细胞连接分子对上皮组织物质转运的调控机制
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摘要
细胞连接分子对上皮组织物质转运有重要的调节作用,其分子机制有待总结归纳。上皮组织中多数细胞连接分子参与形成紧密连接、粘附连接、桥粒连接和间隙连接等连接结构,调控细胞间转运和跨细胞运输。构成紧密连接的Claudin蛋白通过栅栏功能、受体功能和维持上皮细胞极性三种机制在调控上皮组织物质运输中起到至关重要的作用,其它细胞连接分子通过对紧密连接的调控间接影响物质运输。由于Claudin家族的各成员之间的功能代偿作用及转录后调控对Claudin蛋白的表达的重要性,给细胞连接研究造成一定局限,新的研究方法和技术有待发展。该文总结归纳出上皮细胞间连接分子调控物质转运的三种方式及当前应用于检测连接分子的生物技术,为基础和临床研究提供参考。
Cell junction molecules played important roles in regulating the transport of epithelialsubstances,and its molecular mechanisms had not been summarized yet. Most cell junction molecules in the epithelial tissues were involved in the formation of tight junctions,adhesion junctions,desmosome junctions,and gap junctions,regulating intercellular and transcellular transport. The Claudin proteins,which constituted tight junctions,played a crucial role in regulating the transport of epithelial substances through three mechanisms: barrier function,receptor function and maintaining the polarity of epithelial cells. Other cell junction molecules affected the substances transport indirectly through the regulation of tight junctions. Due to the compensatory functions of the members of the Claudin family and the importance of post-transcriptional regulation on the expression of Claudin proteins,the study of cell junctions had been limited,and new research methods and techniques needed to be developed. In this report,the three ways of regulating substance transport by cell junction molecules of epithelial cells and the biotechnology currently used to check the cell junction molecules had been summarized,providing a reference for basic and clinical research.
Cell junction molecules played important roles in regulating the transport of epithelialsubstances,and its molecular mechanisms had not been summarized yet. Most cell junction molecules in the epithelial tissues were involved in the formation of tight junctions,adhesion junctions,desmosome junctions,and gap junctions,regulating intercellular and transcellular transport. The Claudin proteins,which constituted tight junctions,played a crucial role in regulating the transport of epithelial substances through three mechanisms: barrier function,receptor function and maintaining the polarity of epithelial cells. Other cell junction molecules affected the substances transport indirectly through the regulation of tight junctions. Due to the compensatory functions of the members of the Claudin family and the importance of post-transcriptional regulation on the expression of Claudin proteins,the study of cell junctions had been limited,and new research methods and techniques needed to be developed. In this report,the three ways of regulating substance transport by cell junction molecules of epithelial cells and the biotechnology currently used to check the cell junction molecules had been summarized,providing a reference for basic and clinical research.
引文
[1]Schnell U,Cirulli V.EpCAM:Structure and function in health and disease[J].Biochim Biophys Acta,2013,1828(8):1989-2001.
[2]Huang L,Yang Y,Yang F,et al.Functions of EpCAM in physiological processes and diseases[J].Int J Mol Med.2018,42(4):1771-1785.
[3]Marchiando A M,Graham W V,Turner J R.Epithelial barriers in homeostasis and disease[J].Annu Rev Pathol,2010,5(5):119-144.
[4]Cheng C Y,Mruk D D.The Blood-Testis Barrier and its implications for male contraception[J].Pharmacological,2012,64(1):16-64.
[5]Philip R,Heiler S,Mu W,et al.Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer[J].Oncotarget,2015,6(4):2046-2063.
[6]Li Z,Jouret F,Rinehart J,et al.AMP-activated Protein Kinase(AMPK)activation and Glycogen Synthase Kinase-3β(GSK-3β)inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane[J].Journal of Separation Science,2015,37(18):2591-2598.
[7]Sun X,Yang Q,Rogers C J,et al.AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression[J].Cell Death and Differentiation,2017,(4):819-831.
[8]Lu Z,Ding L,Hong H,et al.Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway[J].Experimental Cell Research,2011,317(13):1935-1946.
[9]刘求明,朱杰,郭晓红.紧密连接的构成、装配及其调控研究进展[J].中国科学:生命科学,2018,(3):287-296.[Liu Qiuming,Zhu Jie,Guo Xiaohong.Research progress in the composition,assembly and regulation of tight junction[J].Science in China,Life Science,2018,(3):287-296.]
