PT - JOURNAL ARTICLE AU - Zhen Ni AU - Wenquan Lu AU - Qi Li AU - Chuan Han AU - Ting Yuan AU - Nina Sun AU - Yongquan Shi TI - Analysis of the <em>HNF4A</em> isoform-regulated transcriptome identifies <em>CCL15</em> as a downstream target in gastric carcinogenesis AID - 10.20892/j.issn.2095-3941.2020.0131 DP - 2021 May 01 TA - Cancer Biology and Medicine PG - 530--546 VI - 18 IP - 2 4099 - http://www.cancerbiomed.org/content/18/2/530.short 4100 - http://www.cancerbiomed.org/content/18/2/530.full SO - Cancer Biol Med2021 May 01; 18 AB - Objective: Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, the roles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remain obscure.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-throughput RNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays.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 &lt; 0.05), but no significant differences were found in P2-HNF4A expression (P &gt; 0.05). High P1-HNF4A expression indicated poor prognoses in GC patients (P &lt; 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration in vitro (P &lt; 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumor growth (P &lt; 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A in GC tissues.Conclusions: P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.