Abstract 3696: Determination of the expression patterns and functional implications of microRNAs in ulcerated cutaneous melanoma

Abstract

Abstract Introduction: Ulcerated primary cutaneous melanomas have a poor prognosis and the underlying biology driving this aggressive behavior is largely unexplored. The presence of tumor ulceration at the time of diagnosis of cutaneous melanoma is among the top prognostic indicators for clinical outcome, associated with reduced disease free and overall survival. Thus, ulceration is employed as a clinical and histopathologic criterion for classification of melanomas into a higher tumor stage. microRNAs are small, non-coding RNAs that frequently exhibit dysregulated expression in cancer and can impact tumor biologic behavior via mediation of oncogene or tumor suppressor gene expression. While patterns of microRNA expression in melanoma have been identified that demonstrate their utility as predictive biomarkers of disease progression and metastasis, the microRNA expression profile of cutaneous melanomas with evidence of ulceration has not yet been assessed. Methods: We determined the microRNA expression profile in RNA isolated from formalin-fixed, paraffin-embedded samples of human ulcerated cutaneous melanoma relative non-ulcerated tumors (n=7 each) using the NanoString human miRNA assay platform. The impact of hsa-miR-1469, a novel microRNA demonstrating downregulated expression in ulcerated melanomas in this study, was examined using in vitro functional assays via transfection of melanoma cell lines A375, CHL-1, and MEL39 with a miR-1469 mimic construct. Results: The resultant microRNA expression data demonstrated at least 2-fold change in expression of 9 microRNAs between ulcerated and non-ulcerated melanoma tumors (p <0.01). Among the top differentially expressed miRs were hsa-miR-4286, hsa-miR-4488, and hsa-miR-1469, each with greater than 3.9-fold decreases in expression in the setting of ulceration relative to non-ulcerated tumors (p <0.0029). Restoration of miR-1469 expression resulted in significant reduction in the migration of melanoma tumor cells relative to untransfected and miR-scramble transfected controls in the CHL-1 model (0.41-fold decrease, p = 0.046 and 0.36-fold decrease, p = 0.013, respectively), with similar patterns observed in A375 and MEL39 cell lines. Transfection with a miR-1469 mimic also increased apoptosis in response to fludarabine (2.32-fold increase, p=0.044). Conclusions: The microRNA expression profile generated from this study highlights a subset of microRNAs that may impact disease progression in patients with ulcerated tumors via mediation of tumor cell functions, and provides further molecular characterization of a poorly understood clinical and histopathologic phenotype. Additional studies examining the expression and function of these microRNAs are necessary to determine their utility as predictive biomarkers and role in tumor progression in the setting of ulcerated cutaneous melanoma. Citation Format: Mallory J. DiVincenzo, Casey Ren, Lorena Suarez-Kelly, Maribelle Moufawad, Zoe Barricklow, Paolo Fadda, Lianbo Yu, John H. Howard, Alejandro A. Gru, William E. Carson. Determination of the expression patterns and functional implications of microRNAs in ulcerated cutaneous melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3696.