[10]Ajaz A,Uppada S,Achkar Iman W,et al.Tight junction proteins and signaling pathways in cancer and inflamation:a functional crosstalk[J].Frontiers in Physiology,2019,23(9):1942.
[11]Campenhout CA,Eitelhuber A,Gloeckner CJ,et al.Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases[J].Dev Cell,2011,21(3):479-91.
[12]Bruner H C,Pwb D.Loss of E-Cadherin-dependent cell-cell adhesion and the development and progression of cancer[J].Cold Spring Harbor Perspectives in Biology,2017,10(3):a029330.
[13]Leckband D E,De R J.Cadherin adhesion and mechanotransduction[J].Annu Rev Cell Dev Biol,2014,30(1):291-315.
[14]Lecuit T,Yap A S.E-cadherin junctions as active mechanical integrators in tissue dynamics[J].Nature Cell Biology,2015,17(5):533-539.
[15]Lu C S,Lee Y N,Wang S W,et al.KC21 peptide inhibits angiogenesis and attenuates hypoxia-induced retinopathy[J].Journal of Cardiovascular Translational Research,2019:1-12.
[16]Yahyazadeh Mashhadi SM,Kazemimanesh M,Arashkia A,et al.Shedding light on the EpCAM:An overview[J].Cell Physiol,2019,undefined.
[17]Lei Z,Maeda T,Tamura A,et al.EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins[J].Developmental Biology,2012,371(2):136-145.
[18]Maruhashi R,Akizuki R,Sato T,et al.Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models[J].Biochimica et Biophysica Acta(BBA)-Molecular Cell Research,2018,1865(3):470-479.
[19]Lv Y,Liu W,Ruan Z,et al.Myosin IIA regulated tight junction in oxygen glucose-deprived brain endothelial cells via activation of TLR4/PI3K/Akt/JNK1/2/14-3-3ε/NF-κB/MMP9 signal transduction pathway[J].Cellular and Molecular Neurobiology,2019,39:301-319.
[20]Zhang Y,Zhou S,Deng F,et al.The function and mechanism of preactivated thiomers in triggering epithelial tight junctions opening[J].European Journal of Pharmaceutics and Biopharmaceutics,2018,133:188-199.
[21]Odijk M,Meer A D V D,Levner D,et al.Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems[J].Lab on A Chip,2015,15(3):745-752.
[22]Henry Olivier Y F,Villenave Remi,Cronce Michael J,et al.Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance(TEER)measurements of human epithelial barrier function[J].Lab Chip,2017,17:2264-2271.
[23]Kong W,Huang C,Tang Y,et al.Effect of Bacillus subtilis on Aeromonas hydrophila-induced intestinal mucosal barrier function damage and inflammation in grass carp(Ctenopharyngodon idella)[J].Sci Rep,2017,7:1588.
[24]Gradauer K,Iida M,Watari A,et al.Dodecylmaltoside modulates bicellular tight junction contacts to promote enhanced permeability[J].Molecular Pharmaceutics,2017:acs.molpharmaceut.7b00297.
[25]Kiewiet Mensiena B G,González Rodríguez Martín I,Dekkers Renske,et al.The epithelial barrier-protecting properties of a soy hydrolysate[J].Food Funct,2018,9:4164-4172.
[26]Kawedia J D,Nieman M L,Boivin G P,et al.Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex[J].Proc Natl Acad Sci USA,2007,104(9):3621-3626.
[27]Lee J H,Sahu A,Choi W I,et al.ZOT-derived peptide and chitosan functionalized nanocarrier for oral delivery of protein drug[J].Biomaterials,2016,103:160-169.
[28]L Zhang,H Liu,Y-M Peng,et al.Vascular endothelial growth factor increases GEn C permeability by affecting the distributions of occludin,ZO-1 and tight juction assembly[J].European Review for Medical&Pharmacological Sciences,2015,19(14):2621-2627.
[29]Tsukita S,Furuse M,Itoh M,et al.Multifunctional strands in tight junctions[J].Nat Rev Mol Cell Biol,2001,2(4):285-293.
[30]Powell D W.Barrier function of epithelia[J].American Journal of Physiology,1981,241(4):275-88.
