Kazal型丝氨酸蛋白酶抑制因子SPINK7在食管疾病中的研究进展
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摘要
Kazal型丝氨酸蛋白酶抑制因子7(SPINK7),又名食管癌相关基因2 (ECRG2),是与食管癌发生发展密切相关的抑癌基因。研究显示其在食管癌组织存在表达失调,同时其短串联重复序列多态性与食管癌的易感性关系密切。机制分析表明SPINK7可通过分泌至胞外和留在细胞内两种不同的机制发挥抑癌作用。新近研究表明其表达失调与嗜酸性食管炎的发生有关。本文就SPINK7在食管癌、嗜酸性食管炎等食管相关疾病中的研究进展做一综述,并探讨该分子后续值得研究的问题。
Serine Protease Inhibitor kazal type 7(SPINK7), also named ECRG2(esophageal cancer-related gene 2), is one tumor suppressor gene closely related to tumorigenesis and progression of esophageal carcinoma. Studies revealed that there were correlations between STR polymorphisms of SPINK7 and risks of esophageal squamous cell cancer. SPINK7 serve as tumor suppressor depending on both extracel-lular and intracellular mechanisms. Lately, SPINK7 is reported as one important inflammation regulator during eosinophilic esophagitis development. The aim of present review is to discuss the significant role of SPINK7 in esophageal diseases such as esophageal cancer and eosinophilic esophagitis, then explore the follow-up questions of SPINK7 for further investigation.
Serine Protease Inhibitor kazal type 7(SPINK7), also named ECRG2(esophageal cancer-related gene 2), is one tumor suppressor gene closely related to tumorigenesis and progression of esophageal carcinoma. Studies revealed that there were correlations between STR polymorphisms of SPINK7 and risks of esophageal squamous cell cancer. SPINK7 serve as tumor suppressor depending on both extracel-lular and intracellular mechanisms. Lately, SPINK7 is reported as one important inflammation regulator during eosinophilic esophagitis development. The aim of present review is to discuss the significant role of SPINK7 in esophageal diseases such as esophageal cancer and eosinophilic esophagitis, then explore the follow-up questions of SPINK7 for further investigation.
引文
[1]Rimphanitchayakit V,Tassanakajon A.Structure and function of invertebrate Kazal-type serine proteinase inhibitors[J].Dev Comp Immunol,2010,34(4):377-386.
[2]李海深,曹云,钱朝南.SPINK家族与人类疾病[J].基础医学与临床,2010,30(5):550-553.
[3]Su Tao,Liu Hai-ling,Lu Shi-xin,et al.Cloning and identification of c DNA fragments related to human esophageal cancer[J].Zhonghua Zhong Liu Za Zhi,1998,20(4):254-257.
[4]Cui Y,Bi M,Su T,et al.Molecular cloning and characterization of a novel esophageal cancer related gene[J].Int J Oncol,2010,37(6):1521-1528.
[5]Cui Y,Wang J,Zhang X et al.ECRG2,a novel candidate of tumor suppressor gene in the esophageal carcinoma,interacts directly with metallothionein 2A and links to apoptosis[J].Biochem Biophys Res Commun,2003,302(4):904-915.
[6]Yue CM,Bi MX,Tan W,et al.Short tandem repeat polymorphism in a novel esophageal cancer-related gene(ECRG2)implicates susceptibility to esophageal cancer in Chinese population[J].Int J Cancer,2004,108(2):232-236.
[7]Li Mei-ning,Huang Ge,Guo Li-ping,et al.Inhibitory effects of esophageal cancer related gene 2 on proliferation of human esophageal cancer cell EC9706[J].Zhonghua Yi Xue Za Zhi,2005,85(39):2785-2788.
[8]Kaifi JT,Rawnaq T,Schurr PG,et al.Short tandem repeat polymorphism in exon 4 of esophageal cancer-related gene 2detected in genomic DNA is a prognostic marker for esophageal cancer[J].Am J Surg,2007,194(3):380-384.
[9]Zhang T,Zhao D,Wang Q,et al.MicroRNA-1322 regulates ECRG2 allele specifically and acts as a potential biomarker in patients with esophageal squamous cell carcinoma[J].Mol Carcinog,2013,52(8):581-590.
[10]Azouz NP,Ynga-Durand MA,Jain A,et al.The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses[J].Sci Transl Med,2018.10(444).
[11]Weber C,Fischer J,Redelfs L,et al.The serine protease inhibitor of Kazal-type 7(SPINK7)is expressed in human skin[J].Arch Dermatol Res,2017,309(9):767-771.
