Hsa_circ_0136666 promotes the proliferation and invasion of colorectal cancer through miR-136/SH2B1 axis

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Currently, an increasing evidence showed that circular RNAs (circRNAs) play important roles in tumor progression. However, the effects and underlying mechanisms of circRNAs in CRC progression remain unclear. In the present study, through circRNA high-throughput sequencing and quantitative real-time polymerase chain reaction, we identified that hsa_circ_0136666 was significantly overexpressed in CRC tissues and cell lines. High hsa_circ_0136666 expression was associated with poor overall survival of patients with CRC. In vitro function assays showed that hsa_circ_0136666 inhibition suppressed CRC cell proliferation, migration, invasion, and arrested CRC cells in the G0/G1 phase. Furthermore, we showed that hsa_circ_0136666 inhibition reduced CRC cell growth in vivo. Mechanistically, we revealed that hsa_circ_0136666 could increase SH2B1 expression via competitively binding miR-136 in CRC cells. In addition, SH2B1 overexpression could reverse the effects of hsa_circ_0136666 inhibition on CRC cell progression. In conclusion, our data suggested that hsa_circ_0136666 could promote CRC cell progression via the miR-136/SH2B1 axis, elucidating a novel approach to improve the effectiveness of CRC treatment.     

Hsa_circ_0136666 activates Treg-mediated immune escape of colorectal cancer via miR-497/PD-L1 pathway

PurposeIn the rankings of cancer mortality and incidence worldwide, colorectal cancer ranks fourth and the third, respectively. Circular RNA hsa_circ_0136666 (hsa_circ_0136666) is reported to participate in the growth of colorectal cancer. However, the mechanism by which hsa_circ_0136666 regulates the tumorigenesis of colorectal cancer needs to be further explored. In this study, we report here the role of hsa_circ_0136666 in the aberrant activation of Treg cells and immune evasion of tumor cells, providing a new strategy for the treatment of colorectal cancer.MethodsWestern blotting assay and qRT-PCR assay were used to determine protein and mRNA expression levels. Dual-luciferase reporter assay was used to evaluate the targeted regulatory relationship. RNA immunoprecipitation was used to detect RNA binding. Colony formation assay was utilized to measure the cell proliferation. Flow cytometry was used to assess cell apoptosis. Xenograft model was setup to evaluate tumor growth.ResultsThe results showed that hsa_circ_0136666 and PD-L1 was increased in colorectal cancer cells while miR-497 was decreased in colorectal cancer cells when compared with normal colon epithelial cell line. Hsa_circ_0136666 was demonstrated to directly target miR-497, which also regulated PD-L1 by binding to its 3′UTR. Further mechanistic studies identified that hsa_circ_0136666 controlled cell proliferation and apoptosis via targeting miR-497 and regulating PD-L1 expression. Of note, hsa_circ_0136666 stimulated Treg cells mediated by miR-497/PD-L1 axis and its downstream signal pathway in Treg cells. Finally, hsa_circ_0136666 was found to accelerate the tumor growth in vivo.ConclusionsOur findings demonstrated that hsa_circ_0136666 promoted the expression of PD-L1 by inhibiting miR-497 level in colorectal cancer, thus inducing the activation of Treg cells and leading to the immune escape of tumor, providing a novel mechanistic insight into the pathogenesis of colorectal cancer.     

Circular RNA hsa_circ_0110389 promotes gastric cancer progression through upregulating SORT1 via sponging miR-127-5p and miR-136-5p

Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p–SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p–SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.Subject terms: Gastrointestinal cancer, Non-coding RNAs     

Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6

A growing number of circular RNAs (circRNAs) have been identified and verified in several cancers. However, highly efficient therapeutic methods based on circRNAs in lung cancer remain largely unexplored. In the present study, we identified a novel circular RNA, hsa_circ_103820, based on Gene Expression Omnibus (GEO) data. Functionally, overexpression of hsa_circ_103820 showed significant inhibitory effects on the proliferation, migration and invasion of lung cancer cells, and knockdown of hsa_circ_103820 played promoting roles. Regarding the mechanism, we revealed that miR-200b-3p was a direct target of hsa_circ_103820 and that LATS2 and SOCS6 were the downstream target genes of miR-200b-3p. Therefore, we identified a novel potential tumor suppressive function of hsa_circ_103820 in lung cancer.Subject terms: RNA, Non-small-cell lung cancer     

circ_ARF3 regulates the pathogenesis of osteosarcoma by sponging miR-1299 to maintain CDK6 expression

