MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma

• Published in: PloS one Vol. 9; no. 5; p. e96765
• Main Authors: Wang, Lu-Kai, Hsiao, Tzu-Hung, Hong, Tse-Ming, Chen, Hsuan-Yu, Kao, Shih-Han, Wang, Wen-Lung, Yu, Sung-Liang, Lin, Ching-Wen, Yang, Pan-Chyr
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.05.2014; Public Library of Science (PLoS)
• Subjects: AKT protein; B cells; Biology and Life Sciences; Biotechnology; Bone morphogenetic proteins; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Correlation analysis; Down-Regulation - genetics; Epidermal growth factor; Epidermal growth factor receptors; Epithelial cells; Gene Knockdown Techniques; Gene silencing; Health aspects; Heart diseases; Humans; Insulin; Insulin-like growth factors; Internal medicine; Invasiveness; Kinases; Life sciences; Lung cancer; Lung carcinoma; Lung diseases; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medicine; Medicine and Health Sciences; Metastases; Metastasis; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Mutation; Myogenesis; Neoplasm Invasiveness; Neoplasm Metastasis; Non-coding RNA; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncogene Proteins - genetics; Prognosis; Prostate cancer; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Receptors, Cell Surface - genetics; Regulators; Ribonucleic acid; RNA; Rodents; Signal Transduction - genetics; Signaling; Small cell lung carcinoma; Transforming growth factor-b; Transforming growth factors; Tumor cell lines; Tumor suppressor genes; Tumors; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096765

Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.