Abstract
Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.
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Acknowledgements
This work was supported by the Carte d'Identité des Tumeurs (CIT) program (http://cit.ligue-cancer.net/) from the Ligue Nationale Contre le Cancer and by grants from the Fondation de France (Ref. RAF08005DDA to A.D.), the Institut National du Cancer (INCa) (to A.D. and C.G.), the Conseil Regional de Bourgogne (to C.G.) and the European Commission Seventh Framework Programme (SPEDOC 248835 to C.G.). C.G.'s group is known as 'La Ligue Contre le Cancer'. A.C. is a recipient of an INCa fellowship. We thank B. Iacopetta for critical reading of the manuscript. We thank E. Roux, A. Hamman, E. Fourmaux and E. Bergman for their technical assistance.
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C.D. carried out analyses of aberrant splicing events due to MSI in CRC and genetic study of HSP110 in CRC cells and primary tumors. A.d.T. carried out analyses of wild-type and mutated HSP110 chaperone functions in CRC cells. A.C., M.S., A.L., K.W. and O.B. assisted with the mutational screening of primary CRC. J.G. (with G.J. and A.L.J.) carried out mouse work. L.M. carried out the clinical study and survival analyses. H.Z. and E. Tubacher assisted with the in silico search of candidate genes containing intronic microsatellite sequences. V.P.-L., S.K., J.S., G.M., M.-C.E.-G., L.B.-L., C.L., C.T., J.H.L., Y.P., E. Tiret, J.-F.F. and M.-P.G. provided CRC samples and clinical data. A.D. and C.G. conceived the project, coordinated and directed the study, and wrote the manuscript.
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Dorard, C., de Thonel, A., Collura, A. et al. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med 17, 1283–1289 (2011). https://doi.org/10.1038/nm.2457
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DOI: https://doi.org/10.1038/nm.2457
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