Increasing evidence suggests that circular RNAs are emerging biomarkers or targets for early cancer diagnosis and treatment. However, the studies of circular RNA in osteosarcoma (OS) are limited. In this study we found that circ_ARF3 were highly expressed in osteosarcoma cell lines and tumor tissues. Knocking down circ_ARF3 greatly ceased OS cell growth, impaired cell colony formation and halted cell cycle transition from G1 to S phase. Bioinformatic analysis suggested that miR-1299 is the target of circ_ARF3. Luciferase assay and biotin labeled circ_ARF3 pull down assay confirmed their interactions in OS cells. The regulatory roles of circ_ARF3 on miR-1299 was also investigated. Further bioinformatic analysis showed that CDK6 is the target of miR-1299. Overexpressing miR-1299 in OS cells decreased CDK6 expression and arrested OS cell growth and cell cycle progression. However, the roles of miR-1299 in regulating CDK6 expression, OS cell growth and cell cycle progression were greatly impaired in the presence of circ_ARF3. In general, our study demonstrated that in the OS, highly expressed circ_ARF3 acts as a sponge of miR-1299 to inhibit miR-1299 mediated CDK6 downregulation which further promoted OS pathogenesis. circ_ARF3 could be a potential target for OS treatment in the future.     

Circular RNA hsa_circ_0030018 acts as a sponge of miR-599 to aggravate esophageal carcinoma progression by regulating ENAH expression

Esophageal carcinoma (EC) bears one of the most rapid-growing incidences in cancers, which also has the highest mortality rate worldwide. Multiple studies have authenticated that circular RNAs (circRNAs) significantly work on the progression of cancers. circRNA hsa_circ_0030018 was also verified to exert functions on the development of glioma previously. Nevertheless, the biological function of hsa_circ_0030018 in EC has not been well elucidated yet. In the present study, the results displayed the expression of hsa_circ_0030018 was dramatically increased in EC cells. Inhibition of has_circ_0030018 suppressed cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process in EC. Based on molecular mechanism assays, has_circ_0030018 served as a sponge of miR-599. Enabled homolog (ENAH), which exhibited high expression in EC cells, was confirmed to be a downstream target gene of miR-599. Additionally, has_circ_0030018 positively regulated ENAH expression while miR-599 negatively regulated ENAH expression. Finally, by employing rescue assays, ENAH deficiency partially counteracted the promoting function of miR-599 silence on cell proliferation, migration, and EMT process in EC cotransfected with sh- has_circ_0030018#1 cells. In conclusion, hsa_circ_0030018 acted as a sponge of miR-599 to aggravate EC progression by regulating ENAH expression. Therefore, hsa_circ_0030018 might serve as a promising biomarker and therapeutic target for EC.     

Hsa_circ_0001495 contributes to cervical cancer progression by targeting miR-526b-3p/TMBIM6/mTOR axis

Cervical cancer (CC) is a common gynecological malignant tumor, causing poor survival rate. Circular RNAs (circRNAs) are abundantly expressed in CC with their stable loop structure. However, the underlying mechanism and biological function of circRNAs remained unclear. Using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay, we measured the expression of hsa_circ_0001495, miR-526b-3p, and transmembrane Bax inhibitor motif containing 6 (TMBIM6) in CC tissues and cells. The relationship between miR-526b-3p and hsa_circ_0001495 or TMBIM6 was investigated by bioinformatics analysis, dual-luciferase and RIP analysis. Enzyme linked immunosorbent assay (ELISA) was conducted to evaluate glucose consumption and lactate production. 5-ethynyl-2′-deoxyuridine (EDU) assay were used to test cell proliferation. Cell apoptosis was analyzed by using flow cytometry assay. Transwell and wound-healing assays were used to measure cell invasion and migration. The expression of proteins was examined by western blot. Xenograft assay was applied to detect the effect of hsa_circ_0001495 in vivo. Our finding showed that hsa_circ_0001495 and TMBIM6 expression were upregulated, while miR-526b-3p was downregulated in CC tissues and cell lines. Hsa_circ_0001495 knockdown or TMBIM6 knockdown suppressed cell proliferation, migration, glycolysis, while promoted cell apoptosis in vitro, and hsa_circ_0001495 silence curbed tumor growth in vivo. Beside, hsa_circ_0001495 exerted its function in CC by positively regulating TMBIM6. Furthermore, hsa_circ_0001495 acted as a sponge for miR-526b-3p to regulate TMBIM6 expression. Hsa_circ_0001495/miR-526b-3p/TMBIM6 axis also regulated the phosphorylation of mammalian target of rapamycin (mTOR) in CC cells. In summary, hsa_circ_0001495 regulated the progression of CC by regulating miR-526b-3p/TMBIM6/mTOR pathway.     

