Tumor-mesothelium HOXA11-PDGF BB/TGF 1-miR-181a-5p-Egr1 feedforward amplifier circuity propels mesothelial fibrosis and peritoneal metastasis of gastric cancer

A proportion of gastric cancer (GC) patients suffer from peritoneal metastasis (PM) in the late stage of tumor and these patients have a poor prognosis. To provide more care for GC patient with PM, a deeper exploration of the molecular characteristics of GC-PM is needed. Here we performed the in vitro and in vivo study to illustrate the effect of HOXA11 over-expressed GC cells on peritoneal mesothelial cells (HMrSV5), transcriptomics analyses of HMrSV5 cells co-cultured with HOXA11 over-expressed GC cells, counterparts or alone, cytokine array analyses of serum-free culture medium of HOXA11 over-expressed GC cells, we validated our findings through genetic manipulation of HMrSV5 cells and neutralizing antibodies targeting cytokines secreted by HOXA11 over-expressed GC cells in vitro, as well as utilized human peritoneal metastatic lesions to validate expression of potential targets. We identified that HOXA11 over-expressed GC cells strongly propelled mesothelial fibrosis in vivo and in vitro, and HOXA11 regulated paracrine and autocrine of PDGF BB and TGF beta 1 in GC cells to propel mesothelial fibrosis. Meanwhile, HOXA11 over-expressed GC cells drove PDGF BB and TGF beta 1 secretion to activate developmental-process related genes in HMrSV5 cells, including Egr1, which processes dependent on miR-181a-5p. Then, Egr1 could mediate peritoneal mesothelial fibrosis. Correspondingly, Egr1 over-expressed HMrSV5 cells supported migration and peritoneal dissemination of GC cells. Together our results suggest that a feedforward amplifier circuity governing GC cells and mesothelial cells in peritoneum contribute to peritoneal metastasis of GC cells.