J Exp Clin Cancer Res|复旦大学崔越宏团队揭示胃癌化疗耐药的免疫机制

2022年8月3日 0条评论 251次阅读 0人点赞

最新细胞功能及机制文献分享

胃癌（GC）是全球第二大最常见的恶性肿瘤，也是全球癌症相关死亡率的第三大主要原因。临床研究指出，手术仍是其唯一的可能的治愈方法，但由于缺乏早期症状和有效筛查方法，大多数患者无法在切除的阶段被诊断出来，因此，化疗成为了患者的首选。尽管许多新型化学治疗药物，例如纳米白蛋白结合型紫杉醇（nab-紫杉醇）已被引入临床实践，但由于患者固有或获得性耐药机制是GC化疗治疗的主要障碍，但其分子机制尚需阐明。

2022年1月7日，复旦大学中山医院肿瘤内科崔越宏团队在Journal of Experimental and Clinical Cancer Research上发表了题为“Targeting ZFP64/GAL-1 axis promotes therapeutic effect of nab-paclitaxel and reverses immunosuppressive microenvironment in gastric cancer”的研究论文。在本研究中，团队旨在揭示GC中nab-紫杉醇耐药的潜在机制。揭示ZFP64可通过同时促进细胞化疗抵抗和肿瘤免疫抑制在GC进展中发挥关键作用。nab-紫杉醇和GAL-1抑制剂联合治疗可能对GC患者有益。

据报道，化疗耐药本质上发生在化疗之前或化疗期间，GC中化疗耐药的机制是复杂和多因素的，包括细胞内药物浓度降低、药物靶点改变、细胞存活和死亡途径失调。在已证实的化疗耐药机制中，癌症干细胞（CSC）被认为是化疗耐药的新型原因。CD44作为GC中最早的CSCs标志物，被发现与GC细胞的耐药性呈正相关，抑制CD44可能是治疗GC的一个目标。ZFP64也称ZNF338是一种公认的转录调节因子，其生物学功能在很大程度上仍有待确定，有人认为ZFP64参与免疫应答和肿瘤发生。

在本篇文章中，首先，团队通过对nab-紫杉醇耐药或敏感患者样本进行RNA-seq分析，确定了ZFP64在GC中对nab-紫杉醇耐药至关重要。其次，体外的CCK8、流式细胞术、TUNEL染色、成球试验结合体内皮下成瘤模型，进一步评估了ZFP64的生物学作用。最后，CHIP-seq和双荧光素酶报告基因实验揭示了ZFP64的潜在机制。

结果发现，与癌旁组织样本相比，GC中ZFP64的表达增加，并且ZFP64的上调在对nab-紫杉醇耐药的患者的GC组织中更为明显。此外，高ZFP64表达与GC患者不良预后相关，体外研究进一步证实了这一点，即ZFP64过表达与侵袭性表型、nab-紫杉醇耐药性有关，其可作为GC独立预后指标。CHIP-seq和双荧光素酶报告基因实验分析表明，ZFP64可直接与GAL-1启动子结合并促进GAL-1转录，从而诱导细胞获得CSC表型并建立免疫抑制微环境。重要的是，与单独使用nab-紫杉醇治疗相比，nab-紫杉醇加GAL-1阻断剂可显著增强小鼠模型的抗肿瘤作用，尤其是在人源化小鼠中。

《J Exp Clin Cancer Res|复旦大学崔越宏团队揭示胃癌化疗耐药的免疫机制》

图 ZFP64靶向GAL-1诱导nab-紫杉醇不敏感机制模型示意图。

期刊及DOI号

J Exp Clin Cancer Res. 2022 Jan 7.

doi: 10.1186/s13046-021-02224-x.

题目

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

摘要

背景：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.

方法：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.

结果：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 microenviron-ment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade signifi-cantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice.

结论：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.

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