Abstract
Gemcitabine-based chemotherapy is the most common treatment option for pancreatic ductal adenocarcinoma (PDAC). However, it offers little therapeutic value in many cases due to the rapid development of chemoresistance. MicroRNAs (miRNAs) have been found to play pivotal roles in the chemotherapeutic resistance of PDAC. We found that miR-410-3p was significantly down-regulated in human pancreatic cancer xenograft (HPCx) tumor tissues from gemcitabine-treated mice. Low miR-410-3p expression correlated with gemcitabine resistance in HPCx tumors and PDAC cells as well as poor prognosis in PDAC patients. We also found that miR-410-3p attenuated the gemcitabine resistance of PDAC by targeting the 3′-UTR of HMGB1. Moreover, our study clearly demonstrated that miR-410-3p enhanced chemosensitivity to gemcitabine via inhibiting HMGB1-induced autophagy during chemotherapy in PDAC cells. Our study suggests that miR-410-3p expression may be a useful indicator of the potential for chemoresistance to gemcitabine and provide a potential new therapeutic target for chemoresistance in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer-related death in developed countries and is considered to be an incurable and rapidly lethal disease [1]
We demonstrated that low miR-410-3p expression was associated with gemcitabine resistance in human pancreatic cancer xenograft (HPCx) tumors and pancreatic ductal adenocarcinoma (PDAC) cells as well as poor prognosis in PDAC patients
We found that up-regulation of miR-410-3p expression significantly inhibited chemoresistance to gemcitabine in human PDAC cells (Figure 2B, 2C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer-related death in developed countries and is considered to be an incurable and rapidly lethal disease [1]. The prognosis of patients after complete resection is poor, and >50% of patients develop tumor recurrence, with an estimated 5 year survival of only 20% [2]. Recent reports have suggested that adjuvant chemotherapy following curative surgery significantly prolonged the overall survival time after surgery, and this approach is being adopted as a standard strategy [3, 4]. Gemcitabine is only modestly effective against tumor recurrence and extends overall survival (OS) by approximately 6 months. PDAC will eventually develop resistance to gemcitabine after prolonged exposure [6]. One of the most important factors affecting the poor prognosis of PDAC is considered to be its high resistance to most of the existing chemotherapeutic regimens
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