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Journal of Zhejiang University SCIENCE B

ISSN 1673-1581(Print), 1862-1783(Online), Monthly

2022 Vol.23 No.7 P.587-596

ZNF750 facilitates carcinogenesis via promoting the expression of long non-coding RNA CYTOR and influences pharmacotherapy response in colon adenocarcinoma

Lu XIA, Hexin LIN, Yanming ZHOU, Jiabian LIAN

Xiamen Cell Therapy Research Center, the First Affiliated Hospital of Xiamen University, Xiamen 361000, China; Department of Colorectal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China; Department of Gastrointestinal Surgery, the First Affiliated Hospital of Xiamen University, Xiamen 361000, China; Department of Clinical Laboratory, the First Affiliated Hospital of Xiamen University, Xiamen 361000, China

faster_lian@xmu.edu.cn

Abstract: The epidermal cell differentiation regulator zinc finger protein 750 (ZNF750) is a transcription factor containing the Cys2His2 (C2H2) domain, the zinc finger structure of which is located at the N-terminal 25???46 amino acids of ZNF750. It can promote the expression of differentiation-related factors while inhibiting the expression of progenitor cell-related genes. ZNF750 is directly regulated by p63 (encoded by the TP63 gene, belonging to the TP53 superfamily). The Krppel-like factor 4 (KLF4), repressor element-1 (RE-1)?-silencing transcription factor (REST) corepressor 1 (RCOR1), lysine demethylase 1A (KDM1A), and C-terminal-binding protein 1/2 (CTBP1/2) chromatin regulators cooperate with ZNF750 to repress epidermal progenitor genes and activate the expression of epidermal terminal differentiation genes (Sen et al., 2012; Boxer et al., 2014). Besides, ZNF750 and the regulatory network composed of bone morphogenetic protein (BMP) signaling pathway, long non-coding RNAs (lncRNAs) (anti-differentiation non-coding RNA (ANCR) and tissue differentiation-inducing non-protein coding RNA (TINCR)), musculoaponeurotic fibrosarcoma oncogene (MAF)/MAF family B (MAFB), grainy head-like 3 (GRHL3), and positive regulatory domain zinc finger protein 1 (PRDM1) jointly promote epidermal cell differentiation (Sen et al., 2012).

Key words: Zinc Finger Protein 750; Colon adenocarcinoma; Long non coding RNA; Chemotherapy

Chinese Summary  <25> 锌指蛋白750通过促进长链非编码RNACYTOR表达促进结直肠癌癌变并影响药物治疗反应

夏璐1，林和新2，周彦明3，连加辨4
1厦门大学附属第一医院，厦门市细胞治疗研究中心，中国厦门，361000
2福建医科大学附属第一医院结直肠外科，中国福州，350004
3厦门大学附属第一医院胃肠肿瘤外科，中国厦门，361000
4厦门大学附属第一医院检验科，中国厦门，361000
目的：探讨锌指蛋白750在调控长链非编码RNACYTOR表达进而影响结直肠癌发生发展中的相关表型和机制及其影响药物应答和预后的潜在临床意义。
创新点：聚焦锌指蛋白750在结肠腺癌中的促癌机制，并在其对CYTOR表达的影响及锌指蛋白750-CYTOR与结肠腺癌临床相关分子病理特征和药物疗效预测方面展开研究。
方法：在分子水平，利用蛋白质免疫印迹（western blotting）、染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）、转录组测序（RNA-seq）、逆转录-定量聚合酶链反应（RT-qPCR）等技术手段对ZNF750和CYTOR在结肠腺癌细胞系中的表达进行分析；在细胞水平，通过使用克隆形成（colony formation）、小室迁移（transwell）等方法评估ZNF750对结肠腺癌增殖、侵袭、转移功能表型的影响；在动物水平，评估在免疫缺陷的裸鼠模型中，ZNF750对人结肠腺癌细胞系皮下移植瘤生长能力的影响；对TCGA和GEO数据库中结肠腺癌患者ZNF750-CYTOR的表达量、表达相关性进行生物信息学分析，并评估在对患者预后、肿瘤免疫浸润和常规化疗药物疗效预测中的价值。
结论：锌指蛋白750正向调节CYTOR表达，且锌指蛋白750-CYTOR可促进结肠腺癌细胞的恶性表型。对TCGA或GEO结肠腺癌队列的研究结果显示，锌指蛋白750-CYTOR轴与临床特征间存在三个重要相关性：首先，锌指蛋白750-CYTOR轴在癌变和癌症进展过程上调；其次，锌指蛋白750-CYTOR与肿瘤浸润淋巴细胞（TILs）呈正相关，与免疫检查点基因的表达有关；第三，锌指蛋白750-CYTOR可作为结肠腺癌药物治疗中亚叶酸钙或奥沙利铂等常规化疗药物的反应预测因子。

关键词组：锌指蛋白750；结肠腺癌；长链非编码RNACYTOR；化学药物治疗


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DOI:

10.1631/jzus.B2100939

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On-line Access:

2022-07-06

Received:

2021-11-15

Revision Accepted:

2022-03-21

Crosschecked:

2022-07-06

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