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

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.

SUBMITTER: Wei-Hua W

PROVIDER: S-EPMC7477430 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wei-Hua Wang W Ning Zhou Z Qian Chen C Dao-Wen Jiang J

Journal of Cancer 20200819 20

<b>Background:</b> 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. <b>Methods:</b> RT-PCR and WB assay were employed to assess ZIC2 expression in 20 LAC tumor tissues and the matched non-cancerous tissue ...[more]

PMID: 32922547

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Project description:Stem-like cells in solid tumors are purported to contribute to cancer development and poor treatment outcome. The abilities to self-renew, differentiate, and resist anticancer therapies are hallmarks of these rare cells, and steering them into lineage commitment may be one strategy to curb cancer development or progression. Vitamin D is a prohormone that can alter cell growth and differentiation and may induce the differentiation cancer stem-like cells. In this study, octamer-binding transcription factor 4 (OCT4)-positive/Nanog homeobox (Nanog)- positive lung adenocarcinoma stem-like cells (LACSCs) were enriched from spheroid cultured SPC-A1 cells and differentiated by a two-stage induction (TSI) method, which involved knockdown of hypoxia-inducible factor 1-alpha (HIF1?) expression (first stage) followed by sequential induction with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, VD3) and suberoylanilide hydroxamic acid (SAHA) treatment (second stage). The results showed the HIF1?-knockdowned cells displayed diminished cell invasion and clonogenic activities. Moreover, the TSI cells highly expressed tumor suppressor protein p63 (P63) and forkhead box J1 (FOXJ1) and lost stem cell characteristics, including absent expression of OCT4 and Nanog. These cells regained sensitivity to cisplatin in vitro while losing tumorigenic capacity and decreased tumor cell proliferation in vivo. Our results suggest that induced transdifferentiation of LACSCs by vitamin D and SAHA may become novel therapeutic avenue to alter tumor cell phenotypes and improve patient outcome.The development and progression of lung cancer may involve rare population of stem-like cells that have the ability to grow, differentiate, and resist drug treatment. However, current therapeutic strategies have mostly focused on tumor characteristics and neglected the potential source of cells that may contribute to poor clinical outcome. We generated lung adenocarcinoma stem-like cells from spheroid culture and induced their transdifferentiation by a two-stage method of knocking down HIF1? expression followed by vitamin Dand suberoylanilide hydroxamic acid (VD3/SAHA) treatment. We observed the induced cells lost stem-like characteristics, regained sensitivity to cisplatin, and displayed reduced tumorigenic capacity. These findings suggest that targeting stem-like cells by reverting them to more specialized state may be an approach to treat lung cancer.

Dataset Information

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

Publications

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

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