Korean J Physiol Pharmacol.  2013 Oct;17(5):375-383. 10.4196/kjpp.2013.17.5.375.

Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma

• Lee J

• KMID: 1500231
• DOI: http://doi.org/10.4196/kjpp.2013.17.5.375

Abstract

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

Keyword

Cyclophilin A; Hepatitis C virus; Hepatocellular carcinoma; Peptidyl prolyl isomerase

MeSH Terms

Carcinoma, Hepatocellular*
Carrier Proteins
Cyclophilin A*
Cyclophilins
Cyclosporine
Cyclosporins
Cytosol
Hepacivirus*
Hepatitis B virus
Hepatitis C*
Hepatitis C, Chronic
Hepatitis
Hepatocytes
Liver
Liver Diseases
Liver Neoplasms
RNA Replicase
Carrier Proteins
Cyclophilin A
Cyclophilins
Cyclosporine
Cyclosporins
RNA Replicase

Figure

• 

  Fig. 1 CypA may activate HCC development through inhibiting hypoxia-induced apoptosis and facilitating HCV infection. CypA that is up-regulated by HIF-1 may prevent hypoxia-induced apoptosis in HCC. During HCV infection, hepatocarcinogenesis can be induced by direct and indirect, namely inflammation-mediated, pathways. Direct HCV protein-induced alterations in hepatocyte can be induced by Core, E2 and NS5A proteins and initiate hepatocarcinogenesis. NS5B, NS5A, and CypA are three essential proteins for HCV replication. CypA with NS5A that forms a functional multiprotein complex with the NS5B polymerase promotes HCV replication. High levels of replication that may establish chronic HCV infection increase the risk for cirrhosis and HCC development.

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