[31]Tanaka H,Takechi M,Kiyonari H,et al.Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice[J].Gut,2015,64:1529-38.
[32]Furuse M,Hata M,Furuse K,et al.Claudin-based tight junctions are crucial for the mammalian epidermal barrier:a lesson from Claudin-1-deficient mice[J].Cell Biol,2002,156:1099-111.
[33]刘娇阳,王沂峰.紧密连接蛋白Claudin-8的研究进展[J].中国现代医生,2018,56(18):170-174.[Liu Jiaoyang,Wang Yufeng.Research progress of tight junction protein Claudin-8[J].Modern Doctor of China,2018,56(18):170-174.]
[34]Hayashi D,Tamura A,Tanaka H,et al.Deficiency of Claudin-18causes paracellular H+leakage,up-regulation of interleukin-1,and atrophic gastritis in mice[J].Gastroenterology,2012,142(2):292-304.
[35]Rosenthal R,Günzel D,Theune D,et al.Water channels and barriers formed by claudins[J].Ann N Y Acad Sci,2017,1397:100-109.
[36]Matsumoto K,Imasato,Yamazali Y,et al.Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice[J].Gastroenterology,2014,147(5):1134-1145.e10.
[37]Zhang Y G,Wu S,Lu R,et al.Tight junction CLDN2 gene is a direct target of the vitamin D receptor[J].Scientific Reports,2015,5(1):10642.
[38]Lashhab R,Rumley A C,Arutyunov D,et al.The kidney anion exchanger 1 affects tight junction properties via claudin-4[J].Sci Rep,2019,9:3099.
[39]Tatum RY,Salleng K,Lu Z,et al.Renal salt wasting and chronic dehydration in claudin-7-deficient mice[J].American Journal of Physiology,2010,298(2):24-34.
[40]Tamura A,Hayashi H,Imasato M,et al.Loss of Claudin-15,but not Claudin-2,causes Na+deficiency and glucose malabsorption in mouse small intestine[J].Gastroenterology,2011,140(3):913-923.
[41]Wada M,Tamura A,Takahashi N,et al.Loss of Claudins 2 and 15from mice causes defects in paracellular Na+flow and nutrient transport in gut and leads to death from malnutrition[J].Gastroenterology,2013,144(2):369-380.
[42]Gladden A B,Hebert A M,Schneeberger E E,et al.The NF2tumor suppressor,merlin,regulates epidermal development through the establishment of a junctional polarity complex[J].Developmental Cell,2010,19(5):727-739.
[43]Ueno M,Lee L,Chhabra A,et al.c-Met-dependent multipotent labyrinth trophoblast progenitors establish placental exchange interface[J].Developmental Cell,2013,27(4):373-386.
[44]Lei Z,Maeda T,Tamura A,et al.EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins[J].Developmental Biology,2012,371(2):136-145.
[45]Kozan P A,Mcgeough M D,Pe1a CA,et al.Mutation of EpCAMleads to intestinal barrier and ion transport dysfunction[J].Journal of Molecular Medicine,2015,93(5):535-545.
[46]Mueller J L,Mcgeough M D,Pe1a C A,et al.Functional consequences of EpCAM mutation in mice and men.[J].Am J Physiol GastrointestLiver Physiol,2014,306(4):278-88.
[47]Tunggal J A,Helfrich I,Schmitz A,et al.E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions[J].Embo Journal,2005,24(6):1146-1156.
[48]Xu Guangming,Li Yingmin,Ma Chunling,et al.Restraint stress induced hyperpermeability and damage of the blood-brain barrier in the amygdala of adult rats[J].Front Mol Neurosci,2019,12:32.
[2]Huang L,Yang Y,Yang F,et al.Functions of EpCAM in physiological processes and diseases[J].Int J Mol Med.2018,42(4):1771-1785.
[3]Marchiando A M,Graham W V,Turner J R.Epithelial barriers in homeostasis and disease[J].Annu Rev Pathol,2010,5(5):119-144.
[4]Cheng C Y,Mruk D D.The Blood-Testis Barrier and its implications for male contraception[J].Pharmacological,2012,64(1):16-64.
[5]Philip R,Heiler S,Mu W,et al.Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer[J].Oncotarget,2015,6(4):2046-2063.
