HIP1与AKT/GSK3β信号通路及上皮间充质转化标志性分子在食管鳞癌组织中的表达及其相关性
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摘要
目的:检测亨廷顿蛋白相互作用蛋白1(Huntingtin interacting protein 1,HIP1),AKT/GSK3β信号通路及上皮间充质转化(epithelial-mesenchymal transition,EMT)关键分子蛋白在食管鳞癌中的表达,探讨HIP1表达与AKT/GSK3β信号通路及EMT之间的相关性,为进一步研究HIP1在食管鳞癌中的作用及其机制提供依据。方法:采用免疫组织化学法检测85例食管鳞癌组织及其对应癌旁组织样本中HIP1,p-GSK3β,EMT标志性分子E-cadherin及Vimentin的表达,并统计分析几者在临床病理特征中的表达差异及HIP1与p-GSK3β,E-cadherin,Vimentin表达之间的相关性。采用荧光定量PCR(RT-qPCR)法检测HIP1,GSK3β,E-cadherin及Vimentin基因在食管癌及其癌旁组织中的表达。结果:HIP1,p-GSK3β,E-cadherin及Vimentin在食管鳞癌组织中的阳性表达率分别为91.8%(78/85),82.35%(70/85),15.29%(13/85),80%(68/85),分别与癌旁组织中的表达差异有统计学意义(P<0.001)。HIP1,p-GSK3β,E-cadherin在不同病理分级组间的表达差异有统计学意义(P<0.05),而Vimentin在临床病理特征各组组间的表达差异均无统计学意义(P>0.05)。相关性结果显示,HIP1与p-GSK3β及Vimentin在总的食管鳞癌中的表达均呈显著正相关(P<0.05),HIP1与E-cadherin在总的食管鳞癌中的表达呈显著负相关(P<0.01)。RT-qPCR结果发现,HIP1,GSK3β及Vimentin基因在食管鳞癌中的表达均高于其对应的癌旁组织,而E-cadherin基因在食管鳞癌中的表达低于其对应的癌旁组织。结论:HIP1表达与p-GSK3β,E-cadherin及Vimentin间存在相关性,提示HIP1可能促进食管鳞癌组织中GSK3β及Vimentin的表达,抑制E-cadherin的表达。
Objective: To explore the effect and mechanism of HIP1 in esophageal squamous cell carcinoma(ESCC)carcinogenesis through exam the expression and correlation research of HIP1 with AKT/GSK3β signal pathway and epithelial-mesenchymal transition(EMT) in ESCC. Methods: In this study, HIP1, p-GSK3β, E-cadherin,Vimentin expressions were assessed using immunohistochemistry(IHC) in 85 ESCC and adjacent ESCC tissues and the correlation research of HIP1 with p-GSK3β, E-cadherin, Vimentin were analyzed. RT-qPCR was used to detect the gene expression of HIP1, GSK3β, E-cadherin and Vimentin in ESCC and adjacent ESCC tissues.Results: The expression rate of HIP1, p-GSK3β, E-cadherin, Vimentin in ESCC(91.8%, 82.35%, 15.29%, 80%)showed extremely significance compared with adjacent ESCC tissues(P<0.001). HIP1, p-GSK3β, E-cadherin expression was significantly associated with pathological grades(P<0.05), and there was no significance between Vimentin expression with clinicopathologic features(P>0.05). The correlation research showed that there were significant positive correlations between HIP1 and p-GSK3β, as well as Vimentin(P<0.05), and there was significant negative correlation between HIP1 and E-cadherin(P<0.01). RT-qPCR results showed that compared with adjacent ESCC tissues, HIP1, GSK3β and Vimentin gene were higher expressed in ESCC tissues,but E-cadherin gene was lower expressed in ESCC tissues. Conclusion: HIP1 maybe promote p-GSK3β and Vimentin expression and inhibit E-cadherin expression.
