J Cancer 2019; 10(22):5557-5566. doi:10.7150/jca.35380

Research Paper

Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway

Meiling Ji1*, Wenxiang Li1*, Guodong He1*, Dexiang Zhu1*, Shixu Lv2, Wentao Tang1, Mi Jian1, Peng Zheng1, Liangliang Yang1, Zhipeng Qi3, Yihao Mao1, Li Ren1, Yunshi Zhong3, Yongjiu Tu4, Ye Wei1✉, Jianmin Xu1✉

1. Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China
2. Department of Surgical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
3. Departmentof Endoscopic Center, Zhongshan Hospital Fudan University, Shanghai, China
4. Surgical Department, Hospital 174 of PLA, Xiamen, Fujian, China
* Meiling Ji, Wenxiang Li, Guodong He, Dexiang Zhu contributed equally to this work.

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Citation:
Ji M, Li W, He G, Zhu D, Lv S, Tang W, Jian M, Zheng P, Yang L, Qi Z, Mao Y, Ren L, Zhong Y, Tu Y, Wei Y, Xu J. Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway. J Cancer 2019; 10(22):5557-5566. doi:10.7150/jca.35380. Available from http://www.jcancer.org/v10p5557.htm

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Abstract

Liver metastasis is the main reason for the poor prognosis of colorectal cancer, and identifying molecules involved in liver metastases of colorectal cancer may provide effective therapeutic targets. Zinc-α2-glycoprotein 1(AZGP1) is a candidate biomarker for diagnosis and prognosis in cancer. However, its function and molecular mechanism in metastatic colorectal cancer remains largely unknown. We previously found that up-regulated AZGP1 promotes proliferation, migration and invasion in colorectal cancer cell line, here we elucidated the mechanism of AZGP1 in regulating metastasis. In this article, we found that AZGP1 was also highly expressed in colorectal cancer tissues with liver metastasis relative to those without metastasis, and abundant expression of AZGP1 was associated with poor prognosis, also, AZGP1 down regulation prevented cell metastasis in vivo and in vitro. We further demonstrated that AZGP1 promotes metastasis by regulating the epithelial-mesenchymal transition (EMT) and associating with molecules involved in the focal adhesion pathway, including the adhesion molecule FLNA, which acts as an important protein interactor. More importantly, AZGP1 down regulation inhibited the phosphorylation of FLNA mediated by the restrain of PAK2 kinase, thereby inducing its proteolysis and subsequently affecting its subcellular localization, where it regulates the EMT and promotes metastasis. Collectively, these results highlight AZGP1 as a new and promising therapeutic molecule for liver metastatic colorectal cancer.

Keywords: AZGP1, colorectal cancer, FLNA, metastasis, adhesion pathway