Due to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the NISCH promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients' tissues. NISCH expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high NISCH expression predicted worse prognosis for males. Gene set enrichment analysis suggested signi cant sex-related disparities in predicted association of NISCH with several signaling pathways, as well as with different tumor immune in ltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that ne-tuning of the pathways it regulates is sex-dependent.
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.
Nischarin is a scaffolding protein involved in the regulation of cell cytoskeletal organization and metabolic homeostasis. In breast and ovarian cancers, nischarin has been demonstrated to have tumor suppressive functions. We have found that nischarin was expressed in both the epithelial and stromal compartments of the PDAC patient tissue, in cancer cell lines and patient-derived stellate cells. Of interest, nischarin is a functional imidazoline 1 receptor for which there are several FDA-approved agonists used for treatment of hypertension. The aim of this study was to examine the effects of nischarin agonists on PDAC cancer cells and stellate cells, separately and in co-culture and determine the potential for their repurposing in treatment of PDAC. mRNA sequencing revealed that cancer cell treatment with nischarin agonist rilmenidine induced transcriptional changes associated with regulation of cell adhesion, EMT and vesicular transport. In vitro, rilmenidine treatment of cancer cells decreased their migration and invasion potential and treatment of stellate cells decreased the αSMA-positive fraction. Treatment of cancer cell-stellate cell co-cultures decreased the production of pro-inflammatory cytokines IL-6, IL-8 and CCL-2, known drivers of the metastatic progression. Ultimately, rilmenidine treatment decreased PDAC cell invasion in Tg(fli1: EGFP) zebrafish model. Taken together, nischarin agonist rilmenidine has a potential for limiting the processes involved in PDAC metastatic cascade and may be a good candidate for drug repurposing. Citation Format: Jelena Grahovac, Kristina Živić, Marijana Pavlović, Marija Ostojić, Ana Đurić, Tatjana Srdić-Rajić, Aleksandar Pavić, Danijel Galun. Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2476.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.