J Cancer 2020; 11(20):6070-6080. doi:10.7150/jca.44367

Research Paper

ZIC2 promotes cancer stem cell traits via up-regulating OCT4 expression in lung adenocarcinoma cells

Wang Wei-Hua1*, Zhou Ning1*, Chen Qian2✉, Jiang Dao-Wen1✉

1. Department of thoracic surgery, Minhang Hospital, Fudan University, Shanghai 201100, China.
2. Department of general surgery, Minhang Hospital, Fudan University, Shanghai 201100, China.
*These authors contributed equally to this manuscript.

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Citation:
Wei-Hua W, Ning Z, Qian C, Dao-Wen J. ZIC2 promotes cancer stem cell traits via up-regulating OCT4 expression in lung adenocarcinoma cells. J Cancer 2020; 11(20):6070-6080. doi:10.7150/jca.44367. Available from https://www.jcancer.org/v11p6070.htm

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Abstract

Background: Accumulating evidence has revealed the importance of cancer stem cells (CSCs) in self-renewal and chemoresistance. Previous studies reported high expression of ZIC2 was closely associated with tumorigenesis and CSC traits. However, the role of ZIC2 as a crucial factor for regulating CSC properties in lung adenocarcinoma (LAC) remains elusive.

Methods: RT-PCR and WB assay were employed to assess ZIC2 expression in 20 LAC tumor tissues and the matched non-cancerous tissues. The role of ZIC2 in LAC CSC were analyzed by evaluation of CSC-related markers expression and spheroid formation in vitro. Cisplatin and paclitaxel resistance capacities were evaluated by CCK8 assay, colony formation assay, and flow cytometry analysis. Subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features.

Results: High expression of ZIC2 was found in LAC tumor tissues and indicated a poor overall survival in LAC patients. ZIC2 upregulated an array of CSCs-related genes, including EpCAM, OCT4, SOX2, NANOG, C-Myc and Bmi-1. Knockdown of ZIC2 inhibited sphere-forming capacity and decreased cisplatin and paclitaxel resistance. However, overexpression of ZIC2 achieved opposite effects. Mechanically, ZIC2 acts upstream of OCT4 to promote its expression, resulting in enhancement of CSC traits in LAC.

Conclusion: Our results demonstrated that ZIC2 was crucial for promoting CSC traits in LAC cells, and served as a potential biomarker for predicting prognosis. The ZIC2-OCT4 network will facilitate the evaluation of the potential therapeutic efficacy of chemotherapy and predict patient sensitivity to treatment.

Keywords: lung adenocarcinoma, cancer stem cells, ZIC2, OCT4 activation