Wang Yueqi, Gao Zhihui, Zhang Dexiang, Bo Xiaobo, Wang Yaojie, Wang Jiwen, Shen Sheng, Liu Han, Suo Tao, Pan Hongtao, Ai Zhilong, Liu Houbao
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Subei People's Hospital, Yangzhou, Jiangsu Province, China.
Oncotarget. 2017 Feb 28;8(9):15775-15788. doi: 10.18632/oncotarget.15005.
Cholangiocarcinoma is a rare, but highly fatal malignancy. However, the intrinsic mechanism involved in its tumorigenesis remains obscure. An urgent need remains for a promising target for cholangiocarcinoma biological therapies. Based on comparative proteomical technologies, we found 253 and 231 different spots in gallbladder tumor cell lines and cholangiocarcinoma cell lines, respectively, relative to non-malignant cells. Using Mass Spectrometry (MS) and database searching, we chose seven differentially expressed proteins. High Stathmin expression was found in both cholangiocarcinoma and gallbladder carcinoma cells. Stathmin expression was validated using immunohistochemistry and western blot in cholangiocarcinoma tissue samples and peritumoral tissue. It was further revealed that high Stathmin expression was associated with the repression of staurosporine-induced apoptosis in the cholangiocarcinoma cell. Moreover, we found that Stathmin promoted cancer cell proliferation and inhibited its apoptosis through protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling. Integrin, β1 appears to serve as a partner of Stathmin induction of ERK and Akt signaling by inhibiting apoptosis in the cholangiocarcinoma cell. Understanding the regulation of anti-apoptosis effect by Stathmin might provide new insight into how to overcome therapeutic resistance in cholangiocarcinoma.
胆管癌是一种罕见但极具致命性的恶性肿瘤。然而，其肿瘤发生所涉及的内在机制仍不清楚。迫切需要一个有前景的胆管癌生物治疗靶点。基于比较蛋白质组学技术，相对于非恶性细胞，我们分别在胆囊肿瘤细胞系和胆管癌细胞系中发现了253个和231个不同的蛋白点。通过质谱分析（MS）和数据库检索，我们选择了7种差异表达的蛋白质。在胆管癌和胆囊癌细胞中均发现高表达的Stathmin。利用免疫组织化学和蛋白质印迹法在胆管癌组织样本和瘤周组织中验证了Stathmin的表达。进一步发现，Stathmin高表达与胆管癌细胞中星形孢菌素诱导的凋亡抑制有关。此外，我们发现Stathmin通过蛋白激酶B（Akt）和细胞外信号调节激酶（ERK）信号通路促进癌细胞增殖并抑制其凋亡。整合素β1似乎通过抑制胆管癌细胞凋亡，作为Stathmin诱导ERK和Akt信号通路的协同因子。了解Stathmin对抗凋亡作用的调控机制可能为克服胆管癌治疗耐药性提供新的思路。
