DataSheet_1_LLGL2 Increases Ca2+ Influx and Exerts Oncogenic Activities via PI3K/AKT Signaling Pathway in Hepatocellular Carcinoma.zip

BackgroundLethal giant larvae (Lgl), scaffolding proteins, regulate the epithelial cell apicobasal polarity in Drosophila. They play important roles in asymmetric cell division, cell migration, and progenitor cells self-renewal as tumor suppressors. One of Lgl mammalian homologues proteins, LLGL2 overexpression has been reported in ER+ breast cancer and promotes tumor proliferation through regulating leucine uptake. Nonetheless, the role of LLGL2 in hepatocellular carcinoma (HCC) is still unknown.MethodsTCGA dataset mining, qRT-PCR, Western blot along with immunohistochemistry assays were employed to explore LLGL2 expression in human HCC samples and cell lines. Moreover, the clinical value of LLGL2 was investigated in 156 HCC patients. Furthermore, the role as well as the molecular mechanism of LLGL2 in the progression of HCC was explored through a series of in vitro and in vivo experiments.ResultsLLGL2 was up-regulated in HCC tissues, which was related with certain clinicopathological features including tumor number, vascular invasion as well as advanced stage. High expression of LLGL2 predicted poor prognosis after hepatectomy. LLGL2 promoted HCC cells proliferation, migration and invasion through PI3K/ATK signaling by promoting calcium ion influx.ConclusionOur study identified that LLGL2 is a tumor promoter in HCC for the first time, which could potentially be utilized as a new biomarker and a therapeutic target for HCC.

背景：巨型幼虫致死因子（Lgl）和支架蛋白调节果蝇上皮细胞的顶底极性。它们在不对称细胞分裂、细胞迁移和祖细胞自我更新作为肿瘤抑制因子等方面发挥着重要作用。其中，Lgl哺乳动物同源蛋白之一，LLGL2的过表达已在ER+乳腺癌中报道，并通过调节亮氨酸摄取促进肿瘤增殖。然而，LLGL2在肝细胞癌（HCC）中的作用尚不明确。方法：采用TCGA数据集挖掘、定量逆转录PCR、蛋白质印迹以及免疫组化检测等方法，探索LLGL2在人HCC样本和细胞系中的表达。此外，还调查了156例HCC患者的LLGL2的临床价值。进一步地，通过一系列体外和体内实验，探究了LLGL2在HCC进展中的作用及其分子机制。结果：LLGL2在HCC组织中上调，与某些临床病理特征（如肿瘤数量、血管侵袭和晚期）相关。LLGL2高表达预示着肝切除术后的不良预后。LLGL2通过促进钙离子内流，通过PI3K/ATK信号通路促进HCC细胞的增殖、迁移和侵袭。结论：本研究首次确定LLGL2是HCC的肿瘤促进因子，可能被用作HCC的新生物标志物和治疗靶点。