[12]Kazal LA,Spicer DS,Brahinsky RA.Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas[J].J Am Chem Soc,1948,70(9):3034-3040.
[13]Laskowski M Jr,Kato I.Protein inhibitors of proteinases[J].Annu Rev Biochem,1980,49:593-626.
[14]Wapenaar MC,Monsuur AJ,Poell J,et al.The SPINK gene family and celiac disease susceptibility[J].Immunogenetics,2007,59(5):349-357.
[15]张婧,王军.SPINK1/Spink3的研究进展[J].大连医科大学学报,2015,37(4):398-407.
[16]Liddle RA.Pathophysiology of SPINK mutations in pancreatic development and disease[J].Endocrinol Metab Clin North Am,2006,35(2):345-356.
[17]Lee B,Park I,Jin S,et al.Impaired spermatogenesis and fertility in mice carrying a mutation in the Spink2 gene expressed predominantly in testes[J].J Biol Chem,2011,286(33):29108-29117.
[18]Kherraf ZE,Christou-Kent M,Karaouzene T,et al.SPINK2deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes[J].EMBO Mol Med,2017,9(8):1132-1149.
[19]Tartaglia-Polcini A,Bonnart C,Micheloni A,et al.SPINK5,the defective gene in netherton syndrome,encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing[J].J Invest Dermatol,2006,126(2):315-324.
[20]Feng Y,Geng Y,Zhou T,et al.NMR structure note:human esophageal cancer-related gene 2[J].J Biomol NMR,2012,53(1):65-70.
[21]赫捷,邵康.中国食管癌流行病学现状、诊疗现状及未来对策[J].中国癌症杂志,2011,21(7):501-504.
[22]Zinovyeva MV,Monastyrskaya GS,Kopantzev EP,et al.Identification of some human genes oppositely regulated during esophageal squamous cell carcinoma formation and human embryonic esophagus development[J].Dis Esophagus,2010.23(3):260-270.
[23]Li F,Yoshizawa JM,Kim KM,et al.Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer[J].Clin Chem,2018,64(10):1513-1521.
[24]Huang G,Hu Z,Li M,et al.ECRG2 inhibits cancer cell migration,invasion and metastasis through the down-regulation of u PA/plasmin activity[J].Carcinogenesis,2007,28(11):2274-2281.
[25]Cheng X,Shen Z,Yin Z,et al.ECRG2 regulates cell migration/invasion through urokinase-type plasmin activator receptor(u PAR)/beta1 integrin pathway[J].J Biol Chem,2009,284(45):30897-30906.
[26]Cheng X.,Lu SH,Cui Y.ECRG2 regulates ECM degradation and u PAR/FPRL1 pathway contributing cell invasion/migration[J].Cancer Lett,2010,290(1):87-95.
[27]Lucchesi C,Sheikh MS,Huang Y.Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2[J].Oncogene,2016,35(20):2565-2573.
[28]Song H,Song C,Wang H,et al.Suppression of hepatocarcinoma model in vitro and in vivo by ECRG2 delivery using adenoviral vector[J].Cancer Gene Ther,2012,19(12):875-879.
[29]陈湘川,庞丽娟,陈玲,等.新疆哈萨克族和汉族食管癌组织ECRG2基因遗传多态性与易感性的关系[J].世界华人消化杂志,2007,15(22):2408-2412.
[30]Jain M,Kumar S,Ghoshal UC,et al.Association of ECRG2TCA short tandem repeat polymorphism with the risk of oesophageal cancer in a North Indian population[J].Clin Exp Med,2008,8(2):73-78.
[31]Blessmann M,Kaifi JT,Schurr PG,et al.Short tandem repeat polymorphism in exon 4 of esophageal cancer related gene 2predicts relapse of oral squamous cell carcinoma[J].Oral Oncol,2008,44(2):143-147.
[32]Kaifi JT,Cataldegirmen G,Wachowiak R,et al.Short tandem repeat polymorphisms of exon 4 in Kazal-type gene ECRG2 in pancreatic carcinoma and chronic pancreatitis[J].Anticancer Res,2007,27(1A):69-73.
[33]Huang G,Wang D,Guo L,et al.Monoclonal antibodies to esophageal cancer-related gene2 protein[J].Hybridoma(Larchmt),2005,24(2):86-91.
[34]Geng Y,Feng Y,Xie T,et al.Mapping the putative binding site for uPA protein in Esophageal Cancer-Related Gene 2 by heteronuclear NMR method[J].Arch Biochem Biophys,2008,479(2):153-157.
