Mutant p53 down-regulates let-7 by inhibiting p63 and p73 to induce cell migration and invasion

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NCI	sRNA-4

Authors

• M Subramanian
• P Francis
• S Bilke
• X Ling Li
• T Hara
• K.H Vousden
• P.S. Meltzer
• A Lal

Abstract

Majority of p53 mutations in human cancers are missense mutations, some of these mutations result in loss of tumor suppressor activity but also enable mutant p53 to acquire oncogenic functions to promote tumor progression by increasing invasion and metastasis. The most widely accepted mechanism for mutant p53 gain-of-function is by inhibition of the transcription factors p63 and p73. Similar to mutant p53, microRNAs (miRNAs) play pivotal roles in cell migration and invasion. Although wild-type p53 transactivates the expression of select miRNAs including miR-34a, it is not known whether miRNAs are also embedded in the mutant p53 network. Here, using a deep sequencing approach, we found that specific miRNAs were altered in H1299 (p53-/-) cells stably expressing mutant p53 or a control vector. The oncogenic miRNA miR-155 and the tumor suppressor let-7i were the most up- and down-regulated in mutant p53 cells. Knockdown of p63 and/or p73 in empty vector transfected H1299 stable cells down-regulates mature and pri-let-7i whereas silencing mutant p53 restores let-7i expression. These results suggest that mutant p53 suppresses let-7i transcription by inhibiting p63 and/or p73. The results of how mutant p53 is modulating let-7i expression to promote migration and invasion will be presented.

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