Research paperDownregulation of Peptidylprolyl isomerase A promotes cell death and enhances doxorubicin-induced apoptosis in hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC), one of the major cause of malignant tumor in China, is the fifth-most common cancer and the third cause of cancer-related mortality worldwide (Siegel et al., 2014). The relationship between chronic infection with hepatitis B virus and hepatocellular carcinoma is well established, and some 340,000 cases of HCC are attributable to hepatitis B infection (Parkin, 2006). The clinical characteristics of HCC include highly aggressive, recurring tumor formation that are frequently associated with metastasis to the lungs. To treat HCC patients, surgical resection, chemoembolization, radiation therapy, and liver transplantation have all been employed. However, even with these techniques, the incidence rate is still highly correlated to the death rate, with the five-year survival rate only being modestly improved to approximately 26% in the United States (Maluccio and Covey, 2012, Simard et al., 2012). Although progress has been made in recent decades to better understand and treat HCC, the underlying molecular mechanisms of this aggressive cancer remain elusive (El-Serag and Rudolph, 2007). Therefore, it is critical to explore the cellular signaling cascades operating during HCC pathogenesis in order to provide insights into other diagnosis and treatment options for HCC patients.
Peptidylprolyl isomerase A (PPIA), also known as CYPA, a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerates protein folding. It was originally purified from bovine thymocytes and characterized as the primary cytoplasmic binding protein of the immunosuppressant cyclosporin A (CsA) (Handschumacher et al., 1984). Previous studies have also reported that PPIA is involved in several diseases, including viral infection, cardiovascular disease, and various inflammatory diseases (Franke et al., 1994, Jin et al., 2000, Gwinn et al., 2006). Moreover, this enzyme has also been shown to be a key molecule in multiple biological functions, including molecular chaperoning, protein folding, protein trafficking, immune modulation, and cell signaling (Kern et al., 1995, Galigniana et al., 2004, Syed et al., 2003, Colgan et al., 2004). Phosphorylation of apoptosis signaling-regulating kinase 1 (ASK1) is also regulated by PPIA, which reduces the expression and function of ASK1 as well as its downstream kinases in the JNK and p38 signaling pathways (Kim et al., 2015). Recently, several studies have shown that PPIA is overexpressed in some human cancers, including non-small cell lung cancer, pancreatic adenocarcinoma, tongue squamous cell carcinoma, and head and neck squamous cell carcinoma (Campa et al., 2003, Howard et al., 2005, Qian et al., 2012, Li et al., 2005, Li et al., 2006, Huang et al., 2012, Takahashi et al., 2012). Furthermore, PPIA also appears to participate in cancer proliferation, cell cycle progression, regulation of apoptosis, and cell migration/invasion, all of which play various pathophysiological functions during tumor progression (Li et al., 2008, Semba and Huebner, 2006, Choi et al., 2007, Calhoun et al., 2009). However, although there is a growing body of evidence that PPIA may play a pivotal role during tumor development, our understanding of the precise roles of PPIA in tumor cell proliferation and apoptosis is limited, particularly in HCC.
In the present study, we sought to determine the clinical significance of PPIA in HCC carcinogenesis and progression. To do so, we first established the expression level of PPIA in HCC tissue, followed by functional analysis in multiple liver cancer cell lines. With these data, we further clarified the molecular relationship between PPIA and HCC progression, during which downregulation of PPIA appears to promote cell death and enhance doxorubicin-induced apoptosis.
Section snippets
Patients
Ninety HCC tissues and peritumoral tissues were randomly selected from patients undergoing hepatectomy between 2012 and 2014. Blood samples were collected between May 2014 and November 2014 from Fifty-four patients with histologically documented HCC who were candidated for surgical treatment. The control group consisted of one hundred and five healthy blood donors. All specimens were from our hospital (First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China). Sample
Pattern of PPIA expression in HCC tissues and HCC patients serum
To explore the role of PPIA during HCC pathogenesis, we observed its expression in HCC tissues using Western blotting and real-time PCR. It appears that, at the mRNA level, PPIA was overexpressed in the 51 HCC tissue samples studied compared to their matched peritumoral tissues (Fig. 1A). Moreover, our Western blot analysis indicates that this increase in PPIA mRNA also corresponds to higher PPIA protein expression in the HCC tissues compared to their matched peritumoral tissues (Fig. 1B). For
Discussion
PPIA also was known as CYPA, which is an abundantly expressed protein that possesses peptidyl prolyl cis-trans isomerase activity. Recent research has provided compelling evidence identifying important roles for PPIA in many biological processes. For example, PPIA overexpression has been demonstrated in multiple types of cancer and appears to be related to the clinicopathological symptoms of the patients. Notably, upregulation of PPIA was first reported in HCC in 1998 (Corton et al., 1998).
Conflict of interest
The authors declare that they have no competing interests.
Acknowledgements
This study was supported by grants from the National High Technology Research and Development Program 863 of China (No. 2012AA021002), Science Technology Department of Zhejiang Province (No. 2015C03034), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No. 81421062), National S&T Major Project (No. 2016ZX10002020), the National Health and Family Planning Commission of China (No. 2016138643) and Special Fund for Health Research in the Public
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