Investigation of Cellular Senescence Mechanism in Cholangiocarcinoma Cell Lines
Researcher: Dr. Benchamart Khumkrong
Cholangiocarcinomas (CCA) are malignancies arising from cholangiocytes in the biliary tract and are the second most common type of primary liver cancer. This type of cancer is associated with poor prognosis and limited treatment options. The major risk factors of this cancer are associated with chronic inflammation, cellular injury in the bile duct, and partial obstruction of bile flow caused by various conditions such as primary sclerosing cholangitis (PSC), hepatolithiasis and infestation by liver fluke (Opisthorchis viverrini) Kubo et al. 1995; Sirica 2005; Watanapa et al. 2002.
Recent studies attempt to investigate molecular pathogenesis of this disease, including etiology and molecular alterations. Genetic and epigenetic changes in cholangiocarcinoma have been identified from a number of studies. Alterations of several cellular functions including self-sufficiency and proliferation, apoptosis resistance, escape from senescence, and tumor invasiveness and metastasis, are proposed as factors that contribute to the onset of cholangiocarcinoma (Lazaridis et al. 2005).
Cellular senescence is considered to be one of the tumor suppressor mechanisms which are programmed to control cells from aberrant proliferation. Cellular senescence was initially described by Hayflick who demonstrated that normal human cells had a limited ability to proliferate in culture (Hayflick 1965). Abrogation of cellular senescence barrier is therefore one of the hallmarks of cancer development. Senescent cells can be characterized by 1) the irreversible cell cycle arrest, 2) changes of cell morphology (cell enlargement and flatness), 3) unresponsiveness to mitotic signals yet remain metabolically active, 4) altered gene expression patterns and 5) the expression of senescence-associated β-galactosidase (SA-β-gal). The onset of cellular senescence can be triggered by telomeric DNA shortening and other stimuli such as oxidative stress and oncogene activation. Although chronic inflammation is known to cause cholangiocarcinoma development, the molecular mechanisms in cholangiocarcinoma are not well established. More research is needed to reveal the molecular mechanisms and genetic alterations in cholangiocarcinoma for early detection and improving treatment outcome. Moreover, little is known about cellular senescence mechanism and its involvement with interferon signaling pathways in cholangiocarcinoma.
The purpose of this research project is to investigate the cellular senescence mechanism in cholangiocarcinoma cell lines. Three cholangiocarcinoma cell lines established from Thai patients, namely KKU-100 (poorly-differentiated tubular adenocarcinoma, hilar CCA) (Sripa et al. 2005), RMCCA-1 (well-differentiated adenocarcinoma, peripheral CCA) (Rattanasinganchan et al. 2006), HuCCA-1 (intrahepatic CCA) (Sirisinha et al. 1991) and immortal cholangiocyte cell line MMNK-1 (Maruyama et al. 2004) are used in this study. We will examine the effects of various agents, including DNA demethylating agent, genotoxic drugs, cytokines and oxidative stress, on the onset of cellular senescence and other phenotypic changes that may occur in cholangiocarcinoma cell lines. This research project will be conducted to gain more knowledge on molecular mechanisms relating to the interferon signaling pathway, cell cycle and cellular senescence in cholangiocarcinoma cells. Consequently, research on these areas may provide a better understanding of molecularpathogenesis of cholangiocarcinoma and help to improve treatment strategies.
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