated with miR-200a, while positively correlated with HMGB1 and RAGE, respectively, which further confirmed that TP73-AS1 targeted miR-200a to inhibit its expression, subsequently upregulated HMGB1/RAGE expression to promote HCC cell proliferation.
In summary, it was identified that TP73-AS1 could promote HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation; TP73-AS1 might compete with HMGB1 for miR-200a binding to inhibit miR-200a expression. TP73-AS1 might be a key role in regulating HCC cells proliferation, and may provide a potential therapeutic target for HCC treatment.
Chemokine (C-X-C motif) ligand 1
Long non-coding RNA
We are very grateful to Dr. Sijun Deng for polishing the manuscript.
This work was supported by grants from the National Natural Sciences Foundation of China (81272253; 81201619), the Special National International Technology Cooperation of China (2015DFA31490), the National Major Sciences research Program of China (973 Program, No.2013CB910502), and the Natural Science Foundation of Hunan Province, China (2016JJ3159).
Availability of data and materials
All data generated or analysed during this study are included in this published article. Further details are available on request.
SL and YH designed and performed the experiments, wrote the manuscript. YH, YF, DT and RK have contributed to experimental work and data analysis. RZ and XF conducted the experiments and revised the manuscript. All authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethic Committee of The Xiangya Hospital of the Central South University. All of the enrolled HCC patients signed informed consent forms.
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