[35]Cui YP,Wang JB,Zhang XY,et al.Using yeast two-hybrid system to identify ECRG2 associated proteins and their possible interactions with ECRG2 gene[J].World J Gastroenterol,2003,9(9):1892-1896.
[36]Cheng X,Shen Z,Yang J,et al,ECRG2 disruption leads to centrosome amplification and spindle checkpoint defects contributing chromosome instability[J].J Biol Chem,2008,283(9):5888-5898.
[37]Hou XF,Xu LP,Song HY,et al.ECRG2 enhances the anticancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA[J].World J Gastroenterol,2017,23(10):1796-1803.
[38]Song HY,Deng XH,Yuan GY,et al.Expression of bcl-2 and p53 in induction of esophageal cancer cell apoptosis by ECRG2in combination with cisplatin[J].Asian Pac J Cancer Prev,2014,15(3):1397-401.
[39]Rochman M,Azouz NP,Rothenberg ME.Epithelial origin of eosinophilic esophagitis[J].J Allergy Clin Immunol,2018,142(1):10-23.
[2]李海深,曹云,钱朝南.SPINK家族与人类疾病[J].基础医学与临床,2010,30(5):550-553.
[3]Su Tao,Liu Hai-ling,Lu Shi-xin,et al.Cloning and identification of c DNA fragments related to human esophageal cancer[J].Zhonghua Zhong Liu Za Zhi,1998,20(4):254-257.
[4]Cui Y,Bi M,Su T,et al.Molecular cloning and characterization of a novel esophageal cancer related gene[J].Int J Oncol,2010,37(6):1521-1528.
[5]Cui Y,Wang J,Zhang X et al.ECRG2,a novel candidate of tumor suppressor gene in the esophageal carcinoma,interacts directly with metallothionein 2A and links to apoptosis[J].Biochem Biophys Res Commun,2003,302(4):904-915.
[6]Yue CM,Bi MX,Tan W,et al.Short tandem repeat polymorphism in a novel esophageal cancer-related gene(ECRG2)implicates susceptibility to esophageal cancer in Chinese population[J].Int J Cancer,2004,108(2):232-236.
[7]Li Mei-ning,Huang Ge,Guo Li-ping,et al.Inhibitory effects of esophageal cancer related gene 2 on proliferation of human esophageal cancer cell EC9706[J].Zhonghua Yi Xue Za Zhi,2005,85(39):2785-2788.
[8]Kaifi JT,Rawnaq T,Schurr PG,et al.Short tandem repeat polymorphism in exon 4 of esophageal cancer-related gene 2detected in genomic DNA is a prognostic marker for esophageal cancer[J].Am J Surg,2007,194(3):380-384.
[9]Zhang T,Zhao D,Wang Q,et al.MicroRNA-1322 regulates ECRG2 allele specifically and acts as a potential biomarker in patients with esophageal squamous cell carcinoma[J].Mol Carcinog,2013,52(8):581-590.
[10]Azouz NP,Ynga-Durand MA,Jain A,et al.The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses[J].Sci Transl Med,2018.10(444).
[11]Weber C,Fischer J,Redelfs L,et al.The serine protease inhibitor of Kazal-type 7(SPINK7)is expressed in human skin[J].Arch Dermatol Res,2017,309(9):767-771.
[12]Kazal LA,Spicer DS,Brahinsky RA.Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas[J].J Am Chem Soc,1948,70(9):3034-3040.
[13]Laskowski M Jr,Kato I.Protein inhibitors of proteinases[J].Annu Rev Biochem,1980,49:593-626.
[14]Wapenaar MC,Monsuur AJ,Poell J,et al.The SPINK gene family and celiac disease susceptibility[J].Immunogenetics,2007,59(5):349-357.
[15]张婧,王军.SPINK1/Spink3的研究进展[J].大连医科大学学报,2015,37(4):398-407.
[16]Liddle RA.Pathophysiology of SPINK mutations in pancreatic development and disease[J].Endocrinol Metab Clin North Am,2006,35(2):345-356.
[17]Lee B,Park I,Jin S,et al.Impaired spermatogenesis and fertility in mice carrying a mutation in the Spink2 gene expressed predominantly in testes[J].J Biol Chem,2011,286(33):29108-29117.
[18]Kherraf ZE,Christou-Kent M,Karaouzene T,et al.SPINK2deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes[J].EMBO Mol Med,2017,9(8):1132-1149.
