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

Pascale Palassin,Jacqueline Duffour,Nabila Elarouci,Frédéric Bibeau,Stéphan Jalaguier,Sandrine Bonnet,Thibault Mazard,Vincent Cavaillès,Alexandre Ho-Pun-Cheung,Carole Corsini,Paul Roepman,Olivier Buhard,Abdelhay Boulahtouf,Samuel Pyrdziak,Alex Duval,Evelyne Lopez-Crapez,Jean-Sébastien Hoffmann,Marion Lapierre,A Wagner ,Janick Sèlves ,R Stehle ,Carmen Rodrı́guez ,Florence Boissière ,Simon Thézénas ,Audrey Castet‐Nicolas

doi:10.3390/cancers13174449

Abstract

Simple SummaryThe alteration of mismatch repair (MMR) genes leads to microsatellite instability and plays a key role in colorectal cancer (CRC) pathogenesis and prognosis. The transcription factor NRIP1 is involved in intestinal tumorigenesis and is a good prognostic marker in CRC. In this study, we demonstrate that NRIP1 induces MSH2 and MSH6 MMR gene transcription and reduces microsatellite instability. A dominant-negative truncated NRIP1 mutant amplifies the MMR-deficient phenotype and appears as a key player in MSI-driven tumorigenesis since it significantly correlates with a short overall survival of patients with advanced CRC, especially MLH1-deficient ones.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.

Highlights

Colorectal cancer (CRC) is one of the most common cancers worldwide [1]
We found that Nuclear Receptor Interacting Protein 1 (NRIP1) increases MSH2 and MSH6 gene expression, alters microsatellite stability and mutation repair efficiency and modifies their response to cytotoxic drugs
Littermates, Msh2 and Msh6 mRNA levels were lower in the whole small intestine of RIPKO. Mice, whereas they were increased in RIPTg mice (Figure 1A). These effects appeared to be specific because the expression of other mismatch repair (MMR) genes, such as Mlh1, was not affected by

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancers worldwide [1]. Genetic instability, including chromosomal and microsatellite instability (MSI), is a key event in CRC pathogenesis. MSI is observed in 15% of CRC, due to loss of expression of at least one of the genes involved in the mismatch repair (MMR) system implicated in error correction during DNA replication. Within the MMR system, the DNA recognition complex MutSα consists of MSH2-MSH6 heterodimers. MutSα complex binds to the execution complex MutLα (MLH1 and PMS2) to signal the need to carry out excision and re-synthesis of the mismatched DNA [2]. In sporadic MSI CRC, MLH1 gene promoter hypermethylation is the main cause of MMR deficiency (dMMR) [4]. An inherited component is observed in about 25% of CRCs, and this includes Lynch syndrome (LS), which is due to an autosomal dominant heterozygous constitutional mutation in one of the MMR genes [5]

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