{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:08:44Z","timestamp":1769083724327,"version":"3.49.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:p>Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with <jats:italic toggle=\"yes\">SOX9<\/jats:italic>-high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High <jats:italic toggle=\"yes\">SOX9<\/jats:italic> mRNA level, but not increased expression of <jats:italic toggle=\"yes\">EpCAM<\/jats:italic> mRNA or <jats:italic toggle=\"yes\">K19<\/jats:italic> mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High <jats:italic toggle=\"yes\">SOX9<\/jats:italic> mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased <jats:italic toggle=\"yes\">SOX9<\/jats:italic> mRNA and can be used to predict prognosis in HCC cases.<\/jats:p>","DOI":"10.1097\/pas.0000000000001990","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T23:00:07Z","timestamp":1667430007000},"page":"1-11","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":9,"title":["SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma"],"prefix":"10.1097","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0833-8335","authenticated-orcid":false,"given":"Marianna B.","family":"Ruzinova","sequence":"first","affiliation":[{"name":"Pathology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Pathology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M.","family":"Brunt","sequence":"additional","affiliation":[{"name":"Pathology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles W.","family":"Goss","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeta","family":"Vachharajani","sequence":"additional","affiliation":[{"name":"Surgery"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Surgery"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ta-Chiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Pathology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"R1-20250608","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J Hepatol"},{"key":"R2-20250608","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1200\/EDBK_200939","article-title":"Global epidemiology, prevention, and management of hepatocellular carcinoma","volume":"38","author":"Mak","year":"2018","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"R3-20250608","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrc2499","article-title":"Cancer stem cells in solid tumours: accumulating evidence and unresolved questions","volume":"8","author":"Visvader","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"R4-20250608","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.3748\/wjg.v22.i13.3547","article-title":"Liver cancer stem cell markers: progression and therapeutic implications","volume":"22","author":"Sun","year":"2016","journal-title":"World J Gastroenterol"},{"key":"R5-20250608","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ejca.2007.01.004","article-title":"Prognostic molecular markers in hepatocellular carcinoma: a systematic review","volume":"43","author":"Mann","year":"2007","journal-title":"Eur J Cancer"},{"key":"R6-20250608","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1097\/PAS.0000000000000218","article-title":"SALL4 immunoreactivity predicts prognosis in Western hepatocellular carcinoma patients but is a rare event: a study of 236 cases","volume":"38","author":"Liu","year":"2014","journal-title":"Am J Surg Pathol"},{"key":"R7-20250608","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1365-2559.2006.02468.x","article-title":"The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. 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