[6]Li Z,Jouret F,Rinehart J,et al.AMP-activated Protein Kinase(AMPK)activation and Glycogen Synthase Kinase-3β(GSK-3β)inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane[J].Journal of Separation Science,2015,37(18):2591-2598.
[7]Sun X,Yang Q,Rogers C J,et al.AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression[J].Cell Death and Differentiation,2017,(4):819-831.
[8]Lu Z,Ding L,Hong H,et al.Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway[J].Experimental Cell Research,2011,317(13):1935-1946.
[9]刘求明,朱杰,郭晓红.紧密连接的构成、装配及其调控研究进展[J].中国科学:生命科学,2018,(3):287-296.[Liu Qiuming,Zhu Jie,Guo Xiaohong.Research progress in the composition,assembly and regulation of tight junction[J].Science in China,Life Science,2018,(3):287-296.]
[10]Ajaz A,Uppada S,Achkar Iman W,et al.Tight junction proteins and signaling pathways in cancer and inflamation:a functional crosstalk[J].Frontiers in Physiology,2019,23(9):1942.
[11]Campenhout CA,Eitelhuber A,Gloeckner CJ,et al.Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases[J].Dev Cell,2011,21(3):479-91.
[12]Bruner H C,Pwb D.Loss of E-Cadherin-dependent cell-cell adhesion and the development and progression of cancer[J].Cold Spring Harbor Perspectives in Biology,2017,10(3):a029330.
[13]Leckband D E,De R J.Cadherin adhesion and mechanotransduction[J].Annu Rev Cell Dev Biol,2014,30(1):291-315.
[14]Lecuit T,Yap A S.E-cadherin junctions as active mechanical integrators in tissue dynamics[J].Nature Cell Biology,2015,17(5):533-539.
[15]Lu C S,Lee Y N,Wang S W,et al.KC21 peptide inhibits angiogenesis and attenuates hypoxia-induced retinopathy[J].Journal of Cardiovascular Translational Research,2019:1-12.
[16]Yahyazadeh Mashhadi SM,Kazemimanesh M,Arashkia A,et al.Shedding light on the EpCAM:An overview[J].Cell Physiol,2019,undefined.
[17]Lei Z,Maeda T,Tamura A,et al.EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins[J].Developmental Biology,2012,371(2):136-145.
[18]Maruhashi R,Akizuki R,Sato T,et al.Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models[J].Biochimica et Biophysica Acta(BBA)-Molecular Cell Research,2018,1865(3):470-479.
[19]Lv Y,Liu W,Ruan Z,et al.Myosin IIA regulated tight junction in oxygen glucose-deprived brain endothelial cells via activation of TLR4/PI3K/Akt/JNK1/2/14-3-3ε/NF-κB/MMP9 signal transduction pathway[J].Cellular and Molecular Neurobiology,2019,39:301-319.
[20]Zhang Y,Zhou S,Deng F,et al.The function and mechanism of preactivated thiomers in triggering epithelial tight junctions opening[J].European Journal of Pharmaceutics and Biopharmaceutics,2018,133:188-199.
[21]Odijk M,Meer A D V D,Levner D,et al.Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems[J].Lab on A Chip,2015,15(3):745-752.
[22]Henry Olivier Y F,Villenave Remi,Cronce Michael J,et al.Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance(TEER)measurements of human epithelial barrier function[J].Lab Chip,2017,17:2264-2271.
[23]Kong W,Huang C,Tang Y,et al.Effect of Bacillus subtilis on Aeromonas hydrophila-induced intestinal mucosal barrier function damage and inflammation in grass carp(Ctenopharyngodon idella)[J].Sci Rep,2017,7:1588.
[24]Gradauer K,Iida M,Watari A,et al.Dodecylmaltoside modulates bicellular tight junction contacts to promote enhanced permeability[J].Molecular Pharmaceutics,2017:acs.molpharmaceut.7b00297.
[25]Kiewiet Mensiena B G,González Rodríguez Martín I,Dekkers Renske,et al.The epithelial barrier-protecting properties of a soy hydrolysate[J].Food Funct,2018,9:4164-4172.
[26]Kawedia J D,Nieman M L,Boivin G P,et al.Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex[J].Proc Natl Acad Sci USA,2007,104(9):3621-3626.
[27]Lee J H,Sahu A,Choi W I,et al.ZOT-derived peptide and chitosan functionalized nanocarrier for oral delivery of protein drug[J].Biomaterials,2016,103:160-169.
