Biomarker Identification for Liver Hepatocellular Carcinoma and Cholangiocarcinoma Based on Gene Regulatory Network Analysis

Background: Liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) are two main histological subtypes of primary liver cancer with a unified molecular landscape, and feed-forward loops (FFLs) have been shown to be relevant in these complex diseases. Objective: To date, there has been no comparative analysis of the pathogenesis of LIHC and CHOL based on regulatory relationships. Therefore, we investigated the common and distinct regulatory properties of LIHC and CHOL in terms of gene regulatory networks. Methods: Based on identified FFLs and analysis of pathway enrichment, we constructed pathwayspecific co-expression networks and further predicted biomarkers for these cancers by network clustering. Results: We identified 20 and 36 candidate genes for LIHC and CHOL, respectively. The literature from PubMed supports the reliability of our results. Conclusion: Our results indicated that the hsa01522-Endocrine resistance pathway was associated with both LIHC and CHOL. Additionally, six genes (SPARC, CTHRC1, COL4A1, EDIL3, LAMA4 and OLFML2B) were predicted to be highly associated with both cancers, and COL4A2, CSPG4, GJC1 and ADAMTS7 were predicted to be potential biomarkers of LIHC, and COL6A3, COL1A2, FAP and COL8A1 were predicted to be potential biomarkers of CHOL. In addition, we inferred that the Collagen gene family, which appeared more frequently in our overall prediction results, might be closely related to cancer development.