Abstract
Cellular senescence, a barrier to tumorigenesis, controls aberrant proliferation of cells. We here aimed to investigate cellular senescence in immortalized cholangiocyte and cholangiocarcinoma cell lines using five different inducing agents: 5-aza-2'deoxycytidine, bromodeoxyuridine, interferons (IFNβ and IFNγ), and hydrogen peroxide. We analyzed senescence characteristics, colony formation ability, expression of genes involved in cell cycling and interferon signaling pathways, and protein levels. Treatment with all five agents decreased cell proliferation and induced cellular senescence in immortalized cholangiocyte and cholangiocarcinoma cell lines with different degrees of growth-inhibitory effects depending on cell type and origin. Bromodeoxyuridine gave the strongest stimulus to inhibit growth and induce senescence in most cell lines tested. Expression of p21 and interferon related genes was upregulated in most conditions. The fact that bromodeoxyuridine had the strongest effects on growth inhibition and senescence induction implies that senescence in cholangiocarcinoma cells is likely controlled by DNA damage response pathways relating to the p53/p21 signaling. In addition, interferon signaling pathways may partly regulate this mechanism in cholangiocarcinoma cells.
Highlights
Cholangiocarcinoma (CCA), a lethal cancer of the biliary tract, is the second most common type of primary liver cancer (Parkin et al, 1993)
Treatment with all five agents decreased cell proliferation and induced cellular senescence in immortalized cholangiocyte and cholangiocarcinoma cell lines with different degrees of growth-inhibitory effects depending on cell type and origin
The major risk factors of this cancer associate with chronic inflammation of the bile duct epithelial cells, and partial obstruction of bile flow caused by various conditions such as primary sclerosing cholangitis, hepatolithiasis and infestation by liver fluke (Opisthorchis viverrini) (Kubo et al, 1995; Sirica, 2005; Sripa et al, 2007)
Summary
Cholangiocarcinoma (CCA), a lethal cancer of the biliary tract, is the second most common type of primary liver cancer (Parkin et al, 1993). This cancer is associated with poor prognosis and limited treatment options. The proposed pathways contributing in the development of cholangiocarcinoma include: 1) self-sufficiency and proliferation, 2) apoptosis resistance, 3) escape from senescence, and 4) tumor invasiveness and metastasis (Lazaridis and Gores, 2005). Cellular senescence is considered to be one of the tumor suppressor mechanisms which are programmed to control cells from aberrant proliferation and provide a barrier to cancer progression (Collado et al, 2005; Munoz-Espin and Serrano, 2014). Apart from its role in tumor suppression, characteristics of senescent cells as the senescence-associated secretory phenotype influence the secretion of extracellular matrix and cytokines which can promote tumorigenesis (Kuilman et al, 2008; Coppe et al, 2010; Di et al, 2014)
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