M2型巨噬细胞通过IL-6介导的JAK2/STAT3轴调控肿瘤干性潜能并促进胃癌侵袭迁移OA

AIM:To investigate how M2 type tumor-associated macrophages(M2-TAMs)promote gastric can-cer stemness,invasion and migration through the interleukin 6(IL-6)/Janus kinase 2(JAK2)/signal transducer and acti-vator of transcription 3(STAT3)axis.METHODS:The TCGA database was used to analyze the relationship between the distribution of M2 TAMs in gastric cancer and adjacent normal tissues and the stemness indicators,and verification was performed in gastric cancer patient tissues.In vitro,the sphere forming assay was used to detect the stemness potential of gastric cancer cells,and an M2 TAMs in vitro co-culture system was constructed.qRT-PCR and Western blot techniques were used to detect the changes in tumor stemness markers CD44 and aldehyde dehydrogenase 1(ALDH1),and Transwell assays were used to explore the changes in the migration and invasion abilities of gastric cancer cells.Transcriptome se-quencing was used to screen differential genes and KEGG enrichment analysis was used to explore key pathways,and neu-tralizing antibodies and pathway inhibitors were used for correlation verification.RESULTS:The results of TCGA data-base analysis and in vivo tissue verification both showed that the density of M2-TAMs in gastric cancer tissues was signifi-cantly higher than that in adjacent normal tissues,and the increase in their number was positively correlated with tumor stemness markers(CD44 and ALDH1).The mRNA and protein expression levels of CD44 and ALDH1 in gastric cancer cells co-cultured with M2-TAMs were significantly up-regulated compared with control group.Meanwhile,the sphere-forming rate and invasion and migration abilities of cancer cells in co-culture group were significantly enhanced,and the expression levels of key proteins in JAK2/STAT3 signaling pathway were significantly increased.The results of KEGG pathway analysis showed that STAT3 was a key gene for stemness regulation.Compared with macrophages before polariza-tion,polarized M2-TAMs had 22 up-regulated secreted factors,among which IL-6 was significantly increased and was as-sociated with poor prognosis in patients.The addition of stattic(STAT3 inhibitory compound)and/or IL-6 neutralizing an-tibodies inhibited the stemness,migration and invasion of gastric cancer.All of the above results had P values<0.05.CONCLUSION:The M2-TAMs secrete IL-6 to activate JAK2/STAT3 signaling pathway,thus augmenting cancer stem-ness and promoting the invasion and migration of gastric cancer.