Qin Jian, Cui Zheng, Zhou Jingyi, Zhang Bosen, Lu Ruiqi, Ding Youcheng, Hu Hai, Cai Jingli
Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.
Department of Ultrasonic Medicine, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China.
Transl Oncol. 2023 Nov;37:101764. doi: 10.1016/j.tranon.2023.101764. Epub 2023 Aug 27.
N6-methyladenosine (m6A) is an emerging epigenetic modification, which plays a crucial role in the development of cancer. Nevertheless, the underlying mechanism of m6A-associated proteins and m6A modification in gallbladder cancer remains largely unknown.
The Gene Expression Omnibus database and tissue microarray were used to identify the key m6A-related gene in gallbladder cancer. The function and mechanism of IGF2BP3 were further investigated by knockdown and overexpression techniques in vitro and in vivo.
We found that IGF2BP3 was elevated and correlated with poor prognosis in gallbladder cancer, which can be used as an independent prognostic factor for gallbladder cancer. IGF2BP3 accelerated the proliferation, invasion and migration of gallbladder cancer cells in vitro and in vivo. Mechanistically, IGF2BP3 interacted with and augmented the stability of CLDN4 mRNA by m6A modification. Enhancement of CLDN4 reversed the inhibitory effect of IGF2BP3 deficiency on gallbladder cancer. Furthermore, we demonstrated that IGF2BP3 promotes the activation of NF-κB signaling pathway by up-regulation of CLDN4. Overexpression of IGF2BP3 in gallbladder cancer cells obviously promoted the polarization of immunosuppressive phenotype in macrophages. Besides, Gallbladder cancer cells-derived IGF2BP3 up-regulated the levels of STAT3 in M2 macrophages, and promoted M2 polarization.
We manifested IGF2BP3 promotes the aggressive phenotype of gallbladder cancer by stabilizing CLDN4 mRNA in an m6A-dependent manner and induces macrophage immunosuppressive polarization, which might offer a new theoretical basis for against gallbladder cancer.
N6-甲基腺苷（m6A）是一种新出现的表观遗传修饰，在癌症发展中起关键作用。然而，m6A相关蛋白和m6A修饰在胆囊癌中的潜在机制仍 largely未知。
利用基因表达综合数据库和组织芯片鉴定胆囊癌中关键的m6A相关基因。通过体外和体内的敲低和过表达技术进一步研究IGF2BP3的功能和机制。
我们发现IGF2BP3在胆囊癌中升高且与预后不良相关，可作为胆囊癌的独立预后因素。IGF2BP3在体外和体内加速胆囊癌细胞的增殖、侵袭和迁移。机制上，IGF2BP3通过m6A修饰与CLDN4 mRNA相互作用并增强其稳定性。CLDN4的增强逆转了IGF2BP3缺乏对胆囊癌的抑制作用。此外，我们证明IGF2BP3通过上调CLDN4促进NF-κB信号通路的激活。IGF2BP3在胆囊癌细胞中的过表达明显促进巨噬细胞免疫抑制表型的极化。此外，胆囊癌细胞来源的IGF2BP3上调M2巨噬细胞中STAT3的水平，并促进M2极化。
我们表明IGF2BP3通过以m6A依赖的方式稳定CLDN4 mRNA促进胆囊癌的侵袭性表型，并诱导巨噬细胞免疫抑制极化，这可能为对抗胆囊癌提供新的理论基础。