环状RNA：胃癌诊治的新星

环状RNA (circular RNA,circRNA)是一类闭合环状结构的RNA分子，广泛分布于各种组织中，它比线性RNA更稳定。circRNA分为外显子circRNA、外显子-内含子circRNA和内含子circRNA等3类。circRNA的主要功能为充当微RNA海绵、与RNA结合蛋白结合、翻译成蛋白质和调节转录等。近年来，大量研究表明，circRNA的异常表达在胃癌发生发展过程中起着至关重要的作用。circPTPN22、hsa＿circ＿0001772、circCYFIP2、hsa＿circ＿0017639和circPIP5K1A等的上调以及hsa＿circ＿002059、hsa＿circ＿0000190和circMTO1等的下调与胃癌的增殖和转移密切相关；而hsa＿circ＿0001313等影响胃癌细胞的顺铂耐药性。组织、血浆及外泌体中circPTPN22、hsa＿circ＿102958、hsa＿circ＿0141633、hsa＿circ＿0065149和hsa＿circ＿0026344等是胃癌新型诊断标志物；而hsa＿circ＿0005529、circ-RanGAP1、cir...     

Identification of novel dysregulated circular RNAs in early-stage breast cancer

Breast cancer is a major cause of cancer-related death in women worldwide. Non-coding RNAs are a potential resource to be used as an early diagnostic biomarker for breast cancer. Circular RNAs are a recently identified group of non-coding RNA with a significant role in disease development with potential utility in diagnosis/prognosis in cancer. In this study, we identified 26 differentially expressed circular RNAs associated with early-stage breast cancer. RNA sequencing and two circRNA detection tools (find_circ and DCC) were used to understand the circRNA expression signature in breast cancer. We identified hsa_circ_0006743 (circJMJD1C) and hsa_circ_0002496 (circAPPBP1) to be significantly up-regulated in early-stage breast cancer tissues. Co-expression analysis identified four pairs of circRNA-miRNA (hsa_circ_0023990 : hsa-miR-548b-3p, hsa_circ_0016601 : hsa_miR-1246, hsa_circ_0001946 : hsa-miR-1299 and hsa_circ_0000117:hsa-miR-502-5p) having potential interaction. The miRNA target prediction and network analysis revealed mRNA possibly regulated by circRNAs. We have thus identified circRNAs of diagnostic implications in breast cancer and also observed circRNA-miRNA interaction which could be involved in breast cancer development.     

Circular RNA circBCBM1 promotes breast cancer brain metastasis by modulating miR-125a/BRD4 axis

Circular RNAs (circRNAs) play critical roles in tumorigenesis and the progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown. In this study, we confirmed that circBCBM1 was a stable and cytoplasmic circRNA. Functionally, circBCBM1 promoted the proliferation and migration of 231-BR cells in vitro and growth and brain metastasis in vivo. Mechanistically, circBCBM1 acted as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 (bromodomain containing 4) and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, circBCBM1 overexpression in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients. These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis. CircBCBM1 may serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.     

CircMETTL3, upregulated in a m6A-dependent manner,promotes breast cancer progression

Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 in breast cancer and the underlying molecular mechanism remains unclear. Herein, we report circMETTL3, which has not been explored in breast cancer, and it is markedly upregulated in breast cancer. Moreover, we uncovered that circMETTL3 could facilitate cell proliferation, migration and invasion in breast cancer. Mechanism investigation showed that circMETTL3 might act as a competing endogenous RNA (ceRNA) of miR-31-5p and upregulate its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression. Taken together, our results elucidate that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulate circMETTL3 expression in an m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new therapeutic target for breast cancer.     

