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

• 作者: Zhen Ni Wenquan Lu Qi Li Chuan Han Ting Yuan Nina Sun Yongquan Shi
• 来源期刊: 癌症生物学与医学（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: ORIGINAL ARTICLE
• 页码范围: 530-546
• 页数: 17页
• 语种: 英文
• DOI: 10.20892/j.issn.2095-3941.2020.0131

摘要

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<0.05), but no significant differences were found in P2-HNF4A expression (P>0.05). High P1-HNF4A expression indicated poor prognoses in GC 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 tumor growth (P < 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.