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首页> 外文期刊>Cellular & molecular biology letters. >Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells.
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Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells.

机译：产气荚膜梭菌肠毒素通过claudin-4对正常人胰管上皮细胞和癌细胞的影响。

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The tight junction protein claudin-4 is frequently overexpressed in pancreatic cancer, and is also a receptor for Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE are thought to be useful as a novel therapeutic tool for pancreatic cancer. However, the responses to CPE via claudin-4 remain unknown in normal human pancreatic duct epithelial (HPDE) cells. We introduced the human telomerase reverse transcriptase (hTERT) gene into HPDE cells in primary culture as a model of normal HPDE cells in vitro. hTERT-HPDE cells treated with or without 10% FBS and pancreatic cancer cell lines PANC-1, BXPC3, HPAF-II and HPAC were treated with CPE. In Western blotting, the expression of claudin-4 protein in hTERT-HPDE cells treated with 10% FBS was as high as it was in all of the pancreatic cancer cell lines. In hTERT-HPDE cells with or without 10% FBS, cytotoxicity was not observed at any concentration of CPE, whereas in all pancreatic cancer cell lines, CPE had a dose-dependent cytotoxic effect. In hTERT-HPDE cells with 10% FBS, claudin-4 was localized in the apical-most regions, where there are tight junction areas, in which in all pancreatic cancer cell lines claudin-4 was found not only in the apical-most regions but also at basolateral membranes. In hTERT-HPDE cells with 10% FBS after treatment with CPE, downregulation of barrier function and claudin-4 expression at the membranes was observed. In HPAC cells, the sensitivity to CPE was significantly decreased by knockdown of claudin-4 expression using siRNA compared to the control. These findings suggest that, in normal HPDE cells, the lack of toxicity of CPE was probably due to the localization of claudin-4, which is different from that of pancreatic cancer cells. hTERT-HPDE cells in this culture system may be a useful model of normal HPDE cells not only for physiological regulation of claudin-4 expression but also for developing safer and more effective therapeutic methods targeting claudin-4 in pancreatic cancer.
机译：紧密连接蛋白claudin-4在胰腺癌中经常过度表达，并且也是产气荚膜梭菌肠毒素（CPE）的受体。认为CPE的细胞毒性作用可用作胰腺癌的新型治疗工具。但是，在正常的人胰管上皮细胞（HPDE）中，通过claudin-4对CPE的反应仍然未知。我们将人端粒酶逆转录酶（hTERT）基因引入原代培养的HPDE细胞中，作为体外正常HPDE细胞的模型。用CPE处理用或不用10％FBS处理的hTERT-HPDE细胞以及胰腺癌细胞系PANC-1，BXPC3，HPAF-II和HPAC。在蛋白质印迹法中，用10％FBS处理的hTERT-HPDE细胞中claudin-4蛋白的表达与所有胰腺癌细胞系中的表达一样高。在有或没有10％FBS的hTERT-HPDE细胞中，在任何浓度的CPE下均未观察到细胞毒性，而在所有胰腺癌细胞系中，CPE均具有剂量依赖性细胞毒性作用。在含10％FBS的hTERT-HPDE细胞中，claudin-4定位在最顶端的区域，那里有紧密的连接区域，在所有胰腺癌细胞系中，claudin-4不仅发现在顶端的区域而且在基底外侧膜。 CPE处理后，在含10％FBS的hTERT-HPDE细胞中，观察到屏障功能的下调和膜上claudin-4的表达。在HPAC细胞中，与对照组相比，使用siRNA敲除claudin-4表达可显着降低对CPE的敏感性。这些发现表明，在正常的HPDE细胞中，CPE缺乏毒性可能是由于claudin-4的定位与胰腺癌细胞不同。该培养系统中的hTERT-HPDE细胞可能是正常HPDE细胞的有用模型，不仅可用于调控claudin-4表达的生理学，而且还可用于开发针对胰腺癌claudin-4的更安全有效的治疗方法。

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