IGF2BP3 drives gallbladder cancer progression by m6A-modified CLDN4 and inducing macrophage immunosuppressive polarization

Jian Qin; Zheng Cui; Jingyi Zhou; Bosen Zhang; Ruiqi Lu; Youcheng Ding; Hai Hu; Jingli Cai

doi:10.1016/j.tranon.2023.101764

IGF2BP3 drives gallbladder cancer progression by m6A-modified CLDN4 and inducing macrophage immunosuppressive polarization

Transl Oncol. 2023 Nov:37:101764. doi: 10.1016/j.tranon.2023.101764. Epub 2023 Aug 27.

Authors

Jian Qin¹, Zheng Cui², Jingyi Zhou¹, Bosen Zhang³, Ruiqi Lu³, Youcheng Ding³, Hai Hu³, Jingli Cai⁴

Affiliations

¹ Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.
² Department of Ultrasonic Medicine, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China.
³ Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China.
⁴ Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: 417327108@qq.com.

Abstract

Introduction: 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.

Materials and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Claudin-4; Gallbladder cancer; M2 macrophages; N6-methyladenosine; Prognosis.