MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma

Edit B. Olasz, Lauren N. Seline, Ashley M. Schock, Nathan E. Duncan, Argelia Lopez, Jozef Lazar, Michael J. Flister, Yan Lu, Pengyuan Liu, Olayemi Sokumbi, Catherine A. Harwood, Charlotte M. Proby, Marcy Neuburg, Zelmira Lazarova (Lead / Corresponding author)

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    Abstract

    Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness.

    Original languageEnglish
    Article numbere0125412
    Pages (from-to)1-16
    Number of pages16
    JournalPLoS ONE
    Volume10
    Issue number5
    DOIs
    Publication statusPublished - 4 May 2015

    Keywords

    • Carcinoma, Squamous Cell
    • Cell Line, Tumor
    • Cell Movement
    • Cell Proliferation
    • DNA-Binding Proteins
    • Down-Regulation
    • Gene Expression Profiling
    • Gene Expression Regulation, Neoplastic
    • Humans
    • Immunohistochemistry
    • MicroRNAs
    • Neoplasm Invasiveness
    • Skin Neoplasms
    • Transfection
    • Tumor Suppressor Proteins
    • Journal Article
    • Research Support, Non-U.S. Gov't

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    Cite this

    Olasz, E. B., Seline, L. N., Schock, A. M., Duncan, N. E., Lopez, A., Lazar, J., Flister, M. J., Lu, Y., Liu, P., Sokumbi, O., Harwood, C. A., Proby, C. M., Neuburg, M., & Lazarova, Z. (2015). MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma. PLoS ONE, 10(5), 1-16. [e0125412]. https://doi.org/10.1371/journal.pone.0125412