Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
Highlights
Hepatitis C Virus Replication in the LiverInfection with Hepatitis C Virus (HCV) is one of the major causes for liver damage.
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm
We found that the MAPK signaling pathway as well as the transcription factor c-Jun are up-regulated in HCV replicating hepatocellular carcinoma (HCC) cells [74]
Summary
Infection with Hepatitis C Virus (HCV) is one of the major causes for liver damage. . Cancer cells may need to grow and replicate, even under low oxygen conditions, since regular blood vessels may not be sufficient to provide enough oxygen for their fast growth, while blood vessels newly induced by the tumor still need to grow For these reasons, cancer cells usually undergo a metabolic switch, which enhances metabolite flux through glycolysis (see Figure 3) towards its end-product pyruvate (Pyr). Further downstream metabolite consumption by mitochondrial pyruvate dehydrogenase (PDH), citric acid cycle (or tricarboxylic acid [TCA] cycle) and oxidative phosphorylation is reduced but not completely abolished to still allow for sufficient ATP production [64,65,66] The change to this so-called aerobic glycolysis in tumor cells [61,62] was named the Warburg Effect. The lactate is released from the tumor cells [59,60,61,69] and reused in the liver to produce glucose (known as the “Cori cycle” which is obligatory in the case of muscle working under anaerobic conditions as well as for erythrocytes which do not have mitochondria) [70]
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