Homozygotes for the classic form of alpha-1-antitrypsin (AT) deficiency are predisposed to hepatocellular carcinoma. The deficiency is caused by a mutant protein, ATZ, which is retained in the endoplasmic reticulum (ER) of liver cells in a polymerized form rather than secreted into the blood in its monomeric form. The histologic hallmark of the disease is ATZ-containing globules in some but not all hepatocytes. Liver injury results from a gain-of-toxic function mechanism in which mutant ATZ retained in the ER initiates a series of pathologic events but little is known about the mechanism of carcinogenesis. Several recent observations from my laboratory have led to a novel hypothetical paradigm for the pathogenesis of hepatocellular carcinoma in AT deficiency. First, in vivo BrdU labeling studies in transgenic mouse models of AT deficiency have shown that hepatocytes without ATZ -containing globules (globule-devoid hepatocytes) have increased cell proliferation that is proportional to the number of globule-containing hepatocytes. Globule-containing hepatocytes do not incorporate BrdU and lack signs of cell death. Second, time-lapsed video microscopy of single cells in culture show that ER accumulation of A TZ leads to profound suppression of proliferation. Third, accumulation of ATZ in the ER activates a distinct profile of signaling pathways including NFKB, ER- and mitochondrial-caspases and autophagy but not the unfolded protein response. Fourth, genomic analysis indicates that accumulation of ATZ in the ER alters the expression of several genes that could account for a growth suppressive effect, including upregulation of regulator of G signaling 16 (RGS16). This has led to a hypothetical paradigm for pathogenesis of hepatic carcinoma in AT deficiency in which globule-containing hepatocytes are envisioned as 'sick', growth suppressed and elaborating trans- acting regenerative signals for proliferation of globule-devoid hepatocytes that have a selective proliferative advantage. Chronic regeneration in the presence of tissue injury leads to adenomas and ultimately carcinomas. In this application we propose the use of model cell lines and transgenic mice with inducible expression recently generated in my laboratory and development of several new genetically engineered cell line and transgenic mouse models of AT deficiency to further test the validity of this hypothetical paradigm and its mechanisms.
This application proposes studies that will advance our knowledge of how antitrypsin deficiency and other genetic diseases of the liver lead to liver cancer. This knowledge will allow us to formulate novel strategies for treatment and prevention of liver cancer.
|Wang, Yan; Perlmutter, David H (2014) Targeting intracellular degradation pathways for treatment of liver disease caused by ?1-antitrypsin deficiency. Pediatr Res 75:133-9|
|Chu, Andrew S; Perlmutter, David H; Wang, Yan (2014) Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases. Biomed Res Int 2014:459823|
|Li, Jie; Pak, Stephen C; O'Reilly, Linda P et al. (2014) Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency. PLoS One 9:e87260|
|Ghouse, Raafe; Chu, Andrew; Wang, Yan et al. (2014) Mysteries of ?1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease. Dis Model Mech 7:411-9|
|Silverman, Gary A; Pak, Stephen C; Perlmutter, David H (2013) Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype. J Pediatr 163:320-6|
|Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58|
|Maurice, Nicholas; Perlmutter, David H (2012) Novel treatment strategies for liver disease due to ?1-antitrypsin deficiency. Clin Transl Sci 5:289-94|
|Miedel, Mark T; Graf, Nathan J; Stephen, Kate E et al. (2012) A pro-cathepsin L mutant is a luminal substrate for endoplasmic-reticulum-associated degradation in C. elegans. PLoS One 7:e40145|
|Ding, Jianqiang; Yannam, Govardhana R; Roy-Chowdhury, Namita et al. (2011) Spontaneous hepatic repopulation in transgenic mice expressing mutant human ?1-antitrypsin by wild-type donor hepatocytes. J Clin Invest 121:1930-4|
|Gosai, Sager J; Kwak, Joon Hyeok; Luke, Cliff J et al. (2010) Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin ?1-antitrypsin Z. PLoS One 5:e15460|
Showing the most recent 10 out of 11 publications