Molecular mechanisms underlying Oct4-mediated tumor progression in non-small-cell lung cancer

Abstract

In recent years the incidence of non-small-cell lung cancer (NSCLC) has increased rapidly Because the prognosis of NSCLC is poor there is an urgent need to understand the molecular mechanisms of NSCLC and thereby develop effective treatment During tumor progression cells with malignantly transformed phenotypes disrupt tissue homeostasis Tumor cells usually proliferate indefinitely through their anti-apoptotic properties Furthermore evasion of cell death also leads to ineffective therapy and poor prognosis in cancer patients Therefore elucidating the anti-apoptotic mechanism of tumors and identifying novel therapeutic targets are urgently needed Previous studies have revealed that both Oct4 and Stat1 are overexpressed in NSCLC and play roles in the anti-apoptotic mechanism In this study we investigated whether expression of Oct4 in NSCLC cells induces Stat1 gene expression and ultimately results in anti-apoptosis phenotypes A total of 54 human NSCLC specimens were used to analyze the expression of Oct4 and Stat1 There was a positive correlation between the expression levels of Oct4 and those of Stat1 Furthermore there expression was positively correlated with poor prognosis of the patients Luciferase reporter and chromatin immunoprecipitation (ChIP) assays reveal that Oct4 directly bound to the Stat1 promoter to induce Stat1 expression Expression of the Stat1 downstream anti-apoptotic gene Mcl-1 was increased in Oct4-overexpressing cancer cells Knockdown of Stat1 in Oct4-overexpressing cells sensitized them to cisplatin-induced apoptosis Furthermore in vivo studies indicate that Oct4 promoted Stat1 expression and tumor growth whereas silencing of Stat1 ameliorated Oct4-induced tumor growth Collectively these results suggest the anti-apoptotic role of Oct4 is through upregulating Stat1 expression and may contribute to the poor prognosis in patients with NSCLC

Date of Award	2016 Apr 20
Original language	English
Supervisor	Chao-Liang Wu (Supervisor)