School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK.
School of Human Sciences, London Metropolitan University, London N7 8DB, UK.
Int J Mol Sci. 2022 Aug 4;23(15):8697. doi: 10.3390/ijms23158697.
PADs are a group of calcium-dependent enzymes that play key roles in inflammatory pathologies and have diverse roles in cancers. PADs cause irreversible post-translational modification of arginine to citrulline, leading to changes in protein function in different cellular compartments. PAD isozyme diversity differs throughout phylogeny in chordates, with five PAD isozymes in mammals, three in birds, and one in fish. While the roles for PADs in various human cancers are mounting (both in regards to cancer progression and epigenetic regulation), investigations into animal cancers are scarce. The current pilot-study therefore aimed at assessing PAD isozymes in a range of animal cancers across the phylogeny tree. In addition, the tissue samples were assessed for total protein deimination and histone H3 deimination (CitH3), which is strongly associated with human cancers and also indicative of gene regulatory changes and neutrophil extracellular trap formation (NETosis). Cancers were selected from a range of vertebrate species: horse, cow, reindeer, sheep, pig, dog, cat, rabbit, mink, hamster, parrot, and duck. The cancers chosen included lymphoma, kidney, lung, testicular, neuroendocrine, anaplastic, papilloma, and granulosa cell tumour. Immunohistochemical analysis revealed that CitH3 was strongly detected in all of the cancers assessed, while pan-deimination detection was overall low. Both PAD2 and PAD3 were the most predominantly expressed PADs across all of the cancers assessed, while PAD1, PAD4, and PAD6 were overall expressed at lower, albeit varying, levels. The findings from this pilot study provide novel insights into PAD-mediated roles in different cancers across a range of vertebrate species and may aid in the understanding of cancer heterogeneity and cancer evolution.
PADs 是一组依赖钙的酶，在炎症病理学中发挥关键作用，并且在癌症中有多种作用。PADs 导致精氨酸不可逆的翻译后修饰为瓜氨酸，导致不同细胞区室中蛋白质功能的变化。在脊索动物的系统发育过程中，PAD 同工酶的多样性不同，哺乳动物中有 5 种 PAD 同工酶，鸟类中有 3 种，鱼类中有 1 种。虽然 PADs 在各种人类癌症中的作用越来越多（既涉及癌症进展又涉及表观遗传调控），但对动物癌症的研究却很少。因此，目前的初步研究旨在评估整个系统发育树上一系列动物癌症中的 PAD 同工酶。此外，还评估了组织样本中的总蛋白脱亚胺化和组蛋白 H3 脱亚胺化（CitH3），CitH3 与人类癌症强烈相关，也表明基因调控变化和中性粒细胞细胞外陷阱形成（NETosis）。从一系列脊椎动物物种中选择了癌症：马、牛、驯鹿、绵羊、猪、狗、猫、兔子、貂、仓鼠、鹦鹉和鸭子。选择的癌症包括淋巴瘤、肾、肺、睾丸、神经内分泌、间变性、乳头瘤和颗粒细胞瘤。免疫组织化学分析显示，CitH3 在评估的所有癌症中均强烈检测到，而全脱亚胺化检测总体较低。在评估的所有癌症中，PAD2 和 PAD3 是表达最丰富的 PAD，而 PAD1、PAD4 和 PAD6 的表达总体较低，但变化不同。这项初步研究的结果为 PAD 在一系列脊椎动物物种中的不同癌症中的介导作用提供了新的见解，并可能有助于理解癌症异质性和癌症进化。
