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

ABSTRACT: Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non-protein coding) (PVT1) has been reported to be an oncogenic long non-coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased cell growth in PC cells treated with gemcitabine. We also demonstrate that gemcitabine treatment decreases PVT1 levels and increases its encoded 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 (non-receptor tyrosine kinase) and ras homolog family member A in PC cells, respectively. In particular, we observed that gemcitabine induced Drosha ribonuclease III (Drosha) and DGCR8 microprocessor complex subunit (DGCR8) upregulation and then triggered PVT1 processing. Suppression of Drosha and DGCR8 contributed to a dampened efficacy of gemcitabine, indicating that gemcitabine decreased PVT1 expression by promoting its processing into miRNAs, which in turn resulted in blunted oncogenic signaling in PC cells. Moreover, we demonstrate that gemcitabine chemoresistance was a result of 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 PC.

SUBMITTER: You L

PROVIDER: S-EPMC6275279 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

You Lei L Wang Huanyu H Yang Gang G Zhao Fangyu F Zhang Jingcheng J Liu Ziwen Z Zhang Taiping T Liang Zhiyong Z Liu Changzheng C Zhao Yupei Y

Molecular oncology 20181030 12

Gemcitabine serves as a first-line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well-established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non-protein coding) (PVT1) has been reported to be an oncogenic long non-coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased ...[more]

PMID: 30341811

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Project description:BackgroundGemcitabine is a cornerstone drug for the treatment of all stages of pancreatic cancer and can prolong the survival of patients with pancreatic cancer, but resistance to gemcitabine in pancreatic cancer patients hinders its efficacy. The overexpression of Early growth response 1(EGR1) in pancreatic ductal adenocarcinoma as a mechanism of gemcitabine chemoresistance in pancreatic cancer has not been explored. The major mechanisms of gemcitabine chemoresistance are related to drug uptake, metabolism, and action. One of the common causes of tumor multidrug resistance (MDR) to chemotherapy in cancer cells is that transporter proteins increase intracellular drug efflux and decrease drug concentrations by inducing anti-apoptotic mechanisms. It has been reported that gemcitabine binds to MDR1 with high affinity. The purpose of this research was to investigate the potential mechanisms by which EGR1 associates with MDR1 to regulate gemcitabine resistance in pancreatic cancer cells.MethodsThe following in vitro and in vivo techniques were used in this research to explore the potential mechanisms by which EGR1 binds to MDR1 to regulate gemcitabine resistance in pancreatic cancer cells. Cell culture; in vitro and in vivo study of EGR1 function by loss of function analysis. Binding of EGR1 to the MDR1 promoter was detected using the ChIP assay. qRT-PCR, Western blot assays to detect protein and mRNA expression; use of Annexin V apoptosis detection assay to test apoptosis; CCK8, Edu assay to test cell proliferation viability. The animal model of pancreatic cancer subcutaneous allograft was constructed and the tumours were stained with hematoxylin eosin and Ki-67 expression was detected using immunohistochemistry.FindingsWe revealed that EGR1 expression was increased in different pancreatic cancer cell lines compared to normal pancreatic ductal epithelial cells. Moreover, gemcitabine treatment induced upregulation of EGR1 expression in a dose- and time-dependent manner. EGR1 is significantly enriched in the MDR1 promoter sequence.Upon knockdown of EGR1, cell proliferation was impaired in CFPAC-1 and PANC-1 cell lines, apoptosis was enhanced and MDR1 expression was decreased, thereby partially reversing gemcitabine chemoresistance. In animal experiments, knockdown of EGR1 enhanced the inhibitory effect of gemcitabine on tumor growth compared with the sh-NC group.ConclusionsOur study suggests that EGR1 may be involved in the regulation of MDR1 to enhance gemcitabine resistance in pancreatic cancer cells. EGR1 could be a novel therapeutic target to overcome gemcitabine resistance in pancreatic cancer.

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

Publications

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

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