Analysis of the Isoform-regulated Transcriptome Identifies 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, the roles of different 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- were evaluated in The Cancer Genome Atlas (TCGA) databases and GC tissues. Then, functional assays of P1- and P2- were conducted both and . High-throughput RNA-seq was employed to profile downstream pathways in P1- and P2--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: amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage. Moreover, P1- expression was significantly higher in tumor tissues than in adjacent non-tumor tissues ( < 0.05), but no significant differences were found in P2- expression ( > 0.05). High P1- expression indicated poor prognoses in GC patients ( < 0.01). Furthermore, P1- overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration ( < 0.01). Murine xenograft experiments showed that P1- overexpression promoted tumor growth ( < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1--overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1- in GC tissues.

Conclusions: P1- was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.