Theranostics 2022; 12(16):6865-6882. doi:10.7150/thno.76619 This issue Cite

Research Paper

Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state

Xu Yang1,2*, Guilin Li1*, Yuhua Tian3, Xin Wang3, Jiuzhi Xu4, Ruiqi Liu1, Min Deng1, Chunlei Shao1, Yuwei Pan1, Xi Wu1, Mengzhen Li1, Chaowei Zhang5, Rui Liu6, Jun Qin7, Chen Zhang8, Zhanju Liu9, Xin Wu10, Maksim V. Plikus11, Christopher J. Lengner3, Zongheng Zheng5✉, Cong Lv4✉, Zhengquan Yu1✉

1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
2. College of Agriculture and Life Sciences, Ankang University, Ankang, Shaanxi 725000, China.
3. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4. Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
5. Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
6. Clinical Laboratory, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, China.
7. CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
8. Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China.
9. Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
10. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
11. Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
* These authors contributed equally to this work.

Citation:
Yang X, Li G, Tian Y, Wang X, Xu J, Liu R, Deng M, Shao C, Pan Y, Wu X, Li M, Zhang C, Liu R, Qin J, Zhang C, Liu Z, Wu X, Plikus MV, Lengner CJ, Zheng Z, Lv C, Yu Z. Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state. Theranostics 2022; 12(16):6865-6882. doi:10.7150/thno.76619. https://www.thno.org/v12p6865.htm
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Abstract

Graphic abstract

Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression.

Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues. The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids. Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A.

Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis. MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage. Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation.

Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.

Keywords: Colorectal cancer, Cancer stemness, MEX3A, KLF4, Radio-resistance


Citation styles

APA
Yang, X., Li, G., Tian, Y., Wang, X., Xu, J., Liu, R., Deng, M., Shao, C., Pan, Y., Wu, X., Li, M., Zhang, C., Liu, R., Qin, J., Zhang, C., Liu, Z., Wu, X., Plikus, M.V., Lengner, C.J., Zheng, Z., Lv, C., Yu, Z. (2022). Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state. Theranostics, 12(16), 6865-6882. https://doi.org/10.7150/thno.76619.

ACS
Yang, X.; Li, G.; Tian, Y.; Wang, X.; Xu, J.; Liu, R.; Deng, M.; Shao, C.; Pan, Y.; Wu, X.; Li, M.; Zhang, C.; Liu, R.; Qin, J.; Zhang, C.; Liu, Z.; Wu, X.; Plikus, M.V.; Lengner, C.J.; Zheng, Z.; Lv, C.; Yu, Z. Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state. Theranostics 2022, 12 (16), 6865-6882. DOI: 10.7150/thno.76619.

NLM
Yang X, Li G, Tian Y, Wang X, Xu J, Liu R, Deng M, Shao C, Pan Y, Wu X, Li M, Zhang C, Liu R, Qin J, Zhang C, Liu Z, Wu X, Plikus MV, Lengner CJ, Zheng Z, Lv C, Yu Z. Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state. Theranostics 2022; 12(16):6865-6882. doi:10.7150/thno.76619. https://www.thno.org/v12p6865.htm

CSE
Yang X, Li G, Tian Y, Wang X, Xu J, Liu R, Deng M, Shao C, Pan Y, Wu X, Li M, Zhang C, Liu R, Qin J, Zhang C, Liu Z, Wu X, Plikus MV, Lengner CJ, Zheng Z, Lv C, Yu Z. 2022. Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state. Theranostics. 12(16):6865-6882.

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