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

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

doi:10.3390/cancers13174449

Cited by 5 publications

(11 citation statements)

References 50 publications

(71 reference statements)

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“…We recently demonstrated that RIP140 plays an important role in controlling microsatellite instability through the regulation of MSH2 and MSH6 genes [ 26 ] . To compare the correlation between RIP140 and POLK gene expression in microsatellite stable (MSS) and instable (MSI) CRC tumors, we reanalyzed a transcriptomic dataset from 396 human CRC with both types of tumors [ 34 ] .…”

Section: Resultsmentioning

confidence: 99%

“…In MSI CRC, we identified a frameshift mutation in the RIP140 coding sequence [ 26 ] . This mutation (called RIP MSI ) generated a truncated protein which impaired the biological activity of the RIP140 protein.…”

Section: Resultsmentioning

confidence: 99%

“…We previously described that the transcription factor RIP140 was a key factor in the regulation of intestinal homeostasis and tumorigenesis [ 24 ] . We also showed that RIP140 could be involved in microsatellite stability through the regulation of MSH2/MSH6 gene expression [ 26 ] .…”

Section: Discussionmentioning

confidence: 99%

“…Mouse embryonic fibroblasts (MEFs) derived from wild-type or RIPKO mice previously described [ 24 ] , and the stably transfected MEFs described by Palassin et al [ 26 ] were grown in DMEM-F12 medium supplemented with 10% FCS, 100 U/mL penicillin, 100 mg/mL streptomycin, and 100 mg/mL sodium pyruvate, with 40 µg/mL puromycine for selection of stably transfected cells. HCT116, RKO, SW480, and HT29 human colon cancer cells were grown as previously described [ 26 ] and stably transfected with the empty pEGFP vector (Clontech®) or with the same vector containing the full-length human RIP140 cDNA. The SW620 human cell line was grown identically.…”

Section: Methodsmentioning

confidence: 99%

“…In sporadic CRC, RIP140 mRNA and protein levels significantly correlated with better overall survival of patients and were identified as good prognosis markers [ 24 ] . More recently, we demonstrated that RIP140 was acting as a transcriptional regulator of MSH2 and MSH6 gene expression and was involved in the regulation of the MSI and hypermutator phenotype in CRC cells [ 26 ] . Interestingly, a frameshift mutation in the RIP140 coding sequence identified in MSI CRC tumors exhibits a dominant negative activity and correlates with shorter overall survival of patients with advanced CRC.…”

Section: Introductionmentioning

confidence: 99%

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RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

Palassin¹,

Lapierre²,

Bonnet³

et al. 2022

Cancer Drug Resist

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Aim: The transcription factor RIP140 (receptor interacting protein of 140 kDa) is involved in intestinal tumorigenesis. It plays a role in the control of microsatellite instability (MSI), through the regulation of MSH2 and MSH6 gene expression. The aim of this study was to explore its effect on the expression of POLK, the gene encoding the specialized translesion synthesis (TLS) DNA polymerase κ known to perform accurate DNA synthesis at microsatellites. Methods: Different mouse models and engineered human colorectal cancer (CRC) cell lines were used to analyze by RT-qPCR, while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression. Published DNA microarray datasets were reanalyzed. The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined. Results: RIP140 positively regulates, at the transcriptional level, the expression of the POLK gene, and this effect involves, at least partly, the p53 tumor suppressor. In different cohorts of CRC biopsies (with or without MSI), a strong positive correlation was observed between RIP140 and POLK gene expression. In connection with its effect on POLK levels and the TLS function of this polymerase, the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene. Finally, the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK, thus strengthening the functional link between the two genes in human CRC. Conclusion: The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability, and more generally to the control of genome integrity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

Palassin¹,

Lapierre²,

Bonnet³

et al. 2022

Cancer Drug Resist

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RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells

Sfeir,

Kajdan,

Jalaguier

et al. 2024

Molecular Oncology

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The transcription factor receptor‐interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)‐mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

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RIP140 regulates HES1 oscillatory expression and mitogenic activity in colon cancer cells

Sfeir

Kajdan

Jalaguier

et al. 2023

Preprint

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BackgroundThe transcription factor RIP140 (Receptor Interacting Protein of 140 kDa) regulates intestinal homeostasis and tumorigenesis through the Wnt signaling. In this study, we have investigated its effect on the Notch/HES1 signaling pathway.MethodsThe impact on HES1 expression and activity was evaluated in colorectal cancer (CRC) cell lines and in transgenic mice, invalidated or not for theRip140gene in the intestinal epithelium. A tumor microarray and transcriptomic data sets were used to investigate RIP140 and HES1 expression in relation with patient survival. Statistical comparisons were performed with Mann-Whitney or Kruskal-Wallis orChi2tests.ResultsIn CRC cells, RIP140 positively regulatedHES1gene expression at the transcriptional level via an RBPJ/NICD-mediated mechanism. In support of thesein vitrodata, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, analyzed by immunohistochemistry, thus supporting the positive regulation ofHES1gene expression by RIP140.Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition ofHES1gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140.ConclusionsOur data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway with a dual effect onHES1gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

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

Cited by 5 publications

References 50 publications

RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells

RIP140 regulates HES1 oscillatory expression and mitogenic activity in colon cancer cells

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