PDF(Pubmed)
Abstract：
Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.
摘要：
瓜氨酸化是一种新兴的翻译后修饰，由肽基精氨酸脱亚胺酶（PAD）催化，可将肽基精氨酸转化为肽基瓜氨酸。在人类中,PAD家族由涉及多种疾病的五种同工酶（PAD1-4，6）组成，包括癌症.鉴于高风险（hr）人乳头瘤病毒（HPV）是宫颈癌的病因，在这项研究中，我们试图确定PAD介导的蛋白瓜氨酸化是否在HPV驱动的上皮细胞转化中发挥功能作用.在这里，我们表明总蛋白瓜氨酸化和PAD4表达水平与宫颈癌进展显着相关。具体来说,PAD4的上皮免疫染色显示从低级别（CIN1）到高级别（CIN2，CIN3）宫颈上皮内瘤变的组织评分越来越高，和浸润性鳞状细胞癌（SCC）病变，提出了PAD4可用作肿瘤分期标志物的有吸引力的可能性。此外，利用表皮样宫颈癌细胞系CaSki，其中包含整合的HPV16基因组的多个拷贝，我们显示，通过药理学pan-PAD抑制剂BB-Cl-脒治疗，E6和E7HPV癌蛋白的表达受到损害。始终如一，p53和p21，HPV癌蛋白的两个靶标，被PAD抑制剂上调，经历细胞生长停滞和凋亡。总之,这些发现强调了一种新的机制，通过该机制，hrHPV改变涉及细胞周期和存活的宿主调节途径以获得病毒适应性，这增加了PAD可能是开发新型宿主靶向抗病毒药物以有效预防宫颈癌进展的有吸引力的靶标的可能性。
