Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China; Department of General Surgery, Zhuhai People's Hospital, Guangzhou, Guangdong, China.
Arch Biochem Biophys. 2021 May 15;702:108838. doi: 10.1016/j.abb.2021.108838. Epub 2021 Mar 13.
The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.
代谢拮抗剂 5-氟尿嘧啶（5-FU）是一种广泛用于治疗胃癌（GC）的化疗方案。然而，对 5-FU 的耐药性仍然是临床应用的主要障碍。抗肿瘤化疗药物的治疗会招募肿瘤相关巨噬细胞（TAMs），这些细胞在耐药性的发展中高度涉及，但潜在的分子机制尚不清楚。在这里，我们证明 YAP1 在耐药性 GC 组织中的表达高于敏感性 GC 组织。此外，YAP1 过表达的 GC 分泌的白细胞介素 3（IL-3）可以将巨噬细胞极化为 M2 样表型，并诱导 GLUT3 依赖的糖酵解程序。同时，极化的 M2 巨噬细胞通过分泌 CCL8 和激活 JAK1/STAT3 信号通路的磷酸化来增强肿瘤细胞对 5-FU 的耐药性。
