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Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207.

08:00 EDT 20th October 2018 | BioPortfolio

Summary of "Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207."

Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer. However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted genetic pathways remain unclear. PVT1 has been reported to be an oncogenic long noncoding RNA in tumorigenesis. Here, we showed that the expression of PVT1 is correlated with gemcitabine efficacy in pancreatic cancer therapy. Inhibition of PVT1 led to decreased cell growth in pancreatic cancer cells treated with gemcitabine. We also demonstrated that gemcitabine treatment decreases PVT1 levels and increases its encoded microRNAs (miRNAs), such as the miR-1207 pair (miR-1207-5p/3p). Overexpression of the miR-1207 pair enhanced the chemosensitivity of cells to gemcitabine, whereas silencing of miR-1207-5p/3p to prevent its induction by gemcitabine treatment led to increased cell growth. Mechanistic studies revealed that miR-1207-5p and miR-1207-3p target the SRC proto-oncogene and RhoA in pancreatic cancer cells, respectively. In particular, we observed that gemcitabine induced Drosha and DGCR8 upregulation and then triggered PVT1 processing. Suppression of Drosha and DGCR8 contributed to dampened efficacy of gemcitabine, indicating that gemcitabine decreased PVT1 expression through promoting its processing into microRNAs, which in turn resulted in blunted oncogenic signaling in pancreatic cancer cells. Moreover, we demonstrated that gemcitabine chemoresistance was due to decreased expression of Drosha and DGCR8 in AsPC-1 cells and tumor cell-engrafted models. Overall, our findings define a novel mechanism for understanding the efficacy of gemcitabine chemotherapy in pancreatic cancer.

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Name: Molecular oncology
ISSN: 1878-0261
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