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

Olasz EB, Seline LN, Schock AM, Duncan NE, Lopez A, Lazar J, Flister MJ, Lu Y, Liu P, Sokumbi O, Harwood CA, Proby CM, Neuburg M, Lazarova Z - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Differentially expressed miRNAs in human cSCC tissue.A) PCR array analysis of miRNA expression in cSCC tumors from immunocompetent patients (n = 32). B) PCR array analysis miRNA expression in cSCC tumors from organ transplant recipients (n = 11).
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pone.0125412.g001: Differentially expressed miRNAs in human cSCC tissue.A) PCR array analysis of miRNA expression in cSCC tumors from immunocompetent patients (n = 32). B) PCR array analysis miRNA expression in cSCC tumors from organ transplant recipients (n = 11).

Mentions: To test miRNA expression in cSCC, miRNA transcripts were isolated from cSCC samples of 32 IC patients, 11 OTRs patients (total n = 43), and control non-lesional skin samples (n = 15) and analyzed by qRT-PCR miRNA array. Compared with control samples, 4 miRNAs (miR-135b, miR-142-5p, miR-181a, and miR-18a) were significantly upregulated in cSCC from IC patients, whereas 16 were significantly downregulated in IC cSCC samples (Table 1). Two miRNA were significantly upregulated (miR-135b and miR-181a) and 17 were downregulated in cSCC samples from OTR patients (Table 2). Overall, we observed concordant changes in 11 of 26 differentially expressed genes between cSCC samples from IC and OTR patients. Of these genes, miR-135b had the largest difference in cSCC samples from OTR patients (21.5-fold; p<0.0001) and IC patients (13.3-fold; p<0.0001) compared with non-lesional controls (Fig 1A and 1B).


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

Olasz EB, Seline LN, Schock AM, Duncan NE, Lopez A, Lazar J, Flister MJ, Lu Y, Liu P, Sokumbi O, Harwood CA, Proby CM, Neuburg M, Lazarova Z - PLoS ONE (2015)

Differentially expressed miRNAs in human cSCC tissue.A) PCR array analysis of miRNA expression in cSCC tumors from immunocompetent patients (n = 32). B) PCR array analysis miRNA expression in cSCC tumors from organ transplant recipients (n = 11).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418692&req=5

pone.0125412.g001: Differentially expressed miRNAs in human cSCC tissue.A) PCR array analysis of miRNA expression in cSCC tumors from immunocompetent patients (n = 32). B) PCR array analysis miRNA expression in cSCC tumors from organ transplant recipients (n = 11).
Mentions: To test miRNA expression in cSCC, miRNA transcripts were isolated from cSCC samples of 32 IC patients, 11 OTRs patients (total n = 43), and control non-lesional skin samples (n = 15) and analyzed by qRT-PCR miRNA array. Compared with control samples, 4 miRNAs (miR-135b, miR-142-5p, miR-181a, and miR-18a) were significantly upregulated in cSCC from IC patients, whereas 16 were significantly downregulated in IC cSCC samples (Table 1). Two miRNA were significantly upregulated (miR-135b and miR-181a) and 17 were downregulated in cSCC samples from OTR patients (Table 2). Overall, we observed concordant changes in 11 of 26 differentially expressed genes between cSCC samples from IC and OTR patients. Of these genes, miR-135b had the largest difference in cSCC samples from OTR patients (21.5-fold; p<0.0001) and IC patients (13.3-fold; p<0.0001) compared with non-lesional controls (Fig 1A and 1B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus