Research Papers:

Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1α in ERK-responsive lung cancer

Chun-Wen Cheng _, Po-Ming Chen, Yi-Hsien Hsieh, Chung-Chih Weng, Chia-Wei Chang, Chung-Chin Yao, Pei-Ei Wu and Chen-Yang Shen

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Oncotarget. 2015; 6:44222-44238. https://doi.org/10.18632/oncotarget.5826

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Chun-Wen Cheng1,2, Po-Ming Chen1, Yi-Hsien Hsieh1, Chung-Chih Weng1, Chia-Wei Chang1, Chung-Chin Yao3, Ling-Yueh Hu4, Pei-Ei Wu4, Chen-Yang Shen4,5

1Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

2Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan

3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan

4Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

5College of Public Health, China Medical University, Taichung, Taiwan

Correspondence to:

Chun-Wen Cheng, e-mail: cwcheng@csmu.edu.tw

Chen-Yang Shen, e-mail: bmcys@ibms.sinica.edu.tw

Keywords: Lung cancer, HIF-1α, EMT, miR-622, FOXO3a

Received: May 20, 2015     Accepted: October 13, 2015     Published: October 23, 2015


Metastatic spread of cancer cells portends a poor prognosis and mortality for lung cancer patients. Hypoxia-inducible factor-1α (HIF-1α) enhances tumor cell motility by activating the epithelial-to-mesenchymal transition (EMT), which is considered a prerequisite for metastasis. Recent studies of microRNA involvement in cancer invasion and metastasis have highlighted the role of such RNAs in tumor development. However, little work has been done to identify tumor suppressor microRNAs that target HIF-1α to down-modulate the EMT and thereby counteract the aggressiveness and metastasis of lung cancer cells. Here, we identified the 3′-untranslated region of HIF-1α mRNA as a target of miR-622 and established that miR-622-mediated down-modulation of HIF-1α correlates with decreased levels of mesenchymal proteins, including Snail, β-catenin, and vimentin. Functional analyses revealed that increased miR-622 expression inhibited lung cancer cell migration and invasion in vitro. miR-622 also inhibited the genesis of metastatic lung nodules as demonstrated in a lung cancer xenograft model in which nude mice were transplanted with A549 cells expressing miR-622. Mechanistic analyses showed that overexpression of EGF decreased the miR-622 level in A549 cells, and this reduction could be rescued by administrating U0126, an inhibitor of ERK. Moreover, miR-622 overexpression mediated by the transcription factor FOXO3a decreased the invasiveness of lung tumor cells by inhibiting HIF-1α via inactivation of ERK signaling in U0126-treated A549 cells. These findings highlight the pivotal role of the FOXO3a/miR-622 axis in inhibiting HIF-1α to interfere with tumor metastasis, and this information may contribute to development of novel therapeutic strategies for treating aggressive lung cancer.

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