Mutant P53 Gain-of-function Induces Epithelial-mesenchymal Transition Through Modulation of the MiR-130b-ZEB1 Axis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2012 Aug 1

PMID 22847613

Citations 189

Authors

P Dong

M Karaayvaz

N Jia

M Kaneuchi

J Hamada

H Watari

S Sudo

J Ju

N Sakuragi

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor gene p53 has been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis by regulating microRNA (miRNA) expression. Here, we report that mutant p53 exerts oncogenic functions and promotes EMT in endometrial cancer (EC) by directly binding to the promoter of miR-130b (a negative regulator of ZEB1) and inhibiting its transcription. We transduced p53 mutants into p53-null EC cells, profiled the miRNA expression by miRNA microarray and identified miR-130b as a potential target of mutant p53. Ectopic expression of p53 mutants repressed the expression of miR-130b and triggered ZEB1-dependent EMT and cancer cell invasion. Loss of an endogenous p53 mutation increased the expression of miR-130b, which resulted in reduced ZEB1 expression and attenuation of the EMT phenotype. Furthermore, re-expression of miR-130b suppressed mutant p53-induced EMT and ZEB1 expression. Importantly, the expression of miR-130 was significantly reduced in EC tissues, and patients with higher expression levels of miR-130b survived longer. These data provide a novel understanding of the roles of p53 gain-of-function mutations in accelerating tumor progression and metastasis through modulation of the miR-130b-ZEB1 axis.

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References

Kim E, Deppert W . Transcriptional activities of mutant p53: when mutations are more than a loss. J Cell Biochem. 2004; 93(5):878-86. DOI: 10.1002/jcb.20271. View

Hurst D, Edmonds M, Scott G, Benz C, Vaidya K, Welch D . Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res. 2009; 69(4):1279-83. PMC: 2754225. DOI: 10.1158/0008-5472.CAN-08-3559. View

Scian M, Stagliano K, Deb D, Ellis M, Carchman E, Das A . Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene. 2004; 23(25):4430-43. DOI: 10.1038/sj.onc.1207553. View

Xi Y, Formentini A, Chien M, Weir D, Russo J, Ju J . Prognostic Values of microRNAs in Colorectal Cancer. Biomark Insights. 2007; 2:113-121. PMC: 2134920. View

Su X, Chakravarti D, Cho M, Liu L, Gi Y, Lin Y . TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010; 467(7318):986-90. PMC: 3055799. DOI: 10.1038/nature09459. View

Clape C, Fritz V, Henriquet C, Apparailly F, Fernandez P, Iborra F . miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice. PLoS One. 2009; 4(10):e7542. PMC: 2763222. DOI: 10.1371/journal.pone.0007542. View

Kang Y, Massague J . Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004; 118(3):277-9. DOI: 10.1016/j.cell.2004.07.011. View

Zalcenstein A, Stambolsky P, Weisz L, Muller M, Wallach D, Goncharov T . Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants. Oncogene. 2003; 22(36):5667-76. DOI: 10.1038/sj.onc.1206724. View

Zhang L, Volinia S, Bonome T, Calin G, Greshock J, Yang N . Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2008; 105(19):7004-9. PMC: 2383982. DOI: 10.1073/pnas.0801615105. View

10.

Yip L, Kelly L, Shuai Y, Armstrong M, Nikiforov Y, Carty S . MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011; 18(7):2035-41. PMC: 4157306. DOI: 10.1245/s10434-011-1733-0. View

11.

Forrest A, Kanamori-Katayama M, Tomaru Y, Lassmann T, Ninomiya N, Takahashi Y . Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation. Leukemia. 2009; 24(2):460-6. DOI: 10.1038/leu.2009.246. View

12.

Zalcenstein A, Weisz L, Stambolsky P, Bar J, Rotter V, Oren M . Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Oncogene. 2005; 25(3):359-69. DOI: 10.1038/sj.onc.1209061. View

13.

Yang C, Cai J, Wang Q, Tang H, Cao J, Wu L . Epigenetic silencing of miR-130b in ovarian cancer promotes the development of multidrug resistance by targeting colony-stimulating factor 1. Gynecol Oncol. 2011; 124(2):325-34. DOI: 10.1016/j.ygyno.2011.10.013. View

14.

Fujisawa T, Watanabe J, Kamata Y, Hamano M, Hata H, Kuramoto H . VEGF expression and its reguration by p53 gene transfection in endometrial carcinoma cells. Hum Cell. 2003; 16(1):47-54. DOI: 10.1111/j.1749-0774.2003.tb00128.x. View

15.

Meng Z, Fu X, Chen X, Zeng S, Tian Y, Jove R . miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology. 2010; 52(6):2148-57. PMC: 3076553. DOI: 10.1002/hep.23915. View

16.

Rivlin N, Brosh R, Oren M, Rotter V . Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer. 2011; 2(4):466-74. PMC: 3135636. DOI: 10.1177/1947601911408889. View

17.

Dong P, Xu Z, Jia N, Li D, Feng Y . Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Mol Cancer. 2009; 8:103. PMC: 2779797. DOI: 10.1186/1476-4598-8-103. View

18.

Xi Y, Shalgi R, Fodstad O, Pilpel Y, Ju J . Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer. Clin Cancer Res. 2006; 12(7 Pt 1):2014-24. DOI: 10.1158/1078-0432.CCR-05-1853. View

19.

Chicas A, Molina P, Bargonetti J . Mutant p53 forms a complex with Sp1 on HIV-LTR DNA. Biochem Biophys Res Commun. 2000; 279(2):383-90. DOI: 10.1006/bbrc.2000.3965. View

20.

Kogan-Sakin I, Tabach Y, Buganim Y, Molchadsky A, Solomon H, Madar S . Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. Cell Death Differ. 2010; 18(2):271-81. PMC: 3131887. DOI: 10.1038/cdd.2010.94. View