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posted on 2024-02-02, 14:20 authored by Kazuto Suda, Atsushi Okabe, Junichi Matsuo, Linda Shyue Huey Chuang, Ying Li, Nawaphat Jangphattananont, Naing Naing Mon, Khine Nyein Myint, Akihiro Yamamura, Jimmy Bok-Yan So, Dominic Chih-Cheng Voon, Henry Yang, Khay Guan Yeoh, Atsushi Kaneda, Yoshiaki Ito RUNX3 promotes cancer cell migration and invasion. A, The efficiency of siRUNX3 KD in HGC-27 and LMSU and RUNX3 OE in GAS24 were validated by immunoblot. B, Invasion and migration analysis for siRUNX3 in HGC-27 and LMSU and also RUNX3 OE in GAS24. Experiments were repeated three times. Typical images from one experiment are shown. C, Cell invasion and migration were counted and quantified from 5 different high-power fields in each experiment; ***, P < 0.001; **, P < 0.01; and *, P < 0.05 by a two-tailed Student t test.
Funding
NUS | Cancer Science Institute of Singapore, National University of Singapore (CSI)
MOH | National Medical Research Council (NMRC)
Japan Agency for Medical Research and Development (AMED)
Chiba University (千葉大学)
History
ARTICLE ABSTRACT
Gastric cancer metastasis is a major cause of mortality worldwide. Inhibition of RUNX3 in gastric cancer cell lines reduced migration, invasion, and anchorage-independent growth in vitro. Following splenic inoculation, CRISPR-mediated RUNX3-knockout HGC-27 cells show suppression of xenograft growth and liver metastasis. We interrogated the potential of RUNX3 as a metastasis driver in gastric cancer by profiling its target genes. Transcriptomic analysis revealed strong involvement of RUNX3 in the regulation of multiple developmental pathways, consistent with the notion that Runt domain transcription factor (RUNX) family genes are master regulators of development. RUNX3 promoted “cell migration” and “extracellular matrix” programs, which are necessary for metastasis. Of note, we found pro-metastatic genes WNT5A, CD44, and VIM among the top differentially expressed genes in RUNX3 knockout versus control cells. Chromatin immunoprecipitation sequencing and HiChIP analyses revealed that RUNX3 bound to the enhancers and promoters of these genes, suggesting that they are under direct transcriptional control by RUNX3. We show that RUNX3 promoted metastasis in part through its upregulation of WNT5A to promote migration, invasion, and anchorage-independent growth in various malignancies. Our study therefore reveals the RUNX3-WNT5A axis as a key targetable mechanism for gastric cancer metastasis.
Subversion of RUNX3 developmental gene targets to metastasis program indicates the oncogenic nature of inappropriate RUNX3 regulation in gastric cancer.
