ABSTRACT: Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, necessitating the need for further evaluation of the genome and RNA expression data in order to identify potential therapeutic targets, clarify the roles of these targets in the tumor microenvironment, and explore novel therapeutic drugs against the identified targets. Consequently, in our attempt to explore novel genetic markers associated with the carcinogenesis of CHOL, five genes (SNX15, ATP2A1, PDCD10, BET1, and HMGA2), collectively termed CHOL-hub genes, were identified via integration of differentially expressed genes (DEGs) from relatively large numbers of samples from CHOL GEO datasets. We further explored the biological functions of the CHOL-hub genes and found significant enrichment in several biological process and pathways associated with stem cell angiogenesis, cell proliferation, and cancer development, while the interaction network revealed high genetic interactions with a number of onco-functional genes. In addition, we established associations between the CHOL-hub genes and tumor progression, metastasis, tumor immune and immunosuppressive cell infiltration, dysfunctional T-cell phenotypes, poor prognoses, and therapeutic resistance in CHOL. Thus, we proposed that targeting CHOL-hub genes could be an ideal therapeutic approach for treating CHOLs, and we explored the potential of HLC-018, a novel benzamide-linked small molecule, using molecular docking of ligand-receptor interactions. To our delight, HLC-018 was well accommodated with high binding affinities to binding pockets of CHOL-hub genes; more importantly, we found specific interactions of HLC-018 with the conserved sequence of the AT-hook DNA-binding motif of HMGA2. Altogether, our study provides insights into the immune-oncogenic phenotypes of CHOL and provides valuable information for our ongoing experimental validation.
