Vasohibin 2 decreases the cisplatin sensitivity of hepatocarcinoma cell line by downregulating p53.
Vasohibin 2 decreases the cisplatin sensitivity of hepatocarcinoma cell line by downregulating p53.
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Vasohibin 2 通过下调 p53 降低肝癌细胞系的顺铂敏感性
DOI：
10.1371/journal.pone.0090358
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gao W
中科院分区：
文献类型：
--
作者：
Li Z;Tu M;Han B;Gu Y;Xue X;Sun J;Ge Q;Miao Y;Qian Z;Gao W
肝细胞癌是世界范围内普遍存在的问题。化疗，特别是以顺铂(CDDP)为基础的全身化疗是晚期肝癌的最佳选择。然而，顺铂耐药现象日益普遍，阻碍了顺铂的临床应用。同时，关于血管生成素2(VASH2)的化疗应用还没有达成共识，VASH2可以促进肿瘤细胞的血管生成和增殖。在这项工作中，组织芯片被用来观察VASH2及其在癌症治疗中的可能作用。结果表明，VASH2在肝细胞癌组织中高表达，且与肿瘤分化程度显著相关。为了进一步研究VASH2与抗癌药物联合作用于肝癌细胞的疗效和机制，我们稳定地建立了VASH2高表达和基因敲除细胞系。我们发现VASH2可以影响CDDP的敏感性，在CDDP作用后，VASH2过表达的细胞具有更高的细胞存活率和更低的凋亡率。我们还观察到，CDDP处理后，VASH2过表达下调野生型p53，并抑制促凋亡蛋白BCL2相关X蛋白(Bax)和裂解caspase-3(CC-3)的表达。相反，VASH2基因的敲除显著抑制了这些效应。在体内化疗敏感性研究中，裸鼠皮下注射肿瘤细胞，每隔3天通过腹腔给药接受顺铂治疗。我们发现，VASH2基因敲除显著抑制了肿瘤的生长，增强了顺铂的毒性和肿瘤细胞的凋亡。Western印迹分析显示，VASH2表达下调的肿瘤细胞野生型P53、Bax和CC-3的表达高于对照细胞。总之，我们的结果提示了VASH2在肝癌细胞对顺铂耐药中的新作用，并提示VASH2可能是一个有前途的抗癌靶点。
Hepatocellular carcinoma (HCC) is a prevalent problem worldwide. Chemotherapy, especially cisplatin (CDDP)-based systemic chemotherapy, is the best option for advanced liver cancer. However, CDDP resistance is becoming common and hindering the clinical application of CDDP. Meanwhile, no consensus has been reached regarding the chemotherapeutic use of vasohibin 2 (VASH2), which promotes the angiogenesis and proliferation of cancer cells. In this work, a tissue microarray was used to observe VASH2 and its possible role in cancer treatment. Results showed that VASH2 was highly expressed in HCC tissues and was significantly correlated with cancer differentiation. To further investigate the efficacy and mechanism of the combination of VASH2 with anti-cancer drugs in liver cancer cells, we stably built VASH2 overexpression and knockdown cell lines. We found that VASH2 can influence the CDDP sensitivity and that the cell overexpression of VASH2 had a higher cell viability and lower apoptosis rate after CDDP exposure. We also observed that VASH2 overexpression downregulated wild-type p53, as well as suppressed the expression of the pro-apoptotic protein BCL2-associated X protein (Bax) and cleaved caspase-3 (CC-3) after treatment by CDDP. Conversely, the knockdown of VASH2 significantly inhibited these effects. In an in vivo chemosensitivity study, nude mice were subcutaneously injected with tumor cells and received CDDP treatment through intraperitoneal administration every 3 days. We found that VASH2 knockdown markedly limited the tumor growth and enhanced the CDDP toxicity and apoptosis of tumor cells. Western blot analysis revealed that tumor cells with downregulated VASH2 had a higher expression of wild-type p53, Bax, and CC-3 than control cells. Overall, our results indicated the novel roles of VASH2 in the chemoresistance of hepatocarcinoma cells to CDDP and suggested that VASH2 may be a promising anticancer target.
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