Interaction of Serum microRNAs and Serum Folate With the Susceptibility to Pancreatic Cancer.

Pancreatic cancer (PC) ranks fourth among causes of cancer-related deaths in the United States.1 In China, the adjusted and age-standardized mortality from PC has increased from 1.75 and 2.18 per 100,000 in 1991 to 3.06 and 3.26 per 100,000 in 2000.2 Pancreatectomy provides the only potential for cure. However, most diagnoses of PC are made in advanced stages that are not suitable for resection, which leads to a 5-year survival rate of less than 5%.1 Therefore, investigating the etiology and identifying the risk factors for PC are essential for primary disease prevention. As for most human cancers, environmental and genetic factors have been demonstrated to be involved in the carcinogenesis of PC. The progression of PC is paralleled by the successive accumulation of both genetic and epigenetic alterations, including alterations in the expression of microRNA (miRNA) molecules.3,4 The miRNAs represent a novel class of 18nt to 23nt endogenous small noncoding RNAs. Upon binding to their target mRNAs, they promote posttranscriptional gene silencing by either inhibiting the translation process or cleaving the target mRNAs.5 Consequently, abnormal expression of miRNAs could have an effect on crucial biological processes in cancer, such as cell cycle progression and apoptosis.6 In fact, alterations in miRNA expression have been detected in many types of human tumors, including PC. In 2008, intriguing studies revealed that stable miRNAs also could be detected in serum and/or plasma and therefore might serve as diagnostic biomarkers.7,8 Altered expression of serum miRNAs, including miR-155 and miR-221, has been detected in PC.9–12 Array analysis has also been used to profile the association of blood miRNA levels with different cancers, and miR-16, miR-320, miR-601, and miR-1228 were shown to be differentially expressed between PC cases and controls (P < 0.0001).13 The DNA methylation is believed to be one of the most important mechanisms underlying the regulation of miRNA.14,15 As a cofactor involving the synthesis of S-adenosylmethionine, folate plays an essential role in DNA methylation. Dietary folate deficiency induces hypomethylation, which has been linked to the increased development of cancers, including PC.16,17 Interestingly, the expression of certain miRNAs, including miR-103 and miR-107, was significantly changed under folate-deficient conditions in human lymphoblastoid cells.18 Furthermore, expression of many miRNAs in hepatomas induced by folate and methyl-deficient diets was significantly altered compared with that in the livers from age-matched rats on a normal diet.19 On the basis of these findings, we hypothesized that an association might exist between certain miRNAs and the levels of serum folate in the development of PC. To examine this hypothesis, 6 miRNAs were selected as candidates for investigating the interaction between miRNAs and folate in a PC case-control study of 74 PC patients and 74 controls. Among them, miR-103 and miR-107 have been reported to be differentially regulated by folate deficiency,18 and miR-16,miR-320, miR-601, and miR-1228 were abnormally expressed in PC cases.13