[28]L Zhang,H Liu,Y-M Peng,et al.Vascular endothelial growth factor increases GEn C permeability by affecting the distributions of occludin,ZO-1 and tight juction assembly[J].European Review for Medical&Pharmacological Sciences,2015,19(14):2621-2627.
[29]Tsukita S,Furuse M,Itoh M,et al.Multifunctional strands in tight junctions[J].Nat Rev Mol Cell Biol,2001,2(4):285-293.
[30]Powell D W.Barrier function of epithelia[J].American Journal of Physiology,1981,241(4):275-88.
[31]Tanaka H,Takechi M,Kiyonari H,et al.Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice[J].Gut,2015,64:1529-38.
[32]Furuse M,Hata M,Furuse K,et al.Claudin-based tight junctions are crucial for the mammalian epidermal barrier:a lesson from Claudin-1-deficient mice[J].Cell Biol,2002,156:1099-111.
[33]刘娇阳,王沂峰.紧密连接蛋白Claudin-8的研究进展[J].中国现代医生,2018,56(18):170-174.[Liu Jiaoyang,Wang Yufeng.Research progress of tight junction protein Claudin-8[J].Modern Doctor of China,2018,56(18):170-174.]
[34]Hayashi D,Tamura A,Tanaka H,et al.Deficiency of Claudin-18causes paracellular H+leakage,up-regulation of interleukin-1,and atrophic gastritis in mice[J].Gastroenterology,2012,142(2):292-304.
[35]Rosenthal R,Günzel D,Theune D,et al.Water channels and barriers formed by claudins[J].Ann N Y Acad Sci,2017,1397:100-109.
[36]Matsumoto K,Imasato,Yamazali Y,et al.Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice[J].Gastroenterology,2014,147(5):1134-1145.e10.
[37]Zhang Y G,Wu S,Lu R,et al.Tight junction CLDN2 gene is a direct target of the vitamin D receptor[J].Scientific Reports,2015,5(1):10642.
[38]Lashhab R,Rumley A C,Arutyunov D,et al.The kidney anion exchanger 1 affects tight junction properties via claudin-4[J].Sci Rep,2019,9:3099.
[39]Tatum RY,Salleng K,Lu Z,et al.Renal salt wasting and chronic dehydration in claudin-7-deficient mice[J].American Journal of Physiology,2010,298(2):24-34.
[40]Tamura A,Hayashi H,Imasato M,et al.Loss of Claudin-15,but not Claudin-2,causes Na+deficiency and glucose malabsorption in mouse small intestine[J].Gastroenterology,2011,140(3):913-923.
[41]Wada M,Tamura A,Takahashi N,et al.Loss of Claudins 2 and 15from mice causes defects in paracellular Na+flow and nutrient transport in gut and leads to death from malnutrition[J].Gastroenterology,2013,144(2):369-380.
[42]Gladden A B,Hebert A M,Schneeberger E E,et al.The NF2tumor suppressor,merlin,regulates epidermal development through the establishment of a junctional polarity complex[J].Developmental Cell,2010,19(5):727-739.
[43]Ueno M,Lee L,Chhabra A,et al.c-Met-dependent multipotent labyrinth trophoblast progenitors establish placental exchange interface[J].Developmental Cell,2013,27(4):373-386.
[44]Lei Z,Maeda T,Tamura A,et al.EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins[J].Developmental Biology,2012,371(2):136-145.
[45]Kozan P A,Mcgeough M D,Pe1a CA,et al.Mutation of EpCAMleads to intestinal barrier and ion transport dysfunction[J].Journal of Molecular Medicine,2015,93(5):535-545.
[46]Mueller J L,Mcgeough M D,Pe1a C A,et al.Functional consequences of EpCAM mutation in mice and men.[J].Am J Physiol GastrointestLiver Physiol,2014,306(4):278-88.
[47]Tunggal J A,Helfrich I,Schmitz A,et al.E-cadherin is essential for in vivo epidermal barrier function by regulating tight junctions[J].Embo Journal,2005,24(6):1146-1156.
[48]Xu Guangming,Li Yingmin,Ma Chunling,et al.Restraint stress induced hyperpermeability and damage of the blood-brain barrier in the amygdala of adult rats[J].Front Mol Neurosci,2019,12:32.