Identification of prognostic biomarker in predicting hepatocarcinogenesis from cirrhotic liver using protein and gene signatures

Sun Young Yim, Nahm Ji Hae, Ji Hyun Shin, Yun Seong Jeong, Sang Hee Kang, Young Nyun Park, Soon Ho Um, Ju Seog Lee

Research output: Contribution to journalArticle

Abstract

Introduction: Cirrhosis primes the liver for hepatocellular carcinoma (HCC) development. However, biomarkers that predict HCC in cirrhosis patients are lacking. Thus, we aimed to identify a biomarker directly from protein analysis and relate it with transcriptomic data to validate in larger cohorts. Material and method: Forty-six patients who underwent hepatectomy for HCC that arose from cirrhotic liver were enrolled. Reverse-phase protein array and microarray data of these patients were analyzed. Clinical validation was performed in two independent cohorts and functional validation using cell and tissue microarray (TMA). Results: Systematic analysis performed after selecting 20 proteins from 201 proteins with AUROC >70 effectively categorized patients into high (n = 20) or low (n = 26) risk HCC groups. Proteome-derived late recurrence (PDLR)-gene signature comprising 298 genes that significantly differed between high and low risk groups predicted HCC well in a cohort of 216 cirrhosis patients and also de novo HCC recurrence in a cohort of 259 patients who underwent hepatectomy. Among 20 proteins that were selected for analysis, caveolin-1 (CAV1) was the most dominant protein that categorized the patients into high and low risk groups (P <.001). In a multivariate analysis, compared with other clinical variables, the PDLR-gene signature remained as a significant predictor of HCC (HR 1.904, P = .01). In vitro experiments revealed that compared with mock-transduced immortalized liver cells, CAV1-transduced cells showed significantly increased proliferation (P < .001) and colony formation in soft agar (P < .033). TMA with immunohistochemistry showed that tissues with CAV1 expression were more likely to develop HCC than tissues without CAV1 expression (P = .047). Conclusion: CAV1 expression predicts HCC development, making it a potential biomarker and target for preventive therapy.

Original languageEnglish
Article number104319
JournalExperimental and Molecular Pathology
Volume111
DOIs
Publication statusPublished - 2019 Dec
Externally publishedYes

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Keywords

  • Caveolin-1
  • Hepatocellular carcinoma
  • Liver cirrhosis
  • Reverse-phase protein array

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry

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