LSP1 Involved in Liver Regeneration Termination, Deleted in 50% of Human Liver Cancer, and Major Determinant of Response to Sorafenib
Abstract
Despite hopes that were raised by the introduction of vaccine against Hepatitis B virus (HBV), the control of exposure to fungal toxins (e.g., Aflatoxin), overall decrease in excessive alcohol consumption, and the recent introduction of effective antiviral medications against Hepatitis C virus (HCV), the incidence of liver cancer (hepatocellular carcinoma, HCC) continues to rise rapidly, especially in the Western world. The reasons for this are complicated, but fundamentally they relate to the fact that any chronic liver disease associated with cell replication of the main liver cells (hepatocytes) has a high probability of leading to liver cancer. All of the conditions described above have a high chance of leading to cirrhosis of the liver, a condition in which hepatocytes in cirrhotic nodules rapidly proliferate, and in which typically most liver cancers arise. Just based on existing patients with cirrhosis, tens of thousands of liver cancers are expected to occur in the Western world, including the United States, in the next 20 years. A main offender related to development of cirrhosis in the Western world is the ?Western diet.? This is a diet high in fat and carbohydrates, associated with the current epidemic of obesity, and leading to accumulation of fat in hepatocytes. This can lead to hepatocyte death by slow attrition and development of liver inflammation (non-alcoholic steatohepatitis: NASH). The latter can lead to cirrhosis and to formation of HCC. Military personnel are additionally sensitive to development of HCC due to a variety of toxins and chemicals (in the past, Agent Orange, pesticides, etc.) to which our military is exposed, in addition to ?Western diet,? prior liver diseases leading to cirrhosis, etc. The main chemotherapy against HCC is a compound called Sorafenib. Even though it is the only one available, it is of limited effectiveness, with only about 50% of patients responding and even then offering an extension of life by about 6 months on average. As we were studying the changes in DNA of small early HCC found randomly in cirrhotic livers taken out in the course of liver transplantation, we discovered that the most commonly affected gene was LSP1, a gene unknown in the ?liver literature.? Forty-six percent of HCC had deletion or amplification (5%) of about half (the end portion) of the gene. We studied it out of curiosity, and we found that this ?novel to liver? gene controls the ?activation? of one of the most important signals in hepatocytes, that of ERK. The two forms of ERK (1 and 2) control most signals of hepatocytes associated with cell replication and general functions. Normal LSP1 binds to the complex of proteins that hold ERK together and suppresses ERK function. If LSP1 is deleted, then ERK becomes ?hyperactive? and accentuates growth of hepatocytes, and in the case of the abnormal hepatocytes of HCC, it enhances their cancer behavior. Of interest, the 15% of HCC that have LSP1 amplification (production of many copies of a portion of a gene) actually overproduce the terminal half of the gene, and the ?rump? LSP1 protein actually blocks normal LSP1 from functioning; in terms of normal LSP1 function, this ?amplification? is actually equivalent to a ?deletion.? What is exciting is that activation of ERK is the main target of Sorafenib and that LSP1 controls ERK activation. As the accumulation of findings became ?curiouser,? we found that: (1) Sorafenib is much more effective when LSP1 is deleted. (That may explain why only about 50% of the patients respond properly to Sorafenib). We will perform studies to design diagnostic tests for detecting LSP1 deletions in order to define the patients with liver cancer who would truly benefit from Sorafenib. (2) We are even more excited from the portion of our studies that show that when normal LSP1 is modified by adding a phosphate group (phosphorylation), it appears to cease blocking ERK activation. This happens in hepat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710342
Entities
People
- George Michalopoulos
Organizations
- United States Army
- University of Pittsburgh