SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types

• Published in: PloS one Vol. 12; no. 11; p. e0187814
• Main Authors: Richtig, Georg, Aigelsreiter, Ariane, Schwarzenbacher, Daniela, Ress, Anna Lena, Adiprasito, Jan Basri, Stiegelbauer, Verena, Hoefler, Gerald, Schauer, Silvia, Kiesslich, Tobias, Kornprat, Peter, Winder, Thomas, Eisner, Florian, Gerger, Armin, Stoeger, Herbert, Stauber, Rudolf, Lackner, Carolin, Pichler, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.11.2017; Public Library of Science (PLoS)
• Subjects: Aged; Analysis; Biology and life sciences; Biomarkers, Tumor - metabolism; Biotechnology; Breast cancer; Cancer; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell culture; Cell division; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell survival; Cohort Studies; Development and progression; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic aspects; Genomes; Hepatocellular carcinoma; Hepatocytes; Hepatology; Humans; Immunohistochemistry; Internal medicine; Kinases; Liver; Liver cancer; Liver cirrhosis; Liver Neoplasms - diagnosis; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lungs; Male; Medical prognosis; Medicine; Medicine and Health Sciences; Middle Aged; Multivariate analysis; Mutation; Neoplastic Stem Cells - pathology; Oncology; Ovarian cancer; Pathology; Patients; Physiological aspects; Prognosis; Research and Analysis Methods; siRNA; Sox9 protein; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Stem cell factor; Stem cells; Tumor cell lines; Austria
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187814

SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.