A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis

Murugan Subramanian, P. Francis, S. Bilke, X. L. Li, T. Hara, X. Lu, M. F. Jones, R. L. Walker, Y. Zhu, M. Pineda, C. Lee, L. Varanasi, Y. Yang, L. A. Martinez, J. Luo, S. Ambs, S. Sharma, L. M. Wakefield, P. S. Meltzer, A. Lal

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.

Original languageEnglish
Pages (from-to)1094-1104
Number of pages11
JournalOncogene
Volume34
Issue number9
DOIs
Publication statusPublished - 26 Feb 2015
Externally publishedYes

Fingerprint

Gene Regulatory Networks
Cell Movement
Missense Mutation
Neoplasm Metastasis
Neoplasms
Chromatin Immunoprecipitation
Mutant Proteins
Luciferases
MicroRNAs
Oncogenes
Down-Regulation
Breast Neoplasms
Gene Expression
Cell Line
Mutation
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. / Subramanian, Murugan; Francis, P.; Bilke, S.; Li, X. L.; Hara, T.; Lu, X.; Jones, M. F.; Walker, R. L.; Zhu, Y.; Pineda, M.; Lee, C.; Varanasi, L.; Yang, Y.; Martinez, L. A.; Luo, J.; Ambs, S.; Sharma, S.; Wakefield, L. M.; Meltzer, P. S.; Lal, A.

In: Oncogene, Vol. 34, No. 9, 26.02.2015, p. 1094-1104.

Research output: Contribution to journalArticle

Subramanian, M, Francis, P, Bilke, S, Li, XL, Hara, T, Lu, X, Jones, MF, Walker, RL, Zhu, Y, Pineda, M, Lee, C, Varanasi, L, Yang, Y, Martinez, LA, Luo, J, Ambs, S, Sharma, S, Wakefield, LM, Meltzer, PS & Lal, A 2015, 'A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis', Oncogene, vol. 34, no. 9, pp. 1094-1104. https://doi.org/10.1038/onc.2014.46
Subramanian, Murugan ; Francis, P. ; Bilke, S. ; Li, X. L. ; Hara, T. ; Lu, X. ; Jones, M. F. ; Walker, R. L. ; Zhu, Y. ; Pineda, M. ; Lee, C. ; Varanasi, L. ; Yang, Y. ; Martinez, L. A. ; Luo, J. ; Ambs, S. ; Sharma, S. ; Wakefield, L. M. ; Meltzer, P. S. ; Lal, A. / A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. In: Oncogene. 2015 ; Vol. 34, No. 9. pp. 1094-1104.
@article{86e13e5aeb894272b8f31f110893037d,
title = "A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis",
abstract = "Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.",
author = "Murugan Subramanian and P. Francis and S. Bilke and Li, {X. L.} and T. Hara and X. Lu and Jones, {M. F.} and Walker, {R. L.} and Y. Zhu and M. Pineda and C. Lee and L. Varanasi and Y. Yang and Martinez, {L. A.} and J. Luo and S. Ambs and S. Sharma and Wakefield, {L. M.} and Meltzer, {P. S.} and A. Lal",
year = "2015",
month = "2",
day = "26",
doi = "10.1038/onc.2014.46",
language = "English",
volume = "34",
pages = "1094--1104",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis

AU - Subramanian, Murugan

AU - Francis, P.

AU - Bilke, S.

AU - Li, X. L.

AU - Hara, T.

AU - Lu, X.

AU - Jones, M. F.

AU - Walker, R. L.

AU - Zhu, Y.

AU - Pineda, M.

AU - Lee, C.

AU - Varanasi, L.

AU - Yang, Y.

AU - Martinez, L. A.

AU - Luo, J.

AU - Ambs, S.

AU - Sharma, S.

AU - Wakefield, L. M.

AU - Meltzer, P. S.

AU - Lal, A.

PY - 2015/2/26

Y1 - 2015/2/26

N2 - Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.

AB - Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.

UR - http://www.scopus.com/inward/record.url?scp=84938524828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938524828&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.46

DO - 10.1038/onc.2014.46

M3 - Article

C2 - 24662829

AN - SCOPUS:84938524828

VL - 34

SP - 1094

EP - 1104

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 9

ER -