Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis

Zhongquan Zhao; Xiaoming Cheng; Yubo Wang; Rui Han; Li Li; Tong Xiang; Luhang He; Haixia Long; Bo Zhu; Yong He

doi:10.1371/journal.pone.0095884

Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis

PLoS One. 2014 Apr 30;9(4):e95884. doi: 10.1371/journal.pone.0095884. eCollection 2014.

Authors

Zhongquan Zhao¹, Xiaoming Cheng², Yubo Wang³, Rui Han³, Li Li³, Tong Xiang⁴, Luhang He⁴, Haixia Long⁴, Bo Zhu⁵, Yong He³

Affiliations

¹ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Oncology, Fuzhhou General Hospital of Nanjing Military Commond, Fuzhou, China.
² Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
³ Department of Respiratory Medicine, Daping hospital, Third Military Medical University, Chongqing, China.
⁴ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
⁵ Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Biomedical Analysis Center, Third Military Medical University, Chongqing, China.

Abstract

Objective: Epithelial-mesenchymal transition (EMT) plays an important role in cancer tumorigenesis. However, the underlying mechanisms of EMT in lung adenocarcinoma, and how this process might be inhibited, remain to be explored. This study investigated the role of IL-6 in lung adenocarcinoma cell EMT and explored the potential effects of metformin on this process.

Methods: Invasion assay and MTT assay was performed to determine cell invasion and cell proliferation. Western blotting, immunofluorescence, real-time PCR, ELISA, and immunohistochemistry were performed to detect the expression of IL-6, E-cadherin, Vimentin, and p-STAT3.

Results: We discovered that IL-6, via STAT3 phosphorylation, could promote lung adenocarcinoma cell invasion via EMT in vitro. This was supported by the inverse correlation between E-cadherin and IL-6 expression, positive correlation between IL-6 and vimentin mRNA expression and between STAT3 phosphorylation and IL-6 expression in tumor tissues. Importantly, metformin inhibited tumor growth and distant metastases in tumor-bearing nude mice and reversed IL-6-induced EMT both in vitro and in vivo. Furthermore, we found that blockade of STAT3 phosphorylation might be the underlying mechanism of metformin inhibition of IL-6-induced EMT.

Conclusions: Collectively, our present results show that enhanced IL-6 expression, via STAT3 phosphorylation, is a mechanism of EMT in lung adenocarcinoma. We found that metformin could inhibit IL-6-induced EMT possibly by blocking STAT3 phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / pathology*
Blotting, Western
Cell Division / drug effects*
Cell Line, Tumor
Enzyme-Linked Immunosorbent Assay
Epithelial-Mesenchymal Transition / drug effects*
Humans
Interleukin-6 / physiology*
Lung Neoplasms / pathology*
Metformin / pharmacology*
Neoplasm Metastasis / prevention & control*
Phosphorylation
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor / metabolism

Substances

Interleukin-6
STAT3 Transcription Factor
STAT3 protein, human
Metformin

Grants and funding

This work is supported by the National Natural Science Foundation of China (No. 81172113, No. 81071912, No. 31270845, No. 81222031), the Chongqing Science Technology Commission (CSTC 2011BB5021), the Chinese “863” Program (No. 2012AA02A201) and National Key Basic Research Program of China (No. 2012CB526603 and No. 2010CB529404). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.