Circular RNA hsa_circ_0004015 regulates the proliferation,invasion, and TKI drug resistance of non-small cell lung cancer by miR-1183/PDPK1 signaling pathway

Circular RNAs (circRNAs) were recently reported to be involved in the pathogenesis of Non-small cell lung cancer (NSCLC), however, the molecular mechanisms of circRNAs in cell proliferation, invasion and TKI drug resistance remain largely undetermined. Here, we identified hsa_circ_0004015 was upregulated in NSCLC tissues, and was associated with the poor overall survival rate of NSCLC patients. Knockdown of hsa_circ_0004015 significantly decreased cell viability, proliferation, and invasion, whereas overexpression exhibited opposed effects in vivo and in vitro. Furthermore, hsa_circ_0004015 could enhance the resistance of HCC827 to gefitinib. In mechanism, hsa_circ_0004015 acted as a sponge for miR-1183, and PDPK1 was revealed to be target gene of miR-1183. Subsequently, functional assays illustrated that the oncogenic effects of hsa_circ_0004015 was attributed to the regulation of miR-1183/PDPK1 axis. In conclusion, circ_0016760/miR-1183/PDPK1 signaling pathway might play vital roles in the tumorigenesis of NSCLC.     

Hsa_circ_0092276 promotes doxorubicin resistance in breast cancer cells by regulating autophagy via miR-348/ATG7 axis

Previous study has confirmed that hsa_circ_0092276 is highly expressed in doxorubicin (DOX)-resistant breast cancer cells, indicating that hsa_circ_0092276 may be involved in regulating the chemotherapy resistance of breast cancer. Here we attempted to investigate the biological role of hsa_circ_0092276 in breast cancer. We first constructed DOX-resistant breast cancer cells (MCF-7/DOX and MDA-MB-468/DOX). The 50% inhibiting concentration of MCF-7/DOX and MDA-MB-468/DOX cells was significantly higher than that of their parental breast cancer cells, MCF-7 and MDA-MB-46. MCF-7/DOX and MDA-MB-468/DOX cells also exhibited an up-regulation of drug resistance-related protein MDR1. Compared with MCF-7 and MDA-MB-46 cells, hsa_circ_0092276 was highly expressed in MCF-7/DOX and MDA-MB-468/DOX cells. Hsa_circ_0092276 overexpression enhanced proliferation and the expression of LC3-II/LC3-I and Beclin-1, and repressed apoptosis of breast cancer cells. The effect of hsa_circ_0092276 up-regulation on breast cancer cells was abolished by 3-methyladenine (autophagy inhibitor). Hsa_circ_0092276 modulated autophagy-related gene 7 (ATG7) expression via sponging miR-384. Hsa_circ_0092276 up-regulation promoted autophagy and proliferation, and repressed apoptosis of breast cancer cells, which was abolished by miR-384 overexpression or ATG7 knockdown. In addition, LV-circ_0092276 transfected MCF-7 cell transplantation promoted autophagy and tumor growth of breast cancer in mice. In conclusion, our data demonstrate that hsa_circ_0092276 promotes autophagy and DOX resistance in breast cancer by regulating miR-348/ATG7 axis. Thus, this article highlights a novel competing endogenous RNA circuitry involved in DOX resistance in breast cancer.     

circFBXL5 promotes breast cancer progression by sponging miR‐660

Increasing studies have revealed that circular RNAs (circRNAs) play important roles in cancer progression. However, the potential involvement of circRNAs in breast cancer metastasis to lung is not clear so far. In this study, we conducted circular RNA microarrays of primary breast cancer tissues and lung metastatic tissues. The results revealed that circFBXL5 (hsa_circ_0125597) up‐regulated the most in lung metastatic tissues. Survival analysis revealed that high levels of circFBXL5 correlated with worse outcome of breast cancer. Further experiments showed that knockdown of circFBXL5 inhibited breast cancer cell proliferation and migration to lung. Mechanism study showed that circFBXL5 acted as a sponge for miR‐660 and compete binding to miR‐660 with SRSF6, leading to increased expression of SRSF6. Collectively, our study highlighted the regulatory function of the circFBXL5/miR‐660/SRSF6 pathway in breast cancer progression, which could be potential therapeutic targets for breast cancer.     

Hsa_circ_0003098 promotes bladder cancer progression via miR-377-5p/ACAT2 axis

Accumulating evidence has proven that circRNAs play vital roles in tumor progression. Nevertheless, the mechanisms underlying circRNAs in bladder cancer (BCa) remain largely unknown. The purpose of this study was to identify the role and investigate the potential molecular mechanisms of hsa_circ_0003098 in BCa. We confirmed that hsa_circ_0003098 expression was significantly upregulated in BCa tissues, of which expression was remarkably associated with poor prognosis. Functionally, overexpression of hsa_circ_0003098 promoted BCa cell proliferation, migration, and invasion in vitro as well as tumor growth in vivo. Mechanistically, hsa_circ_0003098 promoted upregulation of ACAT2 expression and induced cholesteryl ester accumulation via acting as a sponge for miR-377-5p. Thus, hsa_circ_0003098 plays an oncogenic role in BCa and may serve as a potential biomarker and therapeutic target for BCa.     

