High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2

// I-Ping Yang 1, 2, * , Hsiang-Lin Tsai 3, 4, 5, 6, * , Ching-Wen Huang 5, 6 , Chien-Yu Lu 7, 8 , Zhi-Feng Miao 6 , Se-Fen Chang 9 , Suh-Hang Hank Juo 1, 4, 10, 11, 12, 13 , Jaw-Yuan Wang 1, 4, 5, 6, 11, 12, 13 1 Department of Genomic Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Nursing, Shu-Zen College of Medicine and Management, Kaohsiung, Taiwan 3 Department of Surgery, Division of General Surgery Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Department of Surgery, Division of Gastroenterology and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 7 Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 9 Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 10 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 11 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 12 Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 13 Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Jaw-Yuan Wang, e-mail: cy614112@ms14.hinet.net , jayuwa@cc.kmu.edu.tw Keywords: hyperglycemia, colorectal cancer, miR-16, DM, prognosis Received: August 29, 2015     Accepted: January 19, 2016     Published: February 25, 2016 ABSTRACT The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (≧110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels ( P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients ( P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably ( P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2 , were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2 .