Pan-cancer analysis reveals that nischarin may not be the universal tumor suppressor

Abstract

Background: Scaffolding protein nischarin (NISCH) was reported to be a tumor suppressor that plays a critical role in breast cancer initiation and progression through regulation of the cytoskeleton dynamics. NISCH expression was reported to be a positive prognostic marker in breast, ovarian and lung cancers. Our group has found that in melanoma, NISCH had positive prognostic value in female patients, but negative in males. These findings opened up a question whether NISCH has tumor type-specific and sex-dependent roles in cancer progression. Results: In this study, we systematically examined in the public databases the prognostic value of NISCH in solid tumors, regulation of its expression and associated signaling pathways with the special emphasis on the possible differences between male and female cancer patients. We found that NISCH expression was decreased in tumor compared to the respective healthy tissues, and that this was most commonly due to the deletions of the NISCH gene and promoter methylation. We also report that, unlike in healthy tissues where it was located in the cytoplasm and at the membrane, NISCH could be observed in the nuclei in tumor tissues. Surprisingly, we found that in many cancer types – colon, liver, skin, ovarian, prostate, and kidney – high NISCH expression was a negative prognostic marker. Gene set enrichment analysis showed that, while there were common pathways associated with NISCH expression in all the examined cancer types, in tumors in which high NISCHexpression was a negative prognostic marker Wnt-Notch-Hedgehog signaling gene networks were enriched. Conclusions: Our study questions the current tumor suppressor status of nischarin and lays a ground for functional studies in a context-dependent manner in cancer.