Down-regulation of miR-124/-214 in cutaneous squamous cell carcinoma mediates abnormal cell proliferation via the induction of ERK

Abstract

Squamous cell carcinoma (SCC) is one of the most common skin cancers. Because its potential to recur and metastasize leads to a poor prognosis and significant mortality, it is necessary to develop new early diagnostic tools and new therapeutic approaches. In this study, we found protein levels of ERK1 and ERK2 were increased in SCC cell lines without changing mRNA levels and that ERK1/2 mediates abnormal cell proliferation in these cells. Then, mechanisms underlying the overexpression of ERK1/2 in SCC were investigated focusing on microRNA. We found that miR-214 is the regulator of ERK1, whereas ERK2 is regulated by miR-124 and miR-214. Expression of miR-124 and miR-214 was significantly down-regulated in SCC in vitro and in vivo. Treatment with 5-aza-deoxycytidine and trichostatin A synergistically recovered the miR-124/-214 down-regulation in SCC cell line. However, bisulphite sequencing revealed the methylation status of miR-124/-214 promoter was not increased in the SCC cell line and tumor tissue. Taken together, the down-regulation of miR-124/-214 in SCC is most likely caused, at least in part, by hypermethylation of other promoter regions rather than the miR-124/-214 promoter. Supplementation of these microRNAs in the SCC cell line reduced the abnormal cell proliferation by normalizing ERK1/2 levels. Additionally, serum concentration of miR-124 was correlated with miR-124 expression levels in the tumor tissues and inversely correlated with tumor progression. On the other hand, miR-214 was not detected in the serum. Investigation of the regulatory mechanisms of keratinocyte proliferation by microRNA may lead to develop new biomarkers and treatments using microRNA.

The expression of miR-124 increases in aged skin to cause cell senescence and it decreases in squamous cell carcinoma

“…The current authors previously reported that the miR-124 expression was down-regulated in cutaneous SCC (14), which results in the overexpression of ERK as a target molecule and subsequent cell proliferation. miR-124 was also reported to be involved in the carcinogenesis of various cancers such as glioblastoma, gastric cancer, hepatocellular cancer, breast cancer, and prostate cancer (15)(16)(17)(18)(19), indicating that miR-124 is a key miRNA in carcinogenesis.…”

Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts

“…Accordingly, both the synthesis and the secretion of exosomes seemed to be up-regulated in SSc fibroblasts, which may be mediated by other factors than TGF-1 activation seen in these cells. For example, the treatment of NS fibroblasts with 5-Aza-deoxycytidine (5-AdC), which is used to relieve the inhibitory effects by DNA methylation in situ [22], led to the significant up-regulation of CD63 ( Figure 2D) in NS fibroblasts, whereas histone deacetylase inhibitors (trichostatin A) did not ( Figure 2E). Thus, exosome levels in fibroblasts can be controlled by DNA methylation, but not by histone acetylation.…”

microRNAs in Cancer Cell Response to Ionizing Radiation

“…ERK1/2, extracellular signal-regulated kinase 1/2; MAPK, mitogenactivated protein kinase; MEK1/2, MAPK kinase 1/2; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; RAS; RTK, receptor tyrosine kinase. and promote cell survival (142,157). One mechanism by which ERK1/2 regulates survival is by activating the expression of anti-apoptotic genes, including miRNAs.…”