Superfund Research Program
Effects of Superfund Toxicants on Liver Cancer Progenitor Cells
Project Leader: Michael Karin
Grant Number: P42ES010337
Funding Period: 2000-2017
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Exposure to certain chemicals found at Superfund sites, such as vinyl chloride, cause fatty changes in the liver accompanied by inflammation and thereby resulting in a condition known as toxicant associated steatohepatitis (TASH). The pathological manifestations of TASH are highly similar to those of non-alcoholic steatohepatitis (NASH). Both TASH and NASH can lead to liver cirrhosis and increase the risk of hepatocellular carcinoma (HCC), the major form of liver cancer. The research team has been studying how altered liver metabolism controls the development of NASH and its progression to HCC. This investigation resulted in the identification of p62/SQSTM1, a multifunctional signaling adaptor protein, as a key regulator of NASH-driven HCC development. Accumulation of p62 in the liver is a response to many types of stress and leads to activation of NRF2, a transcription factor that protects HCC initiating cells from oxidative stress, thereby allowing these cells to accumulate numerous oncogenic mutations. p62 accumulation is deleted in many liver diseases and its elevated expression in non-tumor liver tissue signifies rapid progression to HCC.