MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC

: Warangkana Lohcharoenkal, Masako Harada, Jakob Loven, Florian Meisgen, Ning Xu Landen, Lingyun Zhang, Jan Lapins, Kunal Das Mahapatra, Hao Shi, Liisa Nissinen, Veli-Matti Kähäri, Mona Ståhle, Enikö Sonkoly, Dan Grandér, Marie Arsenian-Henriksson, Andor Pivarcsi

Publisher: ELSEVIER SCIENCE INC

: 2016

: Journal of Investigative Dermatology

: JOURNAL OF INVESTIGATIVE DERMATOLOGY

: J INVEST DERMATOL

: 136

: 12

: 2485

: 2494

: 10

: 0022-202X

DOI: https://doi.org/10.1016/j.jid.2016.06.630

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer and a leading cause of cancer mortality among solid organ transplant recipients. MicroRNAs (miR) are short RNAs that regulate gene expression and cellular functions. Here, we show a negative correlation between miR-203 expression and the differentiation grade of cSCC. Functionally, miR-203 suppressed cell proliferation, cell motility, and the angiogenesis-inducing capacity of cSCC cells in vitro and reduced xenograft tumor volume and angiogenesis in vivo. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 showed dramatic changes in gene networks related to cell cycle and proliferation. Transcription factor enrichment analysis identified c-MYC as a hub of miR-203-induced transcriptomic changes in squamous cell carcinoma. We identified c-MYC as a direct target of miR-203. Overexpression of c-MYC in rescue experiments reversed miR-203einduced growth arrest in cSCC, which highlights the importance of c-MYC within the miR-203eregulated gene network. Together, miR-203 acts as a tumor suppressor in cSCC, and its low expression can be a marker for poorly differentiated tumors. Restoration of miR-203 expression may provide a therapeutic benefit, particularly in poorly differentiated cSCC.