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.
Highlights
Colorectal cancer (CRC) is a significant public health problem
Further stratification of CRC patients according to diabetes mellitus (DM) history status (Table 2) showed that patients in the normal blood glucose level group with or without a DM history had a lower percentage of relapse compared to patients in the high blood glucose level group (P = 0.0001 and 0.0115, respectively)
Investigations of epigenetic modifications have accounted for the majority of research into complex diseases, and studies of this type have indicated that miRs could possibly serve as potential biomarkers of cancer [5, 7, 32]
Summary
Colorectal cancer (CRC) is a significant public health problem. One million new cases of CRC are diagnosed annually worldwide, and approximately half a million of these cases result in death [1]. Radical surgical resection can be highly effective for localized diseases, 25-40% of patients develop recurrence/metastasis after surgery [2]. The recurrence of CRC is a time-limited phenomenon, and it has been shown that the length of patients’ recurrence periods correlates strongly with the length of their survival periods [3, 4]. No ideal biomarker or indicator for predicting the recurrence/metastasis of CRC after operation exists [5, 6]. Continuous efforts have been made to enhance the methods of early tumor detection so as to assist physicians in intensifying surveillance and therapeutic strategies, thereby improving the patients’ prognoses [5, 7, 8]
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