Delisle Ariane, Ferraris Emanuelle, Plante Isabelle
INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7.
INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7. Electronic address: http://www.inrs.ca.
Environ Res. 2015 Nov;143(Pt A):229-40. doi: 10.1016/j.envres.2015.10.020. Epub 2015 Oct 28.
Decreased expression of connexins has been associated with cancer, but the underlying mechanisms are poorly understood. We have previously shown that a 5 day exposure to hexachlorobenzene (HCB) resulted in decreased connexins expression in hepatocytes 45 days later, and that this down-regulation was linked to activation of Akt through the ILK pathway. Because HCB promotes cancer in both the liver and breast, the present study aimed to determine if the mechanisms are similar in both tissues. MCF-12A breast cells were thus transfected with vectors coding for either Akt or a constitutively active form of Akt. In those cells, activation of Akt was correlated with decreased Cx43 levels. Female rats were then exposed to HCB by gavage either following the same protocol used previously for the liver or through a chronic exposure. While no changes were observed after the 5 days exposure protocol, chronic exposure to HCB resulted in increased Akt levels and decreased Cx43 levels in breast cells. In vitro, Akt was activated in MCF-12A cells exposed to HCB either for 7 days or chronically, but no changes were observed in junctional proteins. Together, these results suggested that, while activation of Akt can decrease Cx43 expression in breast cells in vitro, other mechanisms are involved during HCB exposure, leading to a decrease in Cx43 levels in a model- and duration-dependent manner. Finally, we showed that HCB effects are tissue specific, as we did not observe the same results in breast and liver tissues.
连接蛋白的表达降低与癌症相关，但潜在机制尚不清楚。我们之前已经表明，暴露于六氯苯（HCB）5天会导致45天后肝细胞中连接蛋白表达降低，并且这种下调与通过整合素连接激酶（ILK）途径激活Akt有关。由于HCB会促进肝脏和乳腺的癌症发生，因此本研究旨在确定这两种组织中的机制是否相似。因此，用编码Akt或组成型活性形式Akt的载体转染MCF-12A乳腺细胞。在这些细胞中，Akt的激活与Cx43水平降低相关。然后，雌性大鼠按照先前用于肝脏的相同方案通过灌胃暴露于HCB，或者进行慢性暴露。虽然在5天暴露方案后未观察到变化，但慢性暴露于HCB会导致乳腺细胞中Akt水平升高和Cx43水平降低。在体外，暴露于HCB 7天或长期暴露的MCF-12A细胞中Akt被激活，但连接蛋白未观察到变化。总之，这些结果表明，虽然Akt的激活在体外可降低乳腺细胞中Cx43的表达，但在HCB暴露期间涉及其他机制，导致Cx43水平以模型和持续时间依赖性方式降低。最后，我们表明HCB的作用具有组织特异性，因为我们在乳腺和肝脏组织中未观察到相同的结果。
