Liu Fangting, Shi Zhehao, Bao Wenming, Zheng Jiuyi, Chen Kaiyu, Lin Zhihui, Song Hao-Nan, Luo Xin, Dong Qiantong, Jiang Lei, Wang Yi, Chen Gang, Chen Xiaolei
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
Exp Cell Res. 2022 Jun 15;415(2):113118. doi: 10.1016/j.yexcr.2022.113118. Epub 2022 Apr 4.
ZIC2 is involved in the tumor progression of many types of cancers. The role of ZIC2 in the metastasis of colorectal cancer and its mechanism are not yet clear. In this study, we found that high ZIC2 expression was not only associated with poor prognosis, relapse-free survival and advanced metastasis but was also an independent prognostic factor in colorectal cancer patients. Moreover, ZIC2 knockdown inhibited cell proliferation, migration and invasion, while the upregulation of ZIC2 had the opposite effect in vitro. ZIC2 overexpression induced TGF-β1 expression and increased Smad3 phosphorylation. The carcinogenic effects of elevated ZIC2 expression can be eliminated by interfering with the TGF-β1 receptor with inhibitors. This further verified the promoting effect of ZIC2 on the TGF-β signaling pathway. In vivo experiments have also confirmed that ZIC2 can promote liver metastases of colorectal cancer. The results suggest that ZIC2 is associated with poor prognosis and relapse-free survival in colorectal cancer patients. Moreover, ZIC2 promoted colorectal cancer progression and metastasis by activating the TGF-β signaling pathway. Hence, ZIC2 is expected to be a new therapeutic and prognostic target for colorectal cancer in the future.
ZIC2参与多种癌症的肿瘤进展。ZIC2在结直肠癌转移中的作用及其机制尚不清楚。在本研究中，我们发现ZIC2高表达不仅与预后不良、无复发生存期和晚期转移相关，而且是结直肠癌患者的独立预后因素。此外，ZIC2基因敲低抑制细胞增殖、迁移和侵袭，而ZIC2上调在体外具有相反作用。ZIC2过表达诱导TGF-β1表达并增加Smad3磷酸化。用抑制剂干扰TGF-β1受体可消除ZIC2表达升高的致癌作用。这进一步证实了ZIC2对TGF-β信号通路的促进作用。体内实验也证实ZIC2可促进结直肠癌肝转移。结果表明，ZIC2与结直肠癌患者的预后不良和无复发生存期相关。此外，ZIC2通过激活TGF-β信号通路促进结直肠癌进展和转移。因此，ZIC2有望成为未来结直肠癌新的治疗和预后靶点。
