Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors.
Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors.
复制标题
PADI2在肿瘤中的表达、作用及致瘤途径研究
DOI：
10.2147/ott.s92389
复制
发表时间：
2017
影响因子：
4
通讯作者：
Chang X
中科院分区：
文献类型：
--
作者：
Guo W;Zheng Y;Xu B;Ma F;Li C;Zhang X;Wang Y;Chang X
肽精氨酸脱亚胺酶（PAD）催化精氨酸残基转化为瓜氨酸残基，称为瓜氨酸化。最近的研究表明，PAD异构体2 （PADI2）在肿瘤中起重要作用，尽管其致瘤作用和机制在很大程度上尚不清楚。材料与方法采用免疫组织化学法和酶联免疫吸附法（ELISA）分别检测PADI2在肿瘤组织和患者血液中的表达水平。分别用抗padi2 siRNA处理胃肿瘤细胞MNK-45和肝肿瘤细胞Bel-7402，观察细胞增殖、凋亡和迁移情况。采用聚合酶链反应（PCR）阵列，包括Cancer PathwayFinder、Oncogenes and Tumor Suppressor Genes、p53 Signaling Pathway、Signal transduc通路和Tumor Metastasis PCR阵列，研究PADI2在sirna处理肿瘤细胞中的致瘤途径。real-time PCR验证了这一分析。结果免疫组化检测到PADI2在浸润性乳腺导管癌、宫颈鳞状细胞癌、结肠腺癌、肝肝细胞癌、肺癌、卵巢浆液性乳头状腺癌和甲状腺乳头状癌中表达显著升高。ELISA检测到48.3%的肝癌患者、38%的宫颈癌患者和32%的胃癌患者血液中PADI2表达增加了两倍。抗PADI2 sirna处理的MNK-45细胞凋亡增加，细胞增殖和迁移减少；抑制PADI2表达的Bel-7402细胞增殖和迁移增加，细胞凋亡减少。PCR阵列和real-time PCR检测到抗padi2 siRNA处理后，MNK-45细胞和Bel-7402细胞中CXCR2和EPO的表达分别显著降低。结论PADI2在多种类型肿瘤组织及患者血液中表达升高。PADI2可能通过介导CXCR2（一种众所周知的刺激细胞增殖和侵袭的基因）促进胃癌细胞的异常行为。然而，PADI2可能通过调节EPO的表达对肝脏肿瘤细胞的生长和转移产生有害影响，EPO是一个在肿瘤生长中具有争议功能的基因。结果提示PADI2对肿瘤发生的影响是多因素的，取决于肿瘤类型。
Background Peptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. Materials and methods Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. Results Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments. Conclusion PADI2 expression is increased in many types of tumor tissues and patient blood samples. PADI2 may advance abnormal cell behavior in gastric cancers by mediating CXCR2, a well-known gene that stimulates cell proliferation and invasion. However, PADI2 might have deleterious effects on tumor growth and metastasis in liver tumor cells by regulating the expression of EPO, a gene with controversial functions in tumor growth. The results suggest that the effect of PADI2 on tumorigenesis is multifactorial, depending on the tumor type.