miR-181a Promotes Multiple Protumorigenic Functions by Targeting TGFβR3

• Published in: Journal of investigative dermatology Vol. 142; no. 7; pp. 1956 - 1965.e2
• Main Authors: Chitsazzadeh, Vida, Nguyen, Tran N., de Mingo Pulido, Alvaro, Bittencourt, Bruna B., Du, Lili, Adelmann, Charles H., Ortiz Rivera, Ivannie, Nguyen, Kimberly A., Guerra, Leah D., Davis, Andrew, Napoli, Marco, Ma, Wencai, Davis, Richard Eric, Rajapakshe, Kimal, Coarfa, Cristian, Flores, Elsa R., Tsai, Kenneth Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2022
• Subjects: 3' Untranslated Regions - genetics; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation - genetics; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs - genetics; Proteoglycans - genetics; Receptors, Transforming Growth Factor beta - genetics; Skin Neoplasms - pathology; SCC; NHEK; shRNA; OE; 3′-UTR; KC; miRNA; EMT; WT; cSCC
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1016/j.jid.2021.09.040

Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and has a well-defined progression sequence from precancerous actinic keratosis to invasive cSCC. To identify targets for chemoprevention, we previously reported a cross-species analysis to identify the transcriptional drivers of cSCC development and identified miR-181a as a potential oncomiR. We show that the upregulation of miR-181a promotes multiple protumorigenic properties by targeting an understudied component of TGFβ signaling, TGFβR3. miR-181a and TGFβR3 are upregulated and downregulated, respectively, in cSCC. miR-181a overexpression (OE) and TGFβR3 knockdown (KD) significantly suppresses UV-induced apoptosis in HaCaT cells and in primary normal human epidermal keratinocytes. In addition, OE of miR-181a or KD of TGFβR3 by short hairpin RNA enhances anchorage-independent survival. miR-181a OE or TGFβR3 KD enhances cellular migration and invasion and upregulation of epithelial‒mesenchymal transition markers. Luciferase reporter assays demonstrate that miR-181a directly targets the 3′-untranslated region of TGFβR3. miR-181a upregulates phosphorylated SMAD3 levels after TGFβ2 administration and results in elevated SNAIL and SLUG expression. Finally, we confirm in vivo that miR-181a inhibition compromises tumor growth. Importantly, these phenotypes can be reversed with TGFβR3 OE or KD in the context of miR-181a OE or KD, respectively, further highlighting the physiologic relevance of this regulation in cSCC.