Oct4 upregulates osteopontin via Egr1 and is associated with poor outcome in human lung cancer

Yin-Hsun Feng,Gia-Shing Shieh,Pey-Ru Lin,Chao-Liang Wu,Chien-Feng Li,Shuo-Fu Lin,Ai-Li Shiau,Yu-Chu Su,Chao-Ling Tung

doi:10.1186/s12885-019-6014-5

Abstract

BackgroundRoles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. However, the role of Egr1 in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways.MethodsEgr1, osteopontin (OPN) and Oct4 expression in human lung cancer was determined by performing immunohistochemistry. Immunoblotting, ELISA, luciferase reporter assay, chromatin immunoprecipitation assay and RT-PCR were performed to validate the regulation of Oct4-Egr1-OPN axis. Moreover, the effect of Oct4-Egr1-OPN axis on lung cancer progression was evaluated by cell migration assay and mice study.ResultsWe detected Oct4, Egr1, and OPN expression in clinical specimens from 79 lung cancer patients, including 72 adenocarcinomas and 7 squamous cell carcinomas. High expression of Oct4, Egr1, and OPN accounted for 53, 51, and 57% of the patients, respectively. All of the three biomarkers were positively correlated in clinical human lung cancer. Patients with high expression of OPN were significantly associated with shorter disease-free survivals than those with low expression of OPN (p < 0.05). In lung cancer cells, Oct4 transactivated the Egr1 promoter and upregulated Egr1 expression. In a human lung cancer xenograft model, Oct4-overexpressing tumors expressed elevated levels of Egr1. Furthermore, overexpression of Oct4 in lung cancer cells increased the metastatic potential.ConclusionsEgr1 exerts a promoting effect on cancer metastasis in Oct4-overexpressing lung cancer. Thus, therapeutic strategies targeting the Oct4/Egr1/OPN axis may be further explored for the treatment of lung cancer, especially when lung cancer is refractory to conventional treatment due to cancer stem cells.

Highlights

Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer
Therapeutic strategies targeting the Oct4/Egr1/OPN axis may be further explored for the treatment of lung cancer, especially when lung cancer is refractory to conventional treatment due to cancer stem cells
More Oct4 highexpressing tumors belonged to Egr1 high-expressing tumors, whereas tumors with low Oct4 expression consisted of more Egr1 low-expressing tumors (p < 0.005) (Fig. 1b)

Summary

Introduction

Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. The role of Egr in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways. We have previously shown that treatment with suboptimal doses of cisplatin can induce drug resistance and increase the expression of CD44, CD133, ABCG2, and osteopontin (OPN) in human lung cancer cells [7]. We have shown that treatment with cisplatin increases CD44-positive bladder cancer cells expressing Oct, representing cancer stem-like cell subpopulation, which contributes to drug resistance and tumor recurrence [13]. In lung cancer-derived CD133-positive cells, Oct expression maintains the self-renewable, cancer stem-like, and chemoradio-resistant properties of CD133-positive cells [14]. We have reported that oncolytic adenoviruses driven by the Oct promoter or Oct response element (ORE) exert antitumor activities against blander cancer that expresses Oct, validating Oct as a potential therapeutic target for cancer [12, 15]

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