Santo Sara Gomes Espírito, da Silva Tereza Cristina, Vinken Mathieu, Cogliati Bruno, Barbisan Luís Fernando, Romualdo Guilherme Ribeiro
Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, São Paulo, Brazil.
School of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo 05508-270, São Paulo, Brazil.
Antioxidants (Basel). 2022 Nov 30;11(12):2368. doi: 10.3390/antiox11122368.
Colorectal cancer (CRC), associated with an increased intake of processed red meats, saturated fats, and simple carbohydrates accompanied by low dietary fiber, fruits, and vegetables consumption, presents a high epidemiological burden. Connexin43 (Cx43) protein, which forms gap junctions or hemichannels, has tumor suppressor or oncogenic activities in a cancer type- and stage-dependent manner. Cx43 expression varies during colon carcinogenesis, and its functional role is not fully understood. Thus, we evaluated the implications of Cx43 heterologous deletion (Cx43) during the early stages of a chemically induced model of colon carcinogenesis. Female C57BL/6J mice (wild-type or Cx43) were submitted to a colon carcinogenesis model induced by 1,2 dimethylhydrazine (DMH). Mice were euthanized eight hours (week 7) or 30 weeks (week 37) after the last DMH administration to evaluate subacute colon toxicity outcomes or the burden of (pre)neoplastic lesions, respectively. At week 7, Cx43 deficiency inferred no alterations in the DMH-induced increase in systemic (peripheral blood), in situ (colonocytes) DNA damage, and apoptosis in the colonocytes. At week 30, Cx43 mice presented an increase in preneoplastic aberrant crypt foci (ACF) multiplicity, while no alterations were observed in colorectal adenoma (CRA) occurrence, multiplicity, volume, proliferation, growth, and β-catenin immunoexpression. Similarly, an in silico analysis of human CRA showed decreased mRNA expression of Cx43 with no correlation with proliferation, apoptosis, and β-catenin markers. These findings indicate the discrete role of Cx43 in the early stages of chemically induced mouse colon carcinogenesis.
结直肠癌（CRC）与加工红肉、饱和脂肪和简单碳水化合物摄入量增加相关，同时膳食纤维、水果和蔬菜的摄入量较低，其流行病学负担很高。连接蛋白43（Cx43）蛋白形成间隙连接或半通道，在癌症类型和阶段依赖性方式中具有肿瘤抑制或致癌活性。Cx43表达在结肠癌发生过程中有所变化，其功能作用尚未完全了解。因此，我们评估了在化学诱导的结肠癌发生模型早期阶段Cx43异源缺失（Cx43）的影响。将雌性C57BL/6J小鼠（野生型或Cx43）置于由1,2-二甲基肼（DMH）诱导的结肠癌发生模型中。在最后一次给予DMH后8小时（第7周）或30周（第37周）对小鼠实施安乐死，分别评估亚急性结肠毒性结果或（癌前）肿瘤病变的负担。在第7周，Cx43缺乏并未推断出DMH诱导的全身（外周血）、原位（结肠细胞）DNA损伤增加以及结肠细胞凋亡的改变。在第30周，Cx43小鼠的癌前异常隐窝灶（ACF）数量增加，而在结直肠腺瘤（CRA）的发生率、数量、体积、增殖、生长和β-连环蛋白免疫表达方面未观察到改变。同样，对人类CRA的计算机分析显示Cx43的mRNA表达降低，与增殖、凋亡和β-连环蛋白标志物无相关性。这些发现表明Cx43在化学诱导的小鼠结肠癌发生早期阶段具有离散作用。
