Botucatu Medical School, Experimental Research Unit (UNIPEX), Multimodel Drug Screening Platform - Laboratory of Chemically Induced and Experimental Carcinogenesis (MDSP-LCQE), São Paulo State University (UNESP), Botucatu, São Paulo State, Brazil.
School of Veterinary Medicine and Animal Science, Department of Pathology, University of São Paulo (USP), São Paulo, São Paulo State, Brazil.
Int J Exp Pathol. 2023 Dec;104(6):304-312. doi: 10.1111/iep.12491. Epub 2023 Aug 18.
Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1 ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1 female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1 animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.
结直肠癌是全球癌症相关死亡的第三大主要原因，是一种多步骤疾病，以癌前异常隐窝病灶 (ACF) 为早期形态表现。尽管 Pannexin 1 (Panx1) 蛋白在其他癌症类型中具有相反的作用，但它在结直肠癌发生中的作用尚未在跨膜半通道形成中得到研究。因此，本研究旨在研究 Panx1 敲除 (Panx1 ) 对小鼠化学诱导结直肠癌发生早期事件的影响。野生型 (WT) 和 Panx1 雌性 C57BL6J 小鼠通过接受六次腹腔内 1,2-二甲基肼 (DMH) 致癌物给药，接受化学诱导的结直肠癌模型。在最后一次 DMH 给药后 8 小时 (第 7 周) 或 30 周 (第 37 周) 处死动物，以分别评估亚急性结肠毒性结果或 ACF 负担。在第 7 周，Panx1 基因缺失增加了外周血细胞中的 DMH 诱导的遗传毒性、结肠中的丙二醛水平和结肠隐窝中的细胞凋亡 (裂解 caspase-3)。值得注意的是，在第 37 周，Panx1 动物的异常隐窝 (AC)、ACF 平均数量和 ACF 多发性 (每个 ACF 的 AC) 分别增加了 56%、57%和 20%。本质上，我们的研究结果表明，Panx1 基因缺失促进了化学诱导的小鼠结肠癌变过程中癌前 ACF 的发展，并提出了 Panx1 的保护作用。
