探討 Oct4 在肺癌上調控雙特異性去磷酸酶 6 的角色

Abstract

Octamer 4 (Oct4) is a POU domain-containing transcription factor encoded by Pou5f1 and required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells. However, Oct4 has been detected in several human tumors, suggesting a potentially critical role in tumorigenesis. Dual-specificity phosphatase 6 (DUSP6) is one of the mitogen-activated protein kinase (MAPK) phosphatases (MKPs) and its inactivation of extracellular signal-regulated kinases 2 (ERK-2) is believed as to function as a tumor suppressor in pancreatic cancer. In contrast, DUSP6 is closely associated with an increased risk of recurrence and decreased overall survival among patients with non-small cell lung cancer. Moreover, chromatin immunoprecipitation (ChIP) assay revealed that DUSP6 may be a potential downstream target of Oct4 in undifferentiated mouse ES cells. Down-regulation of DUSP6 mRNA expression in Oct4-knockdown mouse ES cells was also demonstrated in the public domain database. However, the mechanism underlying the regulation of DUSP6 expression by Oct4 is still unclear. The aim of this study was to study the association of Oct4 and DUSP6 in lung cancer and to elucidate its mechanism of action. My results revealed that there was a positive correlation between the expression of Oct4 and DUSP6 in lung cancer cells. Overexpression of Oct4 enhanced the expression of DUSP6 at both mRNA and protein levels. Chromatin immunoprecipitation (ChIP) and reporter assays showed that Oct4 enhanced the promoter activity of DUSP6 through direct binding to its promoter to regulate DUSP6 gene expression. Oct4 also enhanced the proliferation rate and migratory ability of lung cancer cells in vivo. Taken together, these results suggest that Oct4 regulates DUSP6 expression to initiate signal transduction cascades, leading to promoting the metastasis of non-small lung cancer cells. In the future, I will focus on studying the effects of Oct4-mediated DUSP6 expression on enhancing tumor migration and invasion in vitro and in vivo.