Date Published: July 20, 2017
Publisher: Public Library of Science
Author(s): Po-Len Liu, Wei-Lun Liu, Jia-Ming Chang, Yung-Hsiang Chen, Yu-Peng Liu, Hsuan-Fu Kuo, Chong-Chao Hsieh, Yu-Sian Ding, Wei-Wei Chen, Inn-Wen Chong, Aamir Ahmad.
MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1.
Lung cancer is the most common malignancy and a leading cause of cancer-related death worldwide. Non-small cell lung cancers (NSCLC), including squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, are the most common types of lung cancer in Taiwan and these malignancies have a low 5-year survival rate compared with many other types of cancer. Notably, mesenchymal-to-epithelial transition (EMT) processes have been found to regulate tumour progression, metastasis, invasion, and drug resistance in NSCLC .
Recent studies have demonstrated that the expression of HMGB1 in NSCLC tumour tissue is markedly increased compared with that in normal tissue. Furthermore, the expression of HMGB1 in lung adenocarcinoma tissue was reported to be significantly higher than that in lung squamous cell carcinoma tissue, and it was associated with patient survival [8, 36]. In this study, we found that a high expression of HMGB1 in lung adenocarcinoma tissues was associated with the expression of cancer EMT markers. This observation indicates that HMGB1 represents an oncogene-like biomarker of lung cancer and is associated with EMT processes.
Our results characterised HMGB1 as a potential target of miR-200c and showed that miR-200c may regulate A549 cell EMT, and cancer progression by targeting HMGB1. Therefore, miR-200c may represent a molecular biomarker of NSCLC outcome, and on the other hand, it could be a therapeutic target for the reduction of lung cancer progression. Further studies of HMGB1-regulated signalling pathways implicated in lung cancer EMT and cancer progression are required to validate the potential of miR-200c for use in therapy for lung cancer.