1. 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
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Palassin, Pascale, Lapierre, Marion, Pyrdziak, Samuel, Wagner, Antoine, Stehle, Régine, Corsini, Carole, Duffour, Jacqueline, Bonnet, Sandrine, Boulahtouf, Abdelhay, Rodriguez, Carmen, Ho-Puncheun, Alexandre, Lopez-Crapez, Evelyne, Boissière-Michot, Florence, Bibeau, Frédéric, Thezenas, Simon, Elarouci, Nabila, Selves, Janick, Hoffmann, Jean-Sébastien, Roepman, Paul, Mazard, Thibault, Buhard, Olivier, Duval, Alex, Jalaguier, Stéphan, Cavaillès, Vincent, Castet-Nicolas, Audrey, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Agendia NV, Agendia NV, Amsterdam, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Formation et de Recherche des Sciences Pharmaceutiques et Biologiques, Ligue Nationale Contre le Cancer (LNCC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gibier, François
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congenital, hereditary, and neonatal diseases and abnormalities ,[SDV]Life Sciences [q-bio] ,nutritional and metabolic diseases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,colorectal cancer ,Article ,digestive system diseases ,[SDV] Life Sciences [q-bio] ,patient prognosis ,mismatch repair ,microsatellite instability ,neoplasms ,RIP140/NRIP1 ,RC254-282 - Abstract
Simple Summary The 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. 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.
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- 2021