MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma.
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.
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Edit B
EB
Olasz
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Lauren N
LN
Seline
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Ashley M
AM
Schock
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Nathan E
NE
Duncan
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Argelia
A
Lopez
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Jozef
J
Lazar
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Michael J
MJ
Flister
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Yan
Y
Lu
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Pengyuan
P
Liu
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Olayemi
O
Sokumbi
Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Catherine A
CA
Harwood
Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom.
Charlotte M
CM
Proby
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Marcy
M
Neuburg
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Zelmira
Z
Lazarova
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C118711:LZTS1 protein, human; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins