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Long non-coding RNA CARLo-5 promotes tumor progression in hepatocellular carcinoma via suppressing miR-200b expression.

ABSTRACT: Long non-coding RNAs (lncRNAs) play key roles in cancer initiation and progression. The aim was to investigate the biological functions and clinical significance of long non-coding RNA CARLo-5 in hepatocellular carcinoma (HCC). QRT-PCR was performed to investigate CARLo-5 expression in HCC tissues and cells. Kaplan-Meier curve and multivariate analysis validated the association between CARLo-5 expression and overall survival (OS) in HCC patients. Cell proliferation and invasion was performed by CCK8 cell proliferation, cell colony formation and transwell invasion assays. Western-blot assay was performed to evaluate the protein expression of Twist1, ZEB1, E-cadherin and Vimentin. Tumor xenografts were performed to evaluate the effect of CARLo-5 on tumor growth in vivo. RNA Immunoprecipitation (RIP) and Chromatin Immunoprecipitation (ChIP) were also performed. Our results showed that CARLo-5 expression was significantly higher in HCC tissues and upregulated CARLo-5 expression was closely correlated with tumor size and advanced tumor stage. Kaplan-Meier curve and multivariate analysis validated that higher CARLo-5 expression predicted a poor prognosis for HCC patients and was an independent risk factor for OS in HCC patients. In vitro, knockdown of CARLo-5 inhibited cell proliferation, colony formation, cell invasion and inhibited the cell epithelial-mesenchymal transition (EMT) by up-regulating the E-cadherin expression and down-regulating Twist1, ZEB1 and vimentin expression in HCC cells. Furthermore, we demonstrated that CARLo-5 inhibited the miR-200b expression via EZH2. In vivo, knockdown of CARLo-5 significantly inhibited the tumor growth. Thus, our results indicated that CARLo-5 represented a novel tumor biomarker and therapeutic target for HCC.

SUBMITTER: Dou C

PROVIDER: S-EPMC5642544 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Long non-coding RNA CARLo-5 promotes tumor progression in hepatocellular carcinoma via suppressing miR-200b expression.

Dou Chunqing C Sun Liyuan L Jin Xin X Han Mingming M Zhang Bao B Jiang Xian X Lv Jinyong J Li Tao T

Oncotarget 20170726 41

Long non-coding RNAs (lncRNAs) play key roles in cancer initiation and progression. The aim was to investigate the biological functions and clinical significance of long non-coding RNA CARLo-5 in hepatocellular carcinoma (HCC). QRT-PCR was performed to investigate CARLo-5 expression in HCC tissues and cells. Kaplan-Meier curve and multivariate analysis validated the association between CARLo-5 expression and overall survival (OS) in HCC patients. Cell proliferation and invasion was performed by ...[more]

PMID: 29050269

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Project description:BackgroundHepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism.MethodsThe differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR.ResultsLncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues.ConclusionLncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.

Project description:BackgroundLong non-coding RNAs (lncRNAs) are widely involved in human cancers' progression by regulating tumor cells' various malignant behaviors. MAPKAPK5-AS1 has been recognized as an oncogene in colorectal cancer. However, the biological role of MAPKAPK5-AS1 in hepatocellular carcinoma (HCC) has not been explored.MethodsQuantitative real-time PCR was performed to detect the level of MAPKAPK5-AS1 in HCC tissues and cell lines. The effects of MAPKAPK5-AS1 on tumor growth and metastasis were assessed via in vitro experiments, including MTT, colony formation, EdU, flow cytometry, transwell assays, and nude mice models. The western blotting analysis was carried out to determine epithelial-mesenchymal transition (EMT) markers and AKT signaling. The interaction between MAPKAPK5-AS1, miR-154-5p, and PLAGL2 were explored by luciferase reporter assay and RNA immunoprecipitation. The regulatory effect of HIF-1? on MAPKAPK5-AS1 was evaluated by chromatin immunoprecipitation.ResultsMAPKAPK5-AS1 expression was significantly elevated in HCC, and its overexpression associated with malignant clinical features and reduced survival. Functionally, MAPKAPK5-AS1 knockdown repressed the proliferation, mobility, and EMT of HCC cells and induced apoptosis. Ectopic expression of MAPKAPK5-AS1 contributed to HCC cell proliferation and invasion in vitro. Furthermore, MAPKAPK5-AS1 silencing suppressed, while MAPKAPK5-AS1 overexpression enhanced HCC growth and lung metastasis in vivo. Mechanistically, MAPKAPK5-AS1 upregulated PLAG1 like zinc finger 2 (PLAGL2) expression by acting as an endogenous competing RNA (ceRNA) to sponge miR-154-5p, thereby activating EGFR/AKT signaling. Importantly, rescue experiments demonstrated that the miR-154-5p/PLAGL2 axis mediated the function of MAPKAPK5-AS1 in HCC cells. Interestingly, we found that hypoxia-inducible factor 1? (HIF-1?), a transcript factor, could directly bind to the promoter to activate MAPKAPK5-AS1 transcription. MAPKAPK5-AS1 regulated HIF-1? expression through PLAGL2 to form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC.ConclusionsOur results reveal a MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC progression and suggest that MAPKAPK5-AS1 could be a potential novel therapeutic target of HCC.

Dataset Information

Long non-coding RNA CARLo-5 promotes tumor progression in hepatocellular carcinoma via suppressing miR-200b expression.

Publications

Long non-coding RNA CARLo-5 promotes tumor progression in hepatocellular carcinoma via suppressing miR-200b expression.

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