So I've been researching for my Cancer Project and came across an interesting article that related a lot to what we have been discussing in class (here). Before I explain the article and share my thought, here are a few facts about HCV and its role in inducing liver cancer.
Basic Facts About Hepatitis C:
- Hepatitis C (HCV) is one of 3 common hepatitis viruses (the others are A and B) that targets the liver.
- HCV is the most common chronic bloodbourne infection in the United States. At any time, approximately 3.2 million people are chronically infected.
- Hepatocellular carcinoma (HCC) is the major cause of death in individuals with chronic HCV; however, it is not yet clear how HCV induces HCC.
- There are two theories as to how HCV induces HCC:
- Inflammation: Chronic inflammation induces necrosis in hepatocytes. The regeneration of cells that follows increases mutagenesis which over time culminates in HCC.
- Viral Proteins: HCV proteins have oncogenic properties that promote cell proliferation
The authors chose to study the latter mechanism. The investigated the role of HCV proteins in carcinogenesis using transgenic mice.
Experiment:
The researchers developed three lines of transgenic mice. The genome of each line was engineered to either carry HCV's core gene, envelope gene, or non-structural genes. The researchers found that only transgenic mice with the core protein developed HCC. Mice with the envelope or non-structural genes did not develop HCC.
The transgenic mice with core gene expressed the core protein in levels that are similar in chronic hepatitis C patients. Two other characteristics suggested that these transgenic mice could serve as a good model organism for research:
- Their liver developed hepatic steatosis (the abnormal retention of lipids in a cell), a characteristic that is also seen in chronic HCV patients.
- Significant inflammation was not observed in the liver of core gene transgenic mice. This ensures that "inflammation theory" does not confound the results.
These results indicated the oncogenic potential of HCV core protein when expressed in vivo.
How does HCV core protein lead to hepatocarcinogenesis?
- In addition to its presence in the cytoplasm, core protein was also present in mitochondria and nuclei.
- Mitochondria: Core gene transgenic mice saw an increase in the production of oxidative stress in the liver. The oxidative stress in the mitochondria resulted in the accumulation of mitochondrial DNA that may contribute to hepatocarcinogenesis. Because inflammation was not observed in transgenic mice, the overproduction of reactive oxygen species (ROS) in the liver could be solely attributed to the core proteins.
- Nucleus:
- Core protein has been found to transcriptionally activate TNF-alpha and IL-1beta. Both TNF-alpha and IL-1beta are cytokines involved in inflammation and the stimulation of an immune response. As we have discussed in class, immune cells may possible contribute to tumorogenesis by releasing mitogens from the ECM.
- Core protein has been found to interact with RXR-alpha, a protein that plays an important role in cell proliferation and metabolism.
- The mitogen-activated protein (MAPK) cascade has also been activated in the core gene transgenic mice. MAPK is a group of serine/threonine kinases that respond to extracellular stimuli and modulate cell proliferation, mitosis, and apoptosis among other things. Specifically, the JNK route within the MAPK cascade is activated. This activates AP-1 which then increases protein levels of cyclin D1 and CDK4 (a ser/thr protein kinase). As discussed in class the increase in receptors can amplify an extracellular signal that leads to increased proliferation.
- Lastly, the core protein has been found to suppress the a tumor suppressor protein named the suppressor of cytokine signaling (SOCS-1).
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| Proposed Mechanism for HCV Induction of Liver Cancer |
Conclusion:
Because the researchers were able to study the role of HCV proteins in the absence of inflammation, there were able to independently determine the its mechanism in inducing HCC. In their conclusion, the authors suggest that both the core protein and increased liver inflammation in humans contributes to liver cancer. The fact that core proteins are able to manipulate so many intracellular pathways involved in cell proliferation explains the high incidence of liver cancer in chronic HCV patients. Unlike the development of other cancers that require the accumulation of genetic mutations over time, several mechanism are working at the same time in HCV patients that leads to genetic aberration and consequently, HCC.
Thoughts:
1) Overall, it seems like this study found a great model for studying HCV and HCC. The mouse model offers a great way to study the mechanism of the HCV proteins without the effects of inflammation.
