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.
Highlights
Cholangiocarcinomas (CHOLs) are hepatobiliary malignancies ranked as the 2nd most prevalent hepatic cancer next to hepatocellular carcinoma [1]
We found that CHOL patients with metastases in one to three axillary lymph nodes exhibited significantly higher expression levels of SNX15, ATP2A1, PDCD10, BET1, and High-mobility group A2 (HMGA2) than patients with no regional lymph node metastasis (Figure 2E)
Our results indicated that SNX15, ATP2A1, PDCD10, BET1, Cells 2021, 10, x FOR PEER REVIEW and HMGA2 could serve as a biomarker signature of tumor progression and metastasis in Schematic flow flow chart chart of of the the study study design design for for identifying identifying and and characterizing characterizing the the pathological pathological role role of of differentially expressed genes (DEGs)
Summary
Cholangiocarcinomas (CHOLs) are hepatobiliary malignancies ranked as the 2nd most prevalent hepatic cancer next to hepatocellular carcinoma [1]. They are characterized by cholangiocyte phenotypic features and are anatomically classified into intrahepatic, perihilar, and distal CHOLs based on their respective locations in the periphery of second-order bile ducts, the right and/or left hepatic duct, and the common bile duct [2]. Percentage occurrences of the perihilar, distal, and intrahepatic types of CHOLs are 50%, 42%, and 8%, respectively [3] These subtypes differ in their etiology, epidemiology, pathogenesis, diagnosis, and treatment [4]. These subtypes are united by a late diagnosis, limited curative options, and poor prognoses [5]; they all have a median survival of 24 months after diagnosis [4].
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