Warangkana Lohcharoenkal

MicroRNA-31 Is Overexpressed in Cutaneous Squamous Cell Carcinoma and Regulates Cell Motility and Colony Formation Ability of Tumor Cells

Cutaneous squamous cell carcinoma (cSCC) is a malignancy of epidermal keratinocytes that is responsible for approximately 20% of skin cancer-related death yearly. We have previously compared the microRNA (miRNA) expression profile of cSCC to healthy skin and found the dysregulation of miRNAs in human cSCC. In this study we show that miR-31 is overexpressed in cSCC (n = 68) compared to healthy skin (n = 34) and precancerous skin lesions (actinic keratosis, n = 12). LNA in situ hybridization revealed that miR-31 was specifically up-regulated in tumor cells. Mechanistic studies of inhibition of endogenous miR-31 in human metastatic cSCC cells revealed suppressed migration, invasion and colony forming ability, whereas overexpression of miR-31 induced these phenotypes. These results indicate that miR-31 regulates cancer-associated phenotypes of cSCC and identify miR-31 as a potential target for cSCC treatment.

MicroRNA-146a suppresses IL-17–mediated skin inflammation and is genetically associated with psoriasis

Background: Psoriasis is an immune‐mediated inflammatory skin disease with a strong genetic background in which activation of IL‐17 signaling is central in the pathogenesis. Little has been known about the role of noncoding RNAs, including microRNAs (miRNAs), in predisposition to the disease. Objective: We sought to investigate the genetic association of single nucleotide polymorphisms in microRNA‐146a (miR‐146a) to psoriasis and to explore its function in the initiation and resolution of the disease. Methods: Analysis of the genetic association of miR‐146a rs2910164 and psoriasis was carried out on 1546 patients with psoriasis and 1526 control subjects. The role of miR‐146a in patients with psoriasis was assessed by using miR‐146a−/− mice in conjunction with the imiquimod‐induced mouse model of psoriasis. The severity of psoriasis‐like skin inflammation was evaluated at morphologic, histologic, and molecular levels. miR‐146a was ectopically overexpressed and inhibited in keratinocytes treated with IL‐17. Synthetic miR‐146a was injected intradermally into mice. Results: Here we report protective association of a functional polymorphism in the miR‐146a precursor (rs2910164). Genetic deficiency in miR‐146a leads to earlier onset and exacerbated pathology of skin inflammation, with increased expression of IL‐17–induced keratinocyte‐derived inflammatory mediators, epidermal hyperproliferation, and increased neutrophil infiltration. Moreover, miR‐146a–deficient mice do not resolve inflammation after discontinuation of imiquimod challenge. The overexpression of miR‐146a suppressed, whereas its inhibition enhanced, IL‐17–driven inflammation in keratinocytes. Functionally, miR‐146a impairs the neutrophil chemoattractant capacity of keratinocytes. Finally, delivery of miR‐146a mimics into the skin leads to amelioration of psoriasiform skin inflammation, decreased epidermal proliferation, and neutrophil infiltration. Conclusions: Our results define a crucial role for miR‐146a in modulating IL‐17–driven inflammation in the skin.

Abstract 1098: MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in man and accounts for approximately 20% of non-melanoma skin cancers. Although most cSCC are benign, poorly differentiated cSCC poses a significant risk of metastasis and death. To date, little is known about the difference in molecular background between low-risk and high risk cSCC. MicroRNAs are short regulatory RNAs that can regulate gene expression and cellular functions. Here we demonstrate for the first time that the expression of miR-203 in cSCC correlates with tumor differentiation grade, being down-regulated in poorly but not in moderately or well differentiated cSCC. In vitro, miR-203 causes a delay in G1 to S phase transition and suppresses cell proliferation in human cSCC cells. Furthermore, miR-203 suppresses scratch-wound closure, cell migration, cell invasion, colony forming ability and angiogenesis-inducing capacity of cSCC cells. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 reveals dramatic changes in gene networks related to carcinogenesis, with significant suppression of genes with known oncogenic functions (e.g. PCNA, EGFR, HGF). Using luciferase reporter assays and site-specific mutagenesis, we identify c-MYC as a novel target of miR-203. Highlighting the importance of c-MYC within miR-203-regulated gene network, in rescue experiments overexpression of c-MYC reverses miR-203-induced growth arrest in cSCC. In vivo, overexpression of miR-203 in cSCC cell lines result in reduced xenograft tumor volume and decreased vessel density. Together our data show that miR-203 acts a tumor suppressor in cSCC, affecting several oncogenic and angiogenic mechanisms. Importantly, its restoration may provide therapeutic benefit in particular in poorly differentiated cSCC. Citation Format: Warangkana Lohcharoenkal, Masako Harada, Jakob Loven, Florian Meisgen, Ning Xu Landen, Lingyun Zhang, Liisa Nissinen, Veli-Matti Kahari, Mona Stahle, Eniko Sonkoly, Dan Grander, Marie Arsenian-Henriksson, Andor Pivarcsi. MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1098.