title: AT-rich interactive domain 2, p110α, p53, and β-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications.
abstract: AT-rich interactive domain 2 (ARID2), catenin (cadherin-associated protein), beta 1, 88kDa (β-catenin), tumor protein 53 (p53), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, β-catenin, p53, and p110α in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110α compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of targeted mechanistic target of rapamycin (serine/threonine kinase) drug therapies.
authors.affiliation: Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: You
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Yinzhi
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Simon
authors.affiliation: Department of Gastroenterology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jen
authors.initials: J
authors.lastname: Au
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: ashlie.burkart@gmail.com.
authors.forename: Ashlie L
authors.initials: AL
authors.lastname: Burkart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C512511:ARID2 protein, human; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D058543:Class Ia Phosphatidylinositol 3-Kinase
keywords: Hepatocarcinogenesis; Immunohistochemistry; Oncoprotein; Recurrence; mTOR