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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.
This article was published in the following journal.
Name: Molecular oncology
Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms res...
Gemcitabine has been considered a first-line chemotherapy agent for the treatment of pancreatic cancer. However, the initial response rate of gemcitabine is low and chemoresistance occurs frequently. ...
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine, use different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of pancreatic ca...
RATIONALE: Drugs used in chemotherapy such as gemcitabine use different ways to stop tumor cells from dividing so they stop growing or die. 3-AP may stop the growth of tumor cells by block...
RATIONALE: Drugs used in chemotherapy such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafeni...
RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. WX-671 ...
Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is PROTO-ONCOGENE PROTEINS C-MET.
C-type lectins that restrict growth of bacteria in the intestinal epithelia and have bactericidal activity against gram-positive and gram-negative bacteria. They also regulate proliferation and differentiation of KERATINOCYTES following injury. Human pancreatitis-associated protein-1 (Reg3a) is overexpressed by pancreatic ACINAR CELLS in patients with CHRONIC PANCREATITIS. It is also highly expressed by pancreatic, bladder, and gastrointestinal cancer cells and may serve as a diagnostic biomarker.
A primary malignant neoplasm of the pancreatic ISLET CELLS. Usually it involves the non-INSULIN-producing cell types, the PANCREATIC ALPHA CELLS and the pancreatic delta cells (SOMATOSTATIN-SECRETING CELLS) in GLUCAGONOMA and SOMATOSTATINOMA, respectively.
An antiviral antibiotic produced by Cephalosporium aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon non-multiplying cells.
A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.
The pancreas secretes a number of important hormones into the digestive tract and the blood stream. Cancers are most commonly exocrine than endocrine (neuroendocrine) tumors. Functional tumors secrete hormones; Insulinoma, Gastrinoma, Somatostatinoma, VI...
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