Understanding the Role of MicroRNA-31 in Regulating Cellular Sensitivity to Chemoradiotherapy in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic adenocarcinoma (PDAC) is a lethal malignancy with a poor survival rate. One main challenge regarding PDAC is resistance to chemotherapy and radiotherapy. Therefore, there is an urgent requirement to characterise the mechanisms underpinning chemo-resistance and radio-resistance in PDAC. Recent evidence has revealed that microRNAs (miR) play a pivotal role in resistance to chemotherapy in other cancer types by controlling drug trafficking and sequestration. Additionally, it is well established that miRs can modulate radio-resistance by altering levels of oxidative stress. MiR-31 has previously been demonstrated to regulate sensitivity to chemoradiotherapy in other cancer types, although it remains largely unexplored in PDAC. Here, we investigated the biological role and potential mechanisms of miR-31 in PDAC chemo-resistance and radio-resistance. Overexpressing miR-31 in BxPC-3 cells significantly promoted clonogenic resistance to platinum-based chemotherapeutics, particularly cisplatin. Reciprocally, suppressing miR-31 in Panc-1 cells enhanced cisplatin sensitivity. Although miR-31 increased chemo-resistance, paradoxically, inductively coupled plasma mass spectrometry (ICP-MS) revealed a higher relative intracellular accumulation of platinum. This was associated with a significantly decreased intranuclear concentration of platinum which may explain the differences in DNA damage induction. In silico analysis displayed ATOX1, a vital drug transporter, as a predictive target of miR-31, may play an essential role in shuttling cisplatin to the nucleus. Overexpressing ATOX1 in PDAC cells displayed increased cisplatin sensitivity and presents as a useful target for modulating chemo-resistance in PDAC. Moreover, it was found that manipulating miR-31 altered radiosensitivity in PDAC cells by regulating oxidative stress and DNA damage. Glutathione peroxidase 8 (GPx8) is an anti-oxidant enzyme that plays an important role in the elimination of reactive oxygen species (ROS). Using online bioinformatics algorithms, we identified the 3'UTR of GPx8 as a predictive target of miR-31. Our study demonstrates that manipulating miR-31 alters GPx8 expression for the first time, thereby regulating ROS detoxification and promoting either a radioresistant or radiosensitive phenotype. Our study demonstrates the potential mechanisms underlying the chemo-resistance and radio-resistance of PDAC cells mediated by drug trafficking and oxidative stress by miR-31, indicating promising targets and therapeutic strategies in PDAC.