[19]Tartaglia-Polcini A,Bonnart C,Micheloni A,et al.SPINK5,the defective gene in netherton syndrome,encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing[J].J Invest Dermatol,2006,126(2):315-324.
[20]Feng Y,Geng Y,Zhou T,et al.NMR structure note:human esophageal cancer-related gene 2[J].J Biomol NMR,2012,53(1):65-70.
[21]赫捷,邵康.中国食管癌流行病学现状、诊疗现状及未来对策[J].中国癌症杂志,2011,21(7):501-504.
[22]Zinovyeva MV,Monastyrskaya GS,Kopantzev EP,et al.Identification of some human genes oppositely regulated during esophageal squamous cell carcinoma formation and human embryonic esophagus development[J].Dis Esophagus,2010.23(3):260-270.
[23]Li F,Yoshizawa JM,Kim KM,et al.Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer[J].Clin Chem,2018,64(10):1513-1521.
[24]Huang G,Hu Z,Li M,et al.ECRG2 inhibits cancer cell migration,invasion and metastasis through the down-regulation of u PA/plasmin activity[J].Carcinogenesis,2007,28(11):2274-2281.
[25]Cheng X,Shen Z,Yin Z,et al.ECRG2 regulates cell migration/invasion through urokinase-type plasmin activator receptor(u PAR)/beta1 integrin pathway[J].J Biol Chem,2009,284(45):30897-30906.
[26]Cheng X.,Lu SH,Cui Y.ECRG2 regulates ECM degradation and u PAR/FPRL1 pathway contributing cell invasion/migration[J].Cancer Lett,2010,290(1):87-95.
[27]Lucchesi C,Sheikh MS,Huang Y.Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2[J].Oncogene,2016,35(20):2565-2573.
[28]Song H,Song C,Wang H,et al.Suppression of hepatocarcinoma model in vitro and in vivo by ECRG2 delivery using adenoviral vector[J].Cancer Gene Ther,2012,19(12):875-879.
[29]陈湘川,庞丽娟,陈玲,等.新疆哈萨克族和汉族食管癌组织ECRG2基因遗传多态性与易感性的关系[J].世界华人消化杂志,2007,15(22):2408-2412.
[30]Jain M,Kumar S,Ghoshal UC,et al.Association of ECRG2TCA short tandem repeat polymorphism with the risk of oesophageal cancer in a North Indian population[J].Clin Exp Med,2008,8(2):73-78.
[31]Blessmann M,Kaifi JT,Schurr PG,et al.Short tandem repeat polymorphism in exon 4 of esophageal cancer related gene 2predicts relapse of oral squamous cell carcinoma[J].Oral Oncol,2008,44(2):143-147.
[32]Kaifi JT,Cataldegirmen G,Wachowiak R,et al.Short tandem repeat polymorphisms of exon 4 in Kazal-type gene ECRG2 in pancreatic carcinoma and chronic pancreatitis[J].Anticancer Res,2007,27(1A):69-73.
[33]Huang G,Wang D,Guo L,et al.Monoclonal antibodies to esophageal cancer-related gene2 protein[J].Hybridoma(Larchmt),2005,24(2):86-91.
[34]Geng Y,Feng Y,Xie T,et al.Mapping the putative binding site for uPA protein in Esophageal Cancer-Related Gene 2 by heteronuclear NMR method[J].Arch Biochem Biophys,2008,479(2):153-157.
[35]Cui YP,Wang JB,Zhang XY,et al.Using yeast two-hybrid system to identify ECRG2 associated proteins and their possible interactions with ECRG2 gene[J].World J Gastroenterol,2003,9(9):1892-1896.
[36]Cheng X,Shen Z,Yang J,et al,ECRG2 disruption leads to centrosome amplification and spindle checkpoint defects contributing chromosome instability[J].J Biol Chem,2008,283(9):5888-5898.
[37]Hou XF,Xu LP,Song HY,et al.ECRG2 enhances the anticancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA[J].World J Gastroenterol,2017,23(10):1796-1803.
[38]Song HY,Deng XH,Yuan GY,et al.Expression of bcl-2 and p53 in induction of esophageal cancer cell apoptosis by ECRG2in combination with cisplatin[J].Asian Pac J Cancer Prev,2014,15(3):1397-401.
[39]Rochman M,Azouz NP,Rothenberg ME.Epithelial origin of eosinophilic esophagitis[J].J Allergy Clin Immunol,2018,142(1):10-23.
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