Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Objective: Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, theroles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remainobscure. Methods: The expression and prognostic values of P1- and P2-HNF4A were evaluated in The Cancer Genome Atlas (TCGA)databases and GC tissues. Then, functional assays of P1- and P2-HNF4A were conducted both in vivo and in vitro. High-throughputRNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and generegulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functionalassays. Results: HNF4A amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage.Moreover, P1-HNF4A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues (P 0.05). High P1-HNF4A expression indicated poor prognoses inGC patients (P < 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation,invasion and migration in vitro (P < 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumorgrowth (P < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enrichedin P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A inGC tissues. Conclusions: P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathwayplayed a pivotal role and may be a promising therapeutic target.