Abstract
Cholangiocarcinoma (CCA) has been well known as the second most common primary tumor of hepatobiliary system. PSMC2 (proteasome 26S subunit ATPase 2) is a key member of the 19S regulatory subunit of 26S proteasome, responsible for catalyzing the unfolding and translocation of substrates into the 20S proteasome, whose role in CCA is totally unknown. In this study, the results of immunohistochemistry analysis showed the upregulation of PSMC2 in CCA tissues compared with normal tissues, which was statistically analyzed to be associated with CCA tumor grade. Subsequently, the loss-of-function study suggested that knockdown of PSMC2 significantly suppressed cell proliferation, cell migration, promoted cell apoptosis and arrested cell cycle distribution in vitro. The decreased tumorigenicity of CCA cells with PSMC2 knockdown was confirmed in vivo by using mice xenograft model. In PSMC2 knockdown cells, pro-apoptotic protein Caspase3 was upregulated; anti-apoptotic proteins such as Bcl-2 and IGF-II were downregulated; among EMT markers, E-cadherin was upregulated while N-cadherin and Vimentin were downregulated, by which may PSMC2 regulates cell apoptosis and migration. Furthermore, through RNA-seq and verification by qPCR, western blotting and co-IP assays, CDK1 was identified as the potential downstream of PSMC2 mediated regulation of CCA. PSMC2 and CDK1 showed mutual regulation effects on expression level of each other. Knockdown of PSMC2 could aggregate the influence of CDK1 knockdown on cellular functions of CCA cells. In summary, our findings suggested that PSMC2 possesses oncogene-like functions in the development and progression of CCA through regulating CDK1, which may be used as an effective therapeutic target in CCA treatment.
Highlights
Cholangiocarcinoma (CCA) is a kind of highly malignant tumor originated from bile duct epithelial cells, accounting for about 3% of digestive system tumors [1,2,3]
Our analyses showed that QBC939 and HCCC-9810 cells exhibited high www.aging-us.com expression levels of PSMC2 expression and were selected to construct a cell model of PSMC2 knockdown for subsequent research (Figure 1B)
We demonstrated that the additional knockdown of PSMC2 in CDK1 knockdown cells had deleterious effects on a range of cellular functions, including colony formation, cell proliferation, cell apoptosis, and migration (P < 0.001, Figure 4C–4G)
Summary
Cholangiocarcinoma (CCA) is a kind of highly malignant tumor originated from bile duct epithelial cells, accounting for about 3% of digestive system tumors [1,2,3]. The current research has revealed some potential risk factors closely www.aging-us.com related to the incidence of CCA, such as papillomatosis of the bile duct, cirrhosis, viral hepatitis, choledochal cyst, chronic hepatolithiasis and so on, the research on the molecular mechanism of CCA is still very insufficient [4]. The proposal of the concept of targeted drugs and the emergence of a large number of molecular targeted drugs have brought a revolution to the treatment of malignant tumors, which has been playing a brilliant role in the treatment of a variety of tumors [5,6,7]. Seeking the key regulatory factors in the occurrence and development of CCA and utilizing them as the target of CCA treatment can lay a solid foundation for changing the treatment mode and efficiency of CCA in the future
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