Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Exp Cell Res. 2011 Oct 1;317(16):2288-98. doi: 10.1016/j.yexcr.2011.06.020. Epub 2011 Jul 8.
The novel tight junction protein marvelD3 contains a conserved MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain like occludin and tricellulin. However, little is yet known about the detailed role and regulation of marvelD3 in normal epithelial cells and cancer cells, including pancreatic cancer. In the present study, we investigated marvelD3 expression in well and poorly differentiated human pancreatic cancer cell lines and normal pancreatic duct epithelial cells in which the hTERT gene was introduced into human pancreatic duct epithelial cells in primary culture, and the changes of marvelD3 during Snail-induced epithelial-mesenchymal transition (EMT) under hypoxia, TGF-β treatment and knockdown of FOXA2 in well differentiated pancreatic cancer HPAC cells. MarvelD3 was transcriptionally downregulated in poorly differentiated pancreatic cancer cells and during Snail-induced EMT of pancreatic cancer cells in which Snail was highly expressed and the fence function downregulated, whereas it was maintained in well differentiated human pancreatic cancer cells and normal pancreatic duct epithelial cells. Depletion of marvelD3 by siRNAs in HPAC cells resulted in downregulation of barrier functions indicated as a decrease in transepithelial electric resistance and an increase of permeability to fluorescent dextran tracers, whereas it did not affect fence function of tight junctions. In conclusion, marvelD3 is transcriptionally downregulated in Snail-induced EMT during the progression for the pancreatic cancer.
新型紧密连接蛋白 marvelD3 包含一个保守的 MARVEL（用于囊泡运输和膜连接的 MAL 和相关蛋白）结构域，类似于紧密连接蛋白和三细胞连接蛋白。然而， marvelD3 在正常上皮细胞和癌细胞（包括胰腺癌）中的详细作用和调控机制还知之甚少。在本研究中，我们研究了 marvelD3 在分化良好和分化不良的人胰腺癌细胞系以及原代培养中 hTERT 基因导入人胰腺导管上皮细胞的正常胰腺导管上皮细胞中的表达，并研究了 marvelD3 在缺氧、TGF-β处理和 FOXA2 敲低条件下 Snail 诱导的上皮-间充质转化（EMT）过程中的变化在分化良好的胰腺癌细胞 HPAC 细胞中。 marvelD3 在分化不良的胰腺癌细胞中以及在高表达 Snail 并下调栅栏功能的胰腺癌细胞的 Snail 诱导 EMT 过程中转录下调，而在分化良好的人胰腺癌细胞和正常胰腺导管上皮细胞中则保持不变。 HPAC 细胞中 marvelD3 的 siRNA 耗竭导致屏障功能下调，表现为上皮电阻降低和荧光葡聚糖示踪剂通透性增加，而对紧密连接的栅栏功能没有影响。综上所述， marvelD3 在胰腺癌进展过程中的 Snail 诱导 EMT 中被转录下调。
