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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 19  |  Page : 2320-2331

XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis


1 Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
2 Department of General Surgery, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi 030001, China

Correspondence Address:
Dr. Ying-Chen Xu
Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.241800

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Background: XB130 is a recently discovered adaptor protein that is highly expressed in many malignant tumors, but few studies have investigated its role in hepatocellular carcinoma (HCC). Therefore, this study explored the relationship between this protein and liver cancer and investigated its molecular mechanism of action. Methods: The expression of XB130 between HCC tissues and adjacent nontumor tissues was compared by real-time polymerase chain reaction, immunochemistry, and Western blotting. XB130 silencing was performed using small hairpin RNA. The effect of silencing XB130 was examined using Cell Counting Kit-8, colony assay, wound healing assay, and cell cycle analysis. Results: We found that XB130 was highly expressed in HCC tissues (cancer tissues vs. adjacent tissues: 0.23 ± 0.02 vs. 0.17 ± 0.02, P < 0.05) and liver cancer cell lines, particularly MHCC97H and HepG2 (MHCC97H and HepG2 vs. normal liver cell line LO-2: 2.35 ± 0.26 and 2.04 ± 0.04 vs. 1.00 ± 0.04, respectively, all P < 0.05). The Cell Counting Kit-8 assay, colony formation assay, and xenograft model in nude mice showed that silencing XB130 inhibited cell proliferative ability both in vivo and in vitro, with flow cytometry demonstrating that the cells were arrested in the G0/G1 phase in HepG2 (HepG2 XB130-silenced group [shA] vs. HepG2 scramble group [NA]: 74.32 ± 5.86% vs. 60.21 ± 3.07%, P < 0.05) and that the number of G2/M phase cells was decreased (HepG2 shA vs. HepG2 NA: 8.06 ± 2.41% vs. 18.36 ± 4.42%, P < 0.05). Furthermore, the cell invasion and migration abilities were impaired, and the levels of the epithelial-mesenchymal transition-related indicators vimentin and N-cadherin were decreased, although the level of E-cadherin was increased after silencing XB130. Western blotting showed that the levels of phosphorylated phosphoinositide 3-kinase (PI3K) and phospho-protein kinase B (p-Akt) also increased, although the level of phosphorylated phosphatase and tensin homolog increased, indicating that XB130 activated the PI3K/Akt pathway. Furthermore, we found that a reduction in XB130 increased liver cancer cell sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Conclusions: Our findings suggest that XB130 might be used as a predictor of liver cancer as well as one of the targets for its treatment.

 

 Abstract in Chinese

XB130敲除抑制肝细胞癌细胞的增殖、侵袭以及转移,并使其对TRAIL诱导的细胞凋亡敏感

摘要

背景:XB130是新近发现的一种在许多恶性肿瘤中高表达的衔接蛋白,但很少有研究表明研究了它在肝细胞癌(HCC)中的作用。因此,本研究探讨了这XB130与肝癌之间的关系并研究其分子作用机制。

方法:采用RT-PCR、免疫组化及蛋白印迹法比较HCC组织与癌旁组织中XB130的表达,并通过shRNA 将XB130沉默。并通过克隆形成实验、划痕实验、集落形成实验及流式细胞术观察其对肝癌细胞系增殖、侵袭、转移及细胞周期的影响。

结果:我们发现XB130在HCC组织中高表达(癌组织与邻近组织:0.23±0.02比0.17±0.02,P <0.05),肝癌细胞系中MHCC97H和HepG2表达最高(MHCC97H和HepG2与正常肝细胞系LO-2:分别为2.35±0.26和2.04±0.04比1.00±0.04,均P <0.05)。CCK-8实验和裸鼠成瘤实验显示,沉默XB130在体内和体外都能抑制细胞增殖能力,流式细胞术检测证明沉默XB130后可以使肝癌细胞在HepG2的G0 / G1期停滞(HepG2 XB130 [shA]与HepG2 [NA]:74.32±5.86% 比 60.21±3.07%,P <0.05),G2 / M期细胞数减少(HepG2 shA 比HepG2 NA:8.06±2.41%比18.36±4.42%,P <0.05)。此外,细胞侵袭转移能力受到损害,且上皮 -间质转化相关指标波形蛋白和N-钙粘蛋白表达下调,E-钙粘蛋白水平上调。 Western blotting显示磷酸化磷酸肌醇3-激酶(PI3K)水平和磷酸化蛋白激酶B(p-Akt)也增加,表明XB130激活了PI3K / Akt通路。此外,我们发现XB130的减少增加了肝癌细胞系对肿瘤坏死因子相关凋亡诱导配体诱导的细胞凋亡的敏感性。

结论:我们的研究结果表明,XB130不仅可以用作肝癌的预测因子,还可以作为肝癌的治疗靶点之一。



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