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LINC00473 通过作为 microRNA-195 的 ceRNA 并增加 HMGA2 表达促进肝癌进展。

LINC00473 promotes hepatocellular carcinoma progression via acting as a ceRNA for microRNA-195 and increasing HMGA2 expression.

机构信息

Department of Hepatobiliary Surgery, Taizhou Central Hospital Affiliated to Taizhou College, Taizhou, 318000, China.

Department of Ultrasound, Taizhou Municipal Hospital, Medical College of Taizhou University, Taizhou, 318000, China.

出版信息

Biomed Pharmacother. 2019 Dec;120:109403. doi: 10.1016/j.biopha.2019.109403. Epub 2019 Sep 25.

Abstract

Hepatocellular carcinoma (HCC) is a most aggressive malignant tumor. Nevertheless, the molecular mechanisms underlying HCC are still completely unclear. LINC00473 is identified as a tumor promoter in many cancers. In this investigation, the function of LINC00473 was specifically focused on. We exhibited that LINC00473 was obviously elevated in HCC cells compared to QSG-7701 cells. Functionally, down-regulation of LINC00473 could prevent HCC cell viability and cell proliferation. For another, HCC cell colony formation capacity was greatly restrained while cell apoptosis was triggered by loss of LINC00473. Meanwhile, would-healing assay and transwell invasion experiments were employed in our present study. As demonstrated, we observed that HCC cell migratory and invasive ability were obviously suppressed by the silence of LINC00473. Apart from these, mechanistic investigations implied miR-195 was a sponge target of LINC00473. It is widely established miR-195 is a famous tumor inhibitory gene regulator in various cancers. Here, we confirmed the binding correlation between LINC00473 and miR-195 using RIP assay. Subsequently, in vivo experiments were employed and it was manifested that LINC00473 was able to promote HCC tumor growth via acting as a ceRNA to inhibit miR-195. HMGA2 is a kind of nuclear-binding protein and it is involved in various cancers. We predicted it as a target of miR-195 and we confirmed their correlation. In addition, HMGA2 was repressed by loss of LINC00473, which was rescued by miR-195 inhibitors. Then, we found that angiogenic fator vascular endothelial growth factor (VEGF) was inhibited by loss of LINC00473 whereas anti-angiogenic factor EPN2 was induced in vivo. Taken all these together, our study revealed the significance of LINC00473/miR-195/HMGA2 signaling axis for the first time in HCC progression. It was suggested the potential possibility of LINC00473 as an indicator for HCC.

摘要

肝细胞癌 (HCC) 是最具侵袭性的恶性肿瘤。然而,HCC 的分子机制仍完全不清楚。LINC00473 被鉴定为许多癌症中的肿瘤促进因子。在本研究中,我们特别关注 LINC00473 的功能。我们发现,与 QSG-7701 细胞相比,LINC00473 在 HCC 细胞中明显升高。功能上,下调 LINC00473 可以防止 HCC 细胞活力和增殖。另一方面,LINC00473 的缺失会触发 HCC 细胞凋亡,并极大地抑制 HCC 细胞集落形成能力。同时,我们在本研究中使用划痕愈合实验和 Transwell 侵袭实验。结果表明,沉默 LINC00473 明显抑制了 HCC 细胞的迁移和侵袭能力。除此之外,机制研究表明 miR-195 是 LINC00473 的海绵靶标。广泛认为,miR-195 是各种癌症中著名的肿瘤抑制基因调控因子。在这里,我们通过 RIP 实验证实了 LINC00473 和 miR-195 之间的结合相关性。随后,进行了体内实验,结果表明 LINC00473 能够通过作为 ceRNA 抑制 miR-195 来促进 HCC 肿瘤生长。HMGA2 是一种核结合蛋白,参与各种癌症。我们预测它是 miR-195 的靶标,并证实了它们之间的相关性。此外,LINC00473 的缺失抑制了 HMGA2,而 miR-195 抑制剂则可以挽救这种情况。然后,我们发现 LINC00473 的缺失抑制了血管内皮生长因子 (VEGF) 等血管生成因子,而体内诱导了 EPN2 等抗血管生成因子。综上所述,我们的研究首次揭示了 LINC00473/miR-195/HMGA2 信号轴在 HCC 进展中的重要性。这表明 LINC00473 作为 HCC 标志物的潜在可能性。

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