Long non-coding RNA TPTEP1 inhibits hepatocellular carcinoma progression by suppressing STAT3 phosphorylation (Retracted Article)
Long non-coding RNA TPTEP1 inhibits hepatocellular carcinoma progression by suppressing STAT3 phosphorylation (Retracted Article)
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DOI：
10.1186/s13046-019-1193-0
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发表时间：
2019-05-09
影响因子：
11.3
通讯作者：
Su, Yang
中科院分区：
文献类型：
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作者：
Ding, Hongda;Liu, Junpeng;Su, Yang
背景肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的肿瘤相关死亡原因，越来越多的研究表明长链非编码RNA（long non-coding RNAs，LncRNA）与HCC的发生、转移和预后密切相关。顺铂是一种众所周知的化疗药物，已广泛用于治疗包括HCC在内的许多人类癌症。本研究旨在探讨顺铂对肝癌细胞LncRNA表达的影响及其机制。采用实时荧光定量聚合酶链反应（qRT-PCR）、细胞增殖、集落形成、细胞侵袭和流式细胞术检测TPTEP 1在肝癌发生发展中的作用。通过RNA下拉、蛋白质印迹、亚细胞分级分离、RNA免疫沉淀和双荧光素酶报告基因测定来研究TPTEP 1使肝细胞癌细胞对顺铂敏感的潜在机制。TPTEP 1对体内肿瘤发生的影响用HCC的皮下异种移植小鼠模型进行。结果顺铂处理的肝癌细胞中TPTEP 1高表达，使肝癌细胞对顺铂诱导的凋亡敏感。TPTEP 1过表达抑制肝癌细胞增殖、致瘤性和侵袭性，而TPTEP 1敲低则促进肝癌细胞增殖、致瘤性和侵袭性。TPTEP 1通过与信号转导和转录激活因子3（STAT 3）相互作用，抑制STAT 3的磷酸化、同源二聚化、核转位和下游基因的转录，从而发挥其抑瘤作用。此外，TPTEP 1过表达明显抑制肿瘤块在体内的皮下异种移植肝癌小鼠模型和TPTEP 1是经常下调肝癌组织中，相比其相应的癌前tissues.ConclusionLncRNA TPTEP 1抑制肝癌细胞的进展，通过影响IL-6/STAT 3信号。总之，我们的研究结果表明TPTEP 1在肝癌进展中的肿瘤抑制作用，并提供了一个新的理解TPTEP 1在肝癌化疗过程中。
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.