title: Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.
abstract: Macroautophagy and chaperone-mediated autophagy (CMA) represent two major lysosomal degradation processes and often compensate for one another to facilitate cell survival. The aim of this study was to determine whether these autophagy pathways could compensate for one another to promote HCC cell survival in the cirrhotic liver. Analysis of normal liver tissue showed no expression of glypican-3 or p62 proteins, suggesting that macroautophagy is the major contributor to autophagic flux under non-pathological conditions. Of 46 cirrhotic livers with HCC examined, 39 (84%) of HCCs showed increased expression of p62, and 36 (78%) showed increased expression of glypican-3, while adjacent non-tumorous hepatocytes were negative for expression of p62 and glypican-3, similar to normal liver tissue. These results suggest that macroautophagy flux is impaired in HCC. Furthermore, more than 95% of HCCs showed altered expression of LAMP-2A compared to the surrounding non-tumorous cirrhotic liver, consistent with induction of CMA in HCC. Elevated expression of glucose-regulated protein 78 (GRP78) and heat shock cognate protein (Hsc70) were detected in 100% of HCC and adjacent non-tumorous cirrhotic livers, suggesting that unresolved ER-stress is associated with HCC risk in liver cirrhosis. Interestingly, inhibition of lysosomal degradation using hydroxychloroquine (HCQ) induced expression of the tumor suppressor p53, promoted apoptosis, and inhibited HCC growth, whereas activation of autophagy using an mTOR inhibitor (Torin1) promoted HCC growth. Results of this study suggest that induction of CMA compensates for the impairment of macroautophagy to promote HCC survival in the cirrhotic liver.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chava
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Yucel
authors.initials: Y
authors.lastname: Aydin
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Partha K
authors.initials: PK
authors.lastname: Chandra
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Dash
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Milad
authors.initials: M
authors.lastname: Chedid
authors.affiliation: The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Swan N
authors.initials: SN
authors.lastname: Thung
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Moroz
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Senior Consultant and Advisor, Sir Ganga Ram Hospital, Department of Pathology, New Delhi, India.
authors.forename: Nabeen C
authors.initials: NC
authors.lastname: Nayak
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Dash
mesh_terms: D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D053673:Glypicans / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C105937:GPC3 protein, human; D053673:Glypicans; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: Pathology Section; chaperone-mediated autophagy; endoplasmic reticulum; hepatocellular carcinoma; liver cirrhosis; macroautophagy