Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

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.

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

“…In contrast with a previous study by Dorard et al 25 , which reported that the HSP110 T 17 deletion was observed in 100% of the tested MSI-H colorectal cancer samples with deletion sizes ranging from 3 to 8 bp, 20 cases (12%) showed no deletion, and the deletion sizes ranged from 1 to 7 bp in this study (Figure 3b). When the HSP110wt expression status and HSP110 T 17 deletion size of each MSI-H colorectal cancer were matched, tumors with low expression of HSP110wt (0/1 þ ) were concentrated in the larger deletion sizes group (Z4 bp) (Figure 3c).…”

“…In conclusion, we identified that the decreased expression of HSP110wt, as well as the increased expression of HSP110DE9 from the report of the Duval group 25 could be a marker that indicates better prognostic subgroups in MSI-H colorectal cancers. Together, this study and the previous results of the Duval group indicate that the HSP110 mutation occurred in most MSI-H colorectal cancers, but its prognostic effects varied according to the expression level of wild-type or mutant HSP110.…”

“…As the C-terminus of HSP110wt is truncated in HSP110DE9 because of exon 9 skipping, 25 HSP110wt expression can be specifically detected using C-terminus-targeting antibodies. Although it seems difficult to develop HSP110DE9-specific antibodies because of overlapping between the whole structure of HSP110DE9 and the partial structure of HSP110wt, 25 it is expected that HSP110DE9-specific immunohistochemistry can produce clearer and more correct results as a prognostic marker in MSI-H colorectal cancer. However, according to our results, HSP110wt-specific immunohistochemistry was successfully validated as a method to identify prognostic subgroups in MSI-H colorectal cancer.…”

“…The main hypothetical concept of this immunohistochemistry study is illustrated in Figure 2. Based on the earlier findings of the Duval group, 25 it was predicted that HSP110wt expression would be inversely correlated with HSP110DE9 expression, HSP110 T 17 deletion size and prognosis (Figure 2). The frequency of each of the four scores is shown in Figure 3a.…”

“…18,19 In addition, the Beta2-microglobulin mutation, myosin 1A expression level, SMAD4 expression level and LINE-1 methylation level have been suggested to be associated with prognosis in patients with MSI-H colorectal cancer, [20][21][22][23][24] but more investigations are needed to establish molecular prognostic markers specific to MSI-H colorectal cancer. Recently, Dorard et al 25 published data indicating the mutant expression of heat shock protein 110 kDa (HSP110, also known as HSP105) as a prognostic and predictive marker in MSI-H colorectal cancer. This mutant HSP110, also expressed as HSP110DE9 because of its exon 9 skipping, may have an important role in sensitizing colorectal cancer cells to chemotherapy, and its overexpression may contribute to a better prognosis for MSI-H colorectal cancer.…”