Abstract 2985: RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling

Abstract

Abstract Basal cell carcinoma (BCCs) and Squamous cell carcinoma (SCCs) are the most common skin neoplasms in the Caucasian population. UVB is considered as the most important etiologic factor for these cancers. The molecular mechanism regulating pathogenesis of these neoplasms is not well defined. Similar to humans Ptch+/−/SKH-1 mice develop both BCCs and SCCs, following chronic UVB-irradiation. We used TaqMan-based Open Array platform containing 796 miRNAs (miRs) to profile miRs associated with BCCs and SCCs. Pathway enrichment analysis was performed using miRPathDB databases at https://mpd.bioinf.uni-sb.de/. 81 miRNAs were differentially expressed in BCCs, of which 54 miRs had cumulative frequency of greater than 1 (FC>1) and 78 miRs were differentially expressed in SCCs, out of which 20 miRs had FC>1. miR-721 was highly induced (123.75 fold, P<0.0430) in BCCs followed by miR-2182, miR-21, miR-451, miR-124a, and miR-685 while downmodulated miRs includes miR-1, miR-133a, miR-133b, and miR-196b. Likewise, miR-21 had maximum fold induction (45.94, P<0.007) in SCCs followed by miR-2182, miR-685, miR-1938, miR-2138, and miR-451 while miR-196b, miR196c, and miR-1 were downmodulated. Kegg pathways analysis revealed that altered miRs belong to Hepatitis B, HIF-1, FoxO, chemokine, adipocytokine, NFκB, cholinergic and TLR signaling pathways. WikiPathway database showed alterations in miRs associated with neovascularization process, Notch Signaling, Pregnane X receptor, α6β4, and BDNF-TrkB signaling. To further investigate the importance of pathways associated with tumor progression, we profiled miRs in residual BCCs and SCCs procured from UAB30 treatment groups. The chemopreventive agent UAB30 is an RXR agonist. In BCCs, UAB30 treatment significantly downmodulated UVB-upregulated miRs. These miRs includes miR-210, miR-546, miR-324-3p, miR-706 and miR-1898. However, UAB30 treatment significantly upregulates miR-380-5p which was downmodulated by UVB-alone. These miRs were involved in immune regulation, Fanconi anemia pathways, FoxO signaling, prostate cancer and p53 signaling. In SCCs, UAB30 treatment significantly reversed the expression of various miRs which were downmodulated by UVB. These miRs were miR-24, miR-26a, miR-30c, miR-328, miR-30b, miR-495 and miR-2100. The expression of miR-21a-3p was downmodulated by UAB30 in SCCs of UVB-exposed group relative to SCCs of untreated but UVB-exposed group. These miRs belong to pathways involved in cell cycle progression, p53 signaling, viral carcinogenesis, Hepatitis B, Melanoma, Prostate cancer, FoxO and PI3K-AKT signaling. In summary, this profiling of miRs in UVB-induced BCC and SCC represents the underlying epigenetic mechanisms that regulate various signaling pathways in these cancers. Our data also show the critical role of miRs responsive to UAB30 treatment in cancer chemoprevention. Citation Format: Mahendra P. Kashyap, Rajesh Sinha, Craig A. Elmets, Venkatram R. Atigadda, Mohammad Athar. RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2985.