MicroRNA-7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF-κB signaling in pancreatic cancer cells.

Abstract

Senescence is activated in response to gemcitabine to prevent the propagation of cancer cells. However, there is little evidence on whether senescence is involved in gemcitabine resistance in pancreatic cancer. Increasing evidence has demonstrated that microRNAs (miRs) are potential regulators of cellular senescence. The present study aimed to investigate whether aberrant miR-7 expression modulated senescence to influence pancreatic cancer resistance to chemotherapy. In the present study, cell senescence assay, ALDEFLUOR™ assay, luciferase reporter assay, flow cytometry, quantitative PCR, immunohistochemistry and western blot analysis were performed to explore the association between senescence and gemcitabine therapy response, and to clarify the underlying mechanisms. The present study revealed that gemcitabine-induced chronically existing senescent pancreatic cells possessed stemness markers. Therapy-induced senescence led to gemcitabine resistance. Additionally, it was found that miR-7 expression was decreased in gemcitabine-resistant pancreatic cancer cells, and that miR-7 acted as an important regulator of cellular senescence by targeting poly (ADP-ribose) polymerase 1 (PARP1)/NF-κB signaling. When miR-7 expression was restored, it was able to sensitize pancreatic cancer cells to gemcitabine. In conclusion, the present study demonstrated that miR-7 regulated cellular senescence and relieved gemcitabine resistance by targeting the PARP1/NF-κB axis in pancreatic cancer cells.