Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Center of Evidence-based Medicine, Fudan University, Shanghai, China.
J Exp Clin Cancer Res. 2022 Jan 7;41(1):14. doi: 10.1186/s13046-021-02224-x.
Chemoresistance 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.
We 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.
ZFP64 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.
Our 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.
化疗耐药是胃癌（GC）治疗的主要障碍，但仍需阐明其分子机制。在这里，我们旨在揭示纳米白蛋白结合紫杉醇（nab-紫杉醇）耐药的胃癌的潜在机制。
我们对nab-紫杉醇耐药或敏感的患者样本进行了 RNA 测序（RNA-seq），并确定锌指蛋白 64（ZFP64）是 GC 中nab-紫杉醇耐药的关键。通过 CCK8、流式细胞术、TUNEL 染色、球体形成试验进行体外研究，建立裸鼠或人源化小鼠皮下肿瘤形成模型以评估 ZFP64 在体内的生物学作用。通过染色质免疫沉淀测序（CHIP-seq）和双荧光素酶报告基因检测来揭示 ZFP64 的潜在机制。
ZFP64 过表达与侵袭性表型、nab-紫杉醇耐药相关，并作为 GC 的独立预后因素。作为转录因子，ZFP64 直接结合半乳糖凝集素 1（GAL-1）启动子并促进 GAL-1 转录，从而诱导 GC 中的干细胞样表型和免疫抑制微环境。重要的是，与单独使用 nab-紫杉醇相比，nab-紫杉醇加 GAL-1 阻断在小鼠模型中显著增强了抗肿瘤作用，尤其是在人源化小鼠中。
我们的数据支持 ZFP64 通过同时促进细胞化疗耐药和肿瘤免疫抑制在 GC 进展中起关键作用。nab-紫杉醇联合 GAL-1 抑制剂的治疗可能使一部分 GC 患者受益。
