TWA1调控RAE1/JAK-STAT信号轴介导M2巨噬细胞浸润促胃癌进展的机制研究

胃癌是导致肿瘤相关死因第四位的恶性肿瘤，但对于其发生发展的分子机制仍然不清楚。我们前期研究发现TWA1在胃癌组织中过表达，高表达的TWA1与胃癌患者预后负相关。生物信息学分析发现TWA1与RAE1的表达具有显著相关性。下调TWA1可以降低RAE1的表达，并下调p-JAK2/JAK2及p-STAT3/STAT3，显著影响EMT相关蛋白的表达，抑制胃癌增殖、迁移及克隆形成。下调RAE1表达却不能影响TWA1表达。GSEA分析显示JAK-STAT通路在TWA1的下游差异表达基因中明显富集。TWA1表达与B细胞、CD8+T细胞、CD4+T细胞等免疫细胞的数量显著相关。使用TWA1稳定低表达的胃癌细胞株与M0巨噬细胞共培养发现，抑制TWA1表达可以显著抑制巨噬细胞的迁移、划痕愈合、克隆形成能力。据此我们推测，TWA1通过直接结合RAE1调控JAK/STAT通路介导M2型巨噬细胞浸润促胃癌发生发展。

Gastric cancer (GC) is the fourth leading cause of tumor-related deaths, but the molecular mechanism of its occurrence and development is still unclear. Our previous study found that TWA1 is overexpressed in GC tissues, and the high expression of TWA1 is negatively correlated with the prognosis of GC patients. Bioinformatics analysis found that the expression of TWA1 and RAE1 had a significant correlation. Down-regulating TWA1 can reduce the expression of RAE1, and down-regulating p-JAK2/JAK2 and p-STAT3/STAT3, significantly affecting the expression of EMT-related proteins, inhibiting GC proliferation, migration and clone formation. Down-regulating the expression of RAE1 did not affect the expression of TWA1. GSEA analysis showed that the JAK-STAT pathway was significantly enriched in the differentially expressed genes downstream of TWA1. The expression of TWA1 is significantly related to the number of immune cells such as B cells, CD8+T cells, and CD4+T cells. Co-cultivation of GC cell lines with stable and low expression of TWA1 and M0 macrophages found that inhibition of TWA1 expression can significantly inhibit the migration, scratch healing, and clonal formation capabilities of macrophages. Based on this, we speculate that TWA1 mediates the infiltration of M2 macrophages and promotes the development of GC through direct binding to RAE1 to regulate the JAK/STAT pathway.