2) How does genetic aberration in mitochondrial DNA contribute to cancer? It is possible that defects metabolic genes might help cancer cells shunt of aerobic respiration in favor of the glycolytic pathway. This was one of the emerging hallmarks discussed in Hanahan and Weinberg's article.
3) In terms of the mechanism, the HCV protein behaved in a way much differently than what we discussed in class. The viral genome did not code for an oncoprotein like v-SRC or insert a promoter region before a protooncogene. Rather, the core proteins somehow affected proteins involved in transduction cascades. Does this increase the the carcinogenic properties of the virus?
This week, we briefly discussed in class that in addition to receptor kinase mutations, other downstream mutations may be necessary to negate the effects of secondary negative feedback systems. After looking online, I found that MAPK was one of several downstream cascades that are affected by receptor kinases. So it turns out that HCV induced HCC was a case in which the receptor was not affected, but rather the downstream protein.
All this made me wonder if mutations or disregulation of proteins further downstream of a transduction cascade are more likely to lead to tumorogenesis. After all, the closer a protein mutation or disruption is to its DNA target, the less likely another negative feedback system can suppress its cell proliferation signal. Could this explain why so many people with HCV develop HCC?
4) In regards to treatment, it seems that the cancer would be more difficult to treat if a downstream target is already being disrupted. If the proteins intracellular, it would be tough for a treatment to target. However, since ultimately all proteins in a transduction cascade lead to the promotion transcription factors that promote genes that give rise to cancer hallmarks, could we eventually learn a way to target treatment at transcription factors?
This got me into thinking about how good viruses are at getting into cells and disrupting out DNA. Could this be a way to deliver treatment? I did a simple Google search and found a vast number of studies uses viruses as gene therapy against cancer. This looked like a fascinating topic for anyone looking into writing another blog.
If you guys have any questions or thoughts feel free to leave a comment.
1) Overall, it seems like this study found a great model for studying HCV and HCC. The mouse model offers a great way to study the mechanism of the HCV proteins without the effects of inflammation.
2) How does genetic aberration in mitochondrial DNA contribute to cancer? It is possible that defects metabolic genes might help cancer cells shunt of aerobic respiration in favor of the glycolytic pathway. This was one of the emerging hallmarks discussed in Hanahan and Weinberg's article.
3) In terms of the mechanism, the HCV protein behaved in a way much differently than what we discussed in class. The viral genome did not code for an oncoprotein like v-SRC or insert a promoter region before a protooncogene. Rather, the core proteins somehow affected proteins involved in transduction cascades. Does this increase the the carcinogenic properties of the virus?
This week, we briefly discussed in class that in addition to receptor kinase mutations, other downstream mutations may be necessary to negate the effects of secondary negative feedback systems. After looking online, I found that MAPK was one of several downstream cascades that are affected by receptor kinases. So it turns out that HCV induced HCC was a case in which the receptor was not affected, but rather the downstream protein.
All this made me wonder if mutations or disregulation of proteins further downstream of a transduction cascade are more likely to lead to tumorogenesis. After all, the closer a protein mutation or disruption is to its DNA target, the less likely another negative feedback system can suppress its cell proliferation signal. Could this explain why so many people with HCV develop HCC?
4) In regards to treatment, it seems that the cancer would be more difficult to treat if a downstream target is already being disrupted. If the proteins intracellular, it would be tough for a treatment to target. However, since ultimately all proteins in a transduction cascade lead to the promotion transcription factors that promote genes that give rise to cancer hallmarks, could we eventually learn a way to target treatment at transcription factors?
This got me into thinking about how good viruses are at getting into cells and disrupting out DNA. Could this be a way to deliver treatment? I did a simple Google search and found a vast number of studies uses viruses as gene therapy against cancer. This looked like a fascinating topic for anyone looking into writing another blog.
If you guys have any questions or thoughts feel free to leave a comment.
Works Cited:
Koike, Kazuhiko. "Hepatitis C Virus Contributes to Hepatocarcinogenesis by Modulating Metabolic and Intracellular Signaling Pathways." Journal of Gastroenterology and Hepatology 22.S1 (2007): S108-111.
"Mitogen-activated Protein Kinase." Wikipedia. Wikimedia Foundation, 05 Jan. 2012. Web. 04 May 2012. <http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase>.
