A Truncated NRIP1 Mutant Amplifies Microsatellite Instability of Colorectal Cancer by Regulating MSH2/MSH6 Expression, and Is a Prognostic Marker of Stage III Tumors

Author:

Palassin PascaleORCID,Lapierre MarionORCID,Pyrdziak Samuel,Wagner AntoineORCID,Stehle Régine,Corsini Carole,Duffour Jacqueline,Bonnet Sandrine,Boulahtouf Abdelhay,Rodriguez Carmen,Ho-Pun-Cheung Alexandre,Lopez-Crapez EvelyneORCID,Boissière-Michot FlorenceORCID,Bibeau Frédéric,Thezenas SimonORCID,Elarouci Nabila,Selves Janick,Hoffmann Jean-SébastienORCID,Roepman Paul,Mazard ThibaultORCID,Buhard Olivier,Duval Alex,Jalaguier Stéphan,Cavaillès VincentORCID,Castet-Nicolas Audrey

Abstract

Microsatellite instability (MSI) is related to the alteration of mismatch repair (MMR) genes and plays a key role in colorectal cancer (CRC) pathogenesis. We previously reported that the transcription factor Nuclear Receptor Interacting Protein 1 (NRIP1) is involved in sporadic intestinal tumorigenesis. The aim of this study was to decipher its role in MSI CRC. By using different mouse models and engineered cell lines, we demonstrated that NRIP1 increased MSH2 and MSH6 MMR gene transcription and mRNA/protein levels. In human CRC cells, NRIP1 expression was associated with decreased MSI and the hypermutator phenotype, and with resistance to chemotherapy drugs. Using a cohort of 194 CRC patients, we detected in 22% of the cases a MSI-induced frameshift mutation in the NRIP1 coding sequence. This genetic alteration generates a truncated protein with a dominant negative activity that increased human CRC cell proliferation and impaired the regulation of MSH2 and MSH6 gene expression. Moreover, the NRIP1 mutant correlated with a decreased overall survival of patients with advanced CRC, especially when MLH1-deficient. By decreasing the expression of MSH2 and MSH6 gene expression, the NRIP1 variant may amplify MLH1-dependent CRC progression and behave as a new prognostic marker of advanced MSI CRC.

Funder

Institut National de la Santé et de la Recherche Médicale

Fondation pour la Recherche Médicale

Ligue Régionale contre le Cancer

Institut National Du Cancer

Centre Hospitalier Régional Universitaire de Montpellier

Université de Montpellier

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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