Open AccessUpregulation of HOXC9 generates interferon‐gamma resistance in gastric cancer by inhibiting the DAPK1/RIG1/STAT1 axis
Author(s) -
Tang Yuanxin,
Wang Taifang,
Yu Yue,
Yan Yuhao,
Wu Chunli
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15043
Subject(s) - stat1 , gene knockdown , biology , cancer research , stat protein , downregulation and upregulation , oncogene , irf1 , irf8 , janus kinase , transcription factor , microbiology and biotechnology , gene , signal transduction , stat3 , biochemistry , cell cycle
Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 ( HOXC9 ) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon‐gamma (IFNγ)‐dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase‐3/7 and phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death‐associated protein kinase 1 ( DAPK1 ) and its downstream retinoic acid‐inducible gene‐I ( RIG1 ) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p‐STAT1 axis.