Thioredoxin-Like Protein 2 Is Overexpressed in Colon Cancer and Promotes Cancer Cell Metastasis by Interaction with Ran
Thioredoxin-Like Protein 2 Is Overexpressed in Colon Cancer and Promotes Cancer Cell Metastasis by Interaction with Ran
复制标题
硫氧还蛋白样蛋白 2 在结肠癌中过度表达，并通过与 ran 相互作用促进癌细胞转移。
DOI：
10.1089/ars.2012.4736
复制
发表时间：
2013-09-20
影响因子：
6.6
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Lu, Yuanyuan;Zhao, Xiaodi;Fan, Daiming
旨在
我们以前的工作确定了硫氧还蛋白样蛋白2（Txl-2）作为与结肠癌相关的单克隆抗体MC 3的靶点，但其潜在的机制仍然知之甚少。Txl-2是一种新的硫氧还蛋白（Trx）和核苷二磷酸激酶家族成员，其被选择性剪接并产生三种不同的Txl-2同种型。本研究探讨了Txl-2在结肠癌中的表达、Txl-2亚型在细胞侵袭和转移中的差异功能以及下游信号传导。
结果
与正常结肠组织相比，结肠癌组织中Txl-2的表达升高，并且与组织学分级和预后高度相关。Txl-2表达的敲低显著抑制癌细胞运动性以及结肠癌细胞的侵袭和转移能力。有趣的是，Txl-2同种型对癌细胞侵袭和转移显示出不同的作用。Txl-2b明显促进细胞的侵袭和转移，Txl-2c明显抑制细胞的侵袭和转移，而Txl-2a对细胞的侵袭和转移无明显影响。此外，Txl-2b和Ran之间的直接相互作用，Ras相关蛋白，酵母双杂交试验和免疫共沉淀法确定。PI 3 K通路是介导Txl-2b诱导肿瘤侵袭和转移的主要通路。
创新
目前的研究为结肠癌的诊断和治疗提供了一种新的生物标志物和靶分子，并为了解选择性剪接在人类癌症中的作用提供了一种新的范式。
结论
我们的研究结果表明Txl-2在结肠癌中表达升高，并且Txl-2b通过与Ran和PI 3 K信号通路相互作用促进细胞侵袭和转移。
AIMS
Our previous work identified thioredoxin-like protein 2 (Txl-2) as the target of the monoclonal antibody MC3 associated with colon cancer, but its underlying mechanisms remain poorly understood. Txl-2, a novel thioredoxin (Trx) and nucleoside diphosphate kinase family member, is alternatively spliced and gives rise to three different Txl-2 isoforms. In this study, Txl-2 expression in colon cancer, differential functions for Txl-2 isoforms in cell invasion and metastasis, and the downstream signaling were investigated.
RESULTS
Txl-2 expression was elevated in colon cancer tissues compared to normal colonic tissues, with a high correlation between the histological grade and prognosis. Knockdown of Txl-2 expression significantly inhibited cancer cell motility, and the invasive and metastatic abilities of colon cancer cells. Interestingly, Txl-2 isoforms showed differential effects on cancer cell invasion and metastasis. Cell invasion and metastasis were significantly promoted by Txl-2b but inhibited by Txl-2c, while no obvious effect was observed for Txl-2a. Furthermore, a direct interaction was identified between Txl-2b and Ran, a Ras-related protein, by yeast two-hybrid assay and coimmunoprecipitation. PI3K pathway was found to be a major pathway mediating Txl-2b induced tumor invasion and metastasis.
INNOVATION
The current study provides a novel biomarker and target molecule for the diagnosis and treatment of colon cancer and provides a novel paradigm to understand how alternative splicing functions in human cancer.
CONCLUSION
Our findings demonstrate an elevated Txl-2 expression in colon cancer and that Txl-2b promotes cell invasion and metastasis through interaction with Ran and PI3K signaling pathway.