Novel roles for MLH3 deficiency and TLE6-Like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression

Peng Chieh Chen, Mari Kuraguchi, John Velasquez, Yuxun Wang, Kan Yang, Robert Edwards, Dan Gillen, Winfried Edelmann, Raju Kucherlapati, Steven M. Lipkin

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

DNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated Mlh3-/-;Apc1638N and Mlh3 -/-;Pms2-/-;Apc1638N (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in Mlh1-/-;Apc1638N mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression.

Original languageEnglish (US)
Article numbere1000092
JournalPLoS Genetics
Volume4
Issue number6
DOIs
StatePublished - Jun 2008

Fingerprint

DNA Mismatch Repair
tumor
carcinogenesis
repair
amplification
Carcinogenesis
DNA
neoplasms
colorectal neoplasms
Neoplasms
mutation
cancer
frameshift mutation
mice
Colorectal Neoplasms
transcriptional activation
cell movement
Transducin
cell proliferation
Frameshift Mutation

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Novel roles for MLH3 deficiency and TLE6-Like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. / Chen, Peng Chieh; Kuraguchi, Mari; Velasquez, John; Wang, Yuxun; Yang, Kan; Edwards, Robert; Gillen, Dan; Edelmann, Winfried; Kucherlapati, Raju; Lipkin, Steven M.

In: PLoS Genetics, Vol. 4, No. 6, e1000092, 06.2008.

Research output: Contribution to journalArticle

Chen, PC, Kuraguchi, M, Velasquez, J, Wang, Y, Yang, K, Edwards, R, Gillen, D, Edelmann, W, Kucherlapati, R & Lipkin, SM 2008, 'Novel roles for MLH3 deficiency and TLE6-Like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression', PLoS Genetics, vol. 4, no. 6, e1000092. https://doi.org/10.1371/journal.pgen.1000092
Chen, Peng Chieh ; Kuraguchi, Mari ; Velasquez, John ; Wang, Yuxun ; Yang, Kan ; Edwards, Robert ; Gillen, Dan ; Edelmann, Winfried ; Kucherlapati, Raju ; Lipkin, Steven M. / Novel roles for MLH3 deficiency and TLE6-Like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. In: PLoS Genetics. 2008 ; Vol. 4, No. 6.
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