Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Cancer Res Commun. 2024 Feb 2;4(2):279-292. doi: 10.1158/2767-9764.CRC-22-0165.
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.
胃癌转移是全球范围内导致死亡的主要原因。在胃癌细胞系中抑制 RUNX3 可减少体外迁移、侵袭和锚定非依赖性生长。在脾接种后，CRISPR 介导的 RUNX3 敲除 HGC-27 细胞显示出对异种移植物生长和肝转移的抑制作用。我们通过对 RUNX3 的靶基因进行分析，探讨了 RUNX3 作为胃癌转移驱动因子的潜力。转录组分析表明，RUNX3 强烈参与了多个发育途径的调控，这与 runt 结构域转录因子（RUNX）家族基因是发育的主要调控因子的观点一致。RUNX3 促进了“细胞迁移”和“细胞外基质”程序，这些程序是转移所必需的。值得注意的是，我们在 RUNX3 敲除与对照细胞中发现了前转移基因 WNT5A、CD44 和 VIM 等差异表达基因中的前 10 位。染色质免疫沉淀测序和 HiChIP 分析表明，RUNX3 结合到这些基因的增强子和启动子上，表明它们受 RUNX3 的直接转录控制。我们表明，RUNX3 通过上调 WNT5A 促进转移，从而促进各种恶性肿瘤的迁移、侵袭和锚定非依赖性生长。因此，我们的研究揭示了 RUNX3-WNT5A 轴作为胃癌转移的一个关键可靶向机制。
将 RUNX3 发育基因靶标向下转化为转移程序表明，在胃癌中，RUNX3 调节的不当是致癌的。
