Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1α in erk-responsive lung cancer
| Autor: | Pei-Ei Wu, Ling-Yueh Hu, Chen-Yang Shen, Yi-Hsien Hsieh, Chia-Wei Chang, Chun-Wen Cheng, Chung-Chin Yao, Chung-Chih Weng, Po-Ming Chen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Pathology
medicine.medical_specialty Epithelial-Mesenchymal Transition Lung Neoplasms Time Factors HIF-1α Mice Nude Antineoplastic Agents Vimentin Biology Transfection Metastasis Cell Movement Cell Line Tumor microRNA medicine Animals Humans Neoplasm Invasiveness Epithelial–mesenchymal transition FOXO3a Neoplasm Metastasis Extracellular Signal-Regulated MAP Kinases Lung cancer 3' Untranslated Regions Protein Kinase Inhibitors A549 cell Mice Inbred BALB C Binding Sites Forkhead Box Protein O3 EMT miR-622 Cancer Forkhead Transcription Factors Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Tumor Burden Enzyme Activation Gene Expression Regulation Neoplastic lung cancer MicroRNAs Oncology Cancer cell Cancer research biology.protein Heterografts Female Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.5826 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|