MiR-338-5p promotes metastasis of colorectal cancer by inhibition of phosphatidylinositol 3-kinase, catalytic subunit type 3-mediated autophagy pathwayResearch in context
Chien-An Chu,
Chung-Ta Lee,
Jenq-Chang Lee,
Yi-Wen Wang,
Ching-Tang Huang,
Sheng-Hui Lan,
Peng-Chan Lin,
Bo-Wen Lin,
Yu-Feng Tian,
Hsiao-Sheng Liu,
Nan-Haw Chow
Affiliations
Chien-An Chu
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan
Chung-Ta Lee
Department of Pathology, National Cheng Kung University Hospital, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital Dou-Liou Branch, Douliou City, Yunlin County, Taiwan
Jenq-Chang Lee
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
Yi-Wen Wang
Department of Pathology, National Cheng Kung University Hospital, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan
Ching-Tang Huang
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan
Sheng-Hui Lan
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
Peng-Chan Lin
Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Bo-Wen Lin
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
Yu-Feng Tian
Department of Health & Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan; Division of Colorectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
Hsiao-Sheng Liu
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Taiwan; Corresponding authors at: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 701, Taiwan.
Nan-Haw Chow
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan; Corresponding authors at: Department of Pathology, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 701, Taiwan.
Background: In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo. Methods: The potential clinical relevance of miR-338-5p and its target gene was analysed on benign colorectal polyps and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis. Findings: PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumour staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumours. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumours. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration and invasion induced by miR-338-5p. Interpretation: MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients. Fund: NCKU Hospital, Taiwan, Ministry of Science and Technology, Taiwan. Keywords: miR-338-5p, PIK3C3, Autophagy and colorectal cancer
