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

PLoS One. 2017 Nov 9;12(11):e0187814. doi: 10.1371/journal.pone.0187814. eCollection 2017.

Abstract

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.

MeSH terms

  • Aged
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular / diagnosis*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cohort Studies
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / diagnosis*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Middle Aged
  • Neoplastic Stem Cells / pathology*
  • Prognosis
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*

Substances

  • Biomarkers, Tumor
  • SOX9 Transcription Factor

Grants and funding

This research project was supported by a grant of the ÖSTERREICHISCHE KREBSHILFE STEIERMARK (to Martin Pichler) and by a grant of the Hans and Blanca Moser Stiftung (to Florian Eisner). Both funding bodies had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.