Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state.
Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state.
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作者：
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
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.
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DOI：
10.1158/1541-7786.mcr-15-0410
发表时间：
2016-04
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Ghaleb AM;Elkarim EA;Bialkowska AB;Yang VW
通讯作者：
Yang VW
影响因子：
2.7
作者：
Ghaleb AM;McConnell BB;Kaestner KH;Yang VW
通讯作者：
Yang VW
分化疗法和终止癌细胞增殖的机制而不会损害正常细胞。
影响因子：
9
作者：
Enane FO;Saunthararajah Y;Korc M
通讯作者：
Korc M
影响因子：
16.6
作者：
Grinat J;Heuberger J;Vidal RO;Goveas N;Kosel F;Berenguer-Llergo A;Kranz A;Wulf-Goldenberg A;Behrens D;Melcher B;Sauer S;Vieth M;Batlle E;Stewart AF;Birchmeier W
通讯作者：
Birchmeier W
影响因子：
5.3
作者：
Evans, Paul M.;Chen, Xi;Liu, Chunming
通讯作者：
Liu, Chunming