Dysregulation of HER2/HER3 signaling axis in Epstein-Barr virus-infected breast carcinoma cells

The role of Epstein-Barr virus (EBV) in the pathogenesis of breast cancer has been of long-standing interest to the field. Breast epithelial cells can be infected by EBV through direct contact with EBV-bearing lymphoblastoid cells, and EBV infection has recently been shown to confer breast cancer cells an increased resistance to chemotherapeutic drugs. In this study, we established EBV-infected breast cancer MCF7 and BT474 cells and demonstrated that EBV infection promotes tumorigenic activity of breast cancer cells. Firstly, we showed that the EBV-infected MCF7-A and BT474-A cells exhibited increased anchorage-independent growth in soft agar. The increased colony formation capacity in soft agar was associated with increased expression and activation of HER2/HER3 signaling cascades, as evidenced by the findings that the treatment of HER2 antibody trastuzumab (Herceptin), phosphatidylinositol 3-kinase inhibitor, or MEK inhibitor completely abolished the tumorigenic capacity. In the EBV-infected breast cancer cells, the expression of EBV latency genes including EBNA1, EBER1, and BARF0 was detected. We next showed that BARF0 alone was sufficient to efficiently up-regulate HER2/HER3 expression and promoted tumorigenic activity in MCF7 and BT474 cells by the use of both overexpression and small interfering RNA knock-down. Collectively, we demonstrated that EBV-encoded BARF0 promotes the tumorigenic activity of breast cancer cells through activation of HER2/HER3 signaling cascades.     

Circular RNA hsa_circ_0053277 promotes the development of colorectal cancer by upregulating matrix metallopeptidase 14 via miR-2467-3p sequestration

Colorectal cancer (CRC), a kind of human gastrointestinal cancer, has been reported to be one of the most common malignant tumors worldwide. Increasing evidence has indicated that circular RNAs exert significant effects on the development of multiple cancers. Nevertheless, whether hsa_circ_0053277 regulates the progression of CRC remains to be explored. In this study, our results showed that the expression of hsa_circ_0053277 was markedly upregulated in CRC tissues and cells. Knockdown of hsa_circ_0053277 inhibited cell proliferation, migration, and epithelial-mesenchymal transition (EMT) process in CRC. miR-2467-3p had a binding site for hsa_circ_0053277. Molecular mechanism assays confirmed that hsa_circ_0053277 could bind with miR-2467-3p. In addition, hsa_circ_0053277 accelerated cell proliferation rate by acting as a sponge for miR-2467-3p in CRC. Matrix metalloproteinase 14 (MMP14) expression was notably upregulated in CRC cells and MMP14 was a downstream target gene of miR-2467-3p. Besides, hsa_circ_0053277 positively regulated MMP14 expression while miR-2467-3p negatively regulated MMP14 expression. Rescue assays verified that MMP14 knockdown countervailed the function of miR-2467-3p inhibitor on cell proliferation, migration, and EMT process in CRC. To sum up, hsa_circ_0053277 facilitated the development of CRC by sponging miR-2467-3p to upregulate MMP14 expression.     

Insight into the molecular mechanism of LINC00152/miR-215/CDK13 axis in hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Nevertheless, its underlying molecular mechanisms are largely unknown. LINC00152 are recently investigated in several cancer types. In our current investigation, we observed LINC00152 was obviously upregulated in HCC cells. LINC00152 was significantly downregulated by infecting LV-shLINC00152 in HepG2 and SNU449 cells. Loss of LINC00152 remarkably repressed HCC cell proliferation, cell colony formation, induced cell apoptosis, and restrained cell migration/invasion. Growing evidence has reported long noncoding RNAs can sponge microRNAs to modulate cancer process. Here, we indicated miR-215 was greatly decreased in HCC and LINC00152 regulated HCC development via sponging miR-215. For another, the binding association between LINC00152 and miR-215 was proved by a series of functional assays. CDK13 was predicted as the target of miR-215. Upregulation of miR-215 greatly depressed CDK13 in HCC cells. Subsequently, the in vivo results demonstrated that silence of LINC00152 restrained HCC development via modulating miR-215 to up-regulate CDK13. Therefore, it was revealed that LINC00152 contributed to the progression of HCC by the modulation of miR-215 and CDK13.