Targeting ZFP64/GAL-1 axis promotes therapeutic effect of nab-paclitaxel and reverses immunosuppressive microenvironment in gastric cancer

Journal of Experimental & Clinical Cancer Research

Zhenbin Shen¹  Weidong Chen¹  Cheng Tang²  Yan Wang²  Shan Yu²  Mengxuan Zhu³  Tianshu Liu³  Pengfei Zhang³  Yuehong Cui³ 

[1] Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China;Department of Medical Oncology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China;Department of Medical Oncology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China;Center of Evidence-based Medicine, Fudan University, Shanghai, China;

关键词: Gastric cancer;    Chemoresistance;    ZFP64;    Cancer stem cell;    Immunosuppression;   

DOI  :  10.1186/s13046-021-02224-x

来源: Springer

【 摘 要 】

BackgroundChemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. Here, we aim to reveal the underlying mechanisms of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resistance in GC.MethodsWe performed RNA sequencing (RNA-seq) on samples from patients who were resistant or sensitive to nab-paclitaxel, and identified Zinc Finger Protein 64 (ZFP64) as critical for nab-paclitaxel resistance in GC. CCK8, flow cytometry, TUNEL staining, sphere formation assays were performed to investigate the effects of ZFP64 in vitro, while subcutaneous tumor formation models were established in nude mice or humanized mice to evaluate the biological roles of ZFP64 in vivo. Chromatin immunoprecipitation sequencing (CHIP-seq) and double-luciferase reporter gene assay were conducted to reveal the underlying mechanism of ZFP64.ResultsZFP64 overexpression was linked with aggressive phenotypes, nab-paclitaxel resistance and served as an independent prognostic factor in GC. As a transcription factor, ZFP64 directly binds to Galectin-1 (GAL-1) promoter and promoted GAL-1 transcription, thus inducing stem-cell like phenotypes and immunosuppressive microenvironment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade significantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice.ConclusionsOur data support a pivotal role for ZFP64 in GC progression by simultaneously promoting cellular chemotherapy resistance and tumor immunosuppression. Treatment with the combination of nab-paclitaxel and a GAL-1 inhibitor might benefit a subgroup of GC patients.

【 授权许可】

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