Long non‑coding RNA MKLN1‑AS aggravates hepatocellular carcinoma progression by functioning as a molecular sponge for miR‑654‑3p, thereby promoting hepatoma‑derived growth factor expression.
Long non‑coding RNA MKLN1‑AS aggravates hepatocellular carcinoma progression by functioning as a molecular sponge for miR‑654‑3p, thereby promoting hepatoma‑derived growth factor expression.
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DOI：
10.3892/ijmm.2020.4722
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发表时间：
2020-11
影响因子：
5.4
通讯作者：
Xue M
中科院分区：
文献类型：
--
作者：
Gao W;Chen X;Chi W;Xue M
长链非编码RNA（lncRNA）由于在乳腺癌和胃癌等人类肿瘤中的重要作用而受到关注。本研究检测了肝细胞癌（HCC）中Muskelin 1反义RNA（MKLN 1-AS）表达的变化，并评价其在HCC中的临床应用价值。此外，目前的研究调查了MKLN 1-AS对HCC细胞恶性特征的影响。MKLN 1-AS在肝癌细胞中的促癌活性的分子机制也被阐明。采用逆转录定量PCR（RT-qPCR）检测肝癌组织和细胞系中MKLN 1-AS的表达。采用Cell Counting Kit-8法和流式细胞术检测MKLN 1-AS对肝癌细胞增殖和凋亡的影响。进行迁移和侵袭测定以及肿瘤异种移植实验以分别分析体外迁移和侵袭以及体内肿瘤生长。采用荧光素酶报告基因分析、RNA免疫沉淀分析、RT-qPCR、Western blotting和拯救实验研究microRNA-654 - 3 p（miR-654- 3 p）、MKLN 1-AS和肝癌衍生生长因子（HDGF）在HCC中的相互作用。MKLN 1-AS在HCC组织和细胞系中上调，并且MKLN 1-AS高表达与HCC患者的总生存期和无病生存期较短相关。在功能上，MKLN 1-AS的敲低损害HCC细胞的增殖、迁移和侵袭，以及诱导细胞凋亡。MKLN 1-AS表达的敲低也抑制了体内细胞增殖。结果表明，MKLN 1-AS在HCC细胞中作为竞争性内源RNA通过海绵状吸收miR-654- 3 p发挥作用。此外，miR-654- 3 p靶向HDGF被MKLN 1-AS正向调节，并且miR-654- 3 p敲低部分消除了这种作用。挽救实验表明，miR-654- 3 p的敲低和HDGF的过表达都消除了HCC中MKLN 1-AS敲低诱导的细胞过程。总之，MKLN 1-AS通过充当miR-654- 3 p的分子海绵来增加HDGF表达，从而在HCC进展期间诱导促癌作用。因此，MKLN 1-AS/miR-654- 3 p/HDGF轴可能为HCC的诊断、预后、预防和治疗提供新的靶点。
Long non-coding RNAs (lncRNAs) have recently gained attention due to their important roles in human cancer types, such as breast and gastric cancer. The present study measured alterations in muskelin 1 antisense RNA (MKLN1-AS) expression in hepatocellular carcinoma (HCC) and evaluated its clinical value in patients with HCC. Additionally, the current study investigated the effects of MKLN1-AS on the malignant features of HCC cells. The detailed molecular mechanisms underlying the cancer-promoting activities of MKLN1-AS in HCC cells were also elucidated. MKLN1-AS expression in HCC tissues and cell lines was detected using reverse-transcription quantitative PCR (RT-qPCR). Cell Counting Kit-8 assays and flow cytometry were used to determine the roles of MKLN1-AS in HCC cell proliferation and apoptosis. Migration and invasion assays, as well as tumor xenograft experiments were conducted to analyze migration and invasion in vitro and tumor growth in vivo, respectively. The interaction among microRNA-654-3p (miR-654-3p), MKLN1-AS and hepatoma-derived growth factor (HDGF) in HCC was investigated using luciferase reporter assay, RNA immunoprecipitation assay, RT-qPCR, western blotting and rescue experiments. MKLN1-AS was upregulated in HCC tissues and cell lines, and a high MKLN1-AS expression was associated with shorter overall survival and disease-free survival in patients with HCC. Functionally, the knockdown of MKLN1-AS impaired HCC cell proliferation, migration and invasion, as well as induced cell apoptosis in vitro. Knockdown of MKLN1-AS expression also inhibited cell proliferation in vivo. The results indicated that MKLN1-AS functioned as a competing endogenous RNA by sponging miR-654-3p in HCC cells. Additionally, miR-654-3p targeting of HDGF was positively modulated by MKLN1-AS, and miR-654-3p knockdown partially abrogated this effect. Rescue experiments demonstrated that knockdown of miR-654-3p and overexpression of HDGF both abolished MKLN1-AS knockdown-induced cellular processes in HCC. In summary, MKLN1-AS induced pro-oncogenic effects during HCC progression by serving as a molecular sponge for miR-654-3p to increase HDGF expression. Therefore, the MKLN1-AS/miR-654-3p/HDGF axis may offer a novel target for the diagnosis, prognosis, prevention and treatment of HCC.
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