Abstract
This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.
Highlights
Pancreatic cancer (PCa) is the fourth leading cause of cancer-related death in Japan and the United States[1] and the seventh worldwide[2]
Small-scale analysis of plasma samples using qRT-PCR to validate the utility of the selected miRNA candidates; (3) large-scale analysis to validate the miR-107 plasma level and investigate how it is associated with clinicopathological characteristics and prognostic outcomes in PCa patients; (4) evaluation of whether miR-107 overexpression in PCa cells induces anti-tumor effects in vitro; and (5) investigation of the tumor suppressor function and dynamics of miR-107 in vivo (Fig. 1a)
Of these 15 miRNAs, we selected six miRNAs, miR-451, miR-126, miR-145, miR-146b-5p, miR-491-5p, and miR107, which were previously reported to have a tumor suppressor role because our previous studies revealed that some tumor suppressor miRNAs in plasma were significantly down-regulated in cancer patients compared with healthy volunteers[30, 32, 33], and the down-regulation of tumor suppressor miRNAs in the blood stream might be related to tumor progression and poor prognostic outcomes[32]
Summary
Pancreatic cancer (PCa) is the fourth leading cause of cancer-related death in Japan and the United States[1] and the seventh worldwide[2]. The development of novel molecular mechanisms and/or therapeutic targets is necessary to improve the prognosis of PCa. MicroRNAs (miRNAs), which are small non-coding RNAs, regulate the translation of specific protein-coding genes. MicroRNAs (miRNAs), which are small non-coding RNAs, regulate the translation of specific protein-coding genes Since their discovery in 199311, numerous studies have identified alterations in miRNA expression that are correlated with the progression of various diseases, including the development and progression of several cancer types[12,13,14,15]. We identified that some tumor suppressor miRNAs in plasma, such as let-7a in gastric cancer[30] and miR-375 in esophageal[32] and pancreatic cancer[33], were significantly down-regulated in cancer patients compared with healthy volunteers. We suggested the novel theory that the down-regulation of some tumor suppressor miRNAs in the blood stream could be correlated with tumor progression and poor prognostic outcomes[32]
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