Objective: To explore the effect and mechanism of HIP1 in esophageal squamous cell carcinoma(ESCC)carcinogenesis through exam the expression and correlation research of HIP1 with AKT/GSK3β signal pathway and epithelial-mesenchymal transition(EMT) in ESCC. Methods: In this study, HIP1, p-GSK3β, E-cadherin,Vimentin expressions were assessed using immunohistochemistry(IHC) in 85 ESCC and adjacent ESCC tissues and the correlation research of HIP1 with p-GSK3β, E-cadherin, Vimentin were analyzed. RT-qPCR was used to detect the gene expression of HIP1, GSK3β, E-cadherin and Vimentin in ESCC and adjacent ESCC tissues.Results: The expression rate of HIP1, p-GSK3β, E-cadherin, Vimentin in ESCC(91.8%, 82.35%, 15.29%, 80%)showed extremely significance compared with adjacent ESCC tissues(P<0.001). HIP1, p-GSK3β, E-cadherin expression was significantly associated with pathological grades(P<0.05), and there was no significance between Vimentin expression with clinicopathologic features(P>0.05). The correlation research showed that there were significant positive correlations between HIP1 and p-GSK3β, as well as Vimentin(P<0.05), and there was significant negative correlation between HIP1 and E-cadherin(P<0.01). RT-qPCR results showed that compared with adjacent ESCC tissues, HIP1, GSK3β and Vimentin gene were higher expressed in ESCC tissues,but E-cadherin gene was lower expressed in ESCC tissues. Conclusion: HIP1 maybe promote p-GSK3β and Vimentin expression and inhibit E-cadherin expression.
引文
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11.张亚斌,孙盈,孙蕾,等.HIP1在食管癌中的表达及其临床意义[J].现代肿瘤医学,2018,26(21):3401-3404.ZHANG Yabin,SUN Ying,SUN Lei,et al.Expression of HIP1 in esophageal squamous cell carcinoma and its clinical significance[J]Journal of Modern Oncology,2018,26(21):3401-3404.
12.Socinski MA,Crowell R,Hensing TE,et al.Treatment of non-small cell lung cancer,stage IV:ACCP evidence-based clinical practice guidelines(2nd edition)[J].Chest,2007,132(3 Suppl):277S-289S.
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14.Felip E,Gridelli C,Baas P,et al.Metastatic non-small-cell lung cancer:consensus on pathology and molecular tests,first-line,second-line,and third-line therapy:1st ESMO Consensus Conference in Lung Cancer;Lugano 2010[J].Ann Oncol,2011;22:1507-1519.
15.van Klaveren RJ.Lung cancer screening[J].Eur J Cancer,2011,47(Suppl 3):S147-S155.
16.Hsu CY,Lin CH,Jan YH,et al.HIP1 is an early-stage prognostic biomarker of lung adenocarcinoma and suppresses metastasis via Aktmediated EMT[J].Am J Respir Crit Care Med,2016,193(8):869-880.
17.Kao SH,Wang WL,Chen CY,et al.GSK3beta controls epithelialmesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug[J].Oncogene,2014,33:3172-3182.
18.Scanlon CS,Van Tubergen EA,Inglehart RC,et al.Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma[J]J Dent Res,2013,92(2):114-121.
19.Turley EA,Veiseh M,Radisky DC,et al.Mechanisms of disease:epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression?[J].Nat Clin Pract Oncol,2008,5(5):280-290.
20.Denlinger CE,Ikonomidis JS,R eed CE,et al.Epithelial to mesenchymal transition:the doorway to metastasis in human lung cancers[J].J Thorac Cardiovasc Surg,2010,140(3):505-513.
21.Zheng H,Kang Y.Multilayer control of the EMT master regulators[J]Oncogene,2014,33(14):1755-1763.
22.De Craene B,Berx G.Regulatory networks defining EMT during cancer initiation and progression[J].Nat Rev Cancer,2013,13(2):97-110.
23.Yang J,Weinberg RA.Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis[J].Dev Cell,200814(6):818-829.
2.Wanker EE,Rovira C,Scherzinger E,et al.HIP-I:a huntingtin interacting protein isolated by the yeast two-hybrid system[J].Hum Mol Genet,1997,6(3):487-495.
3.Wijayatunge R,Holmstrom SR,Foley SB,et al.Deficiency of the Endocytic Protein Hip1 Leads to Decreased Gdpd3 Expression,Low Phosphocholine,and Kypholordosis[J].Mol Cell Biol,2018,38(23).
4.Li D,Chen F,Ding J,et al.Knockdown of HIP1 expression promotes ligand-induced endocytosis of EGFR in Hela cells[J].Oncol Rep,201738(6):3387-3391.
5.Peng L,Yang Q,Xu X,et al.Huntingtin-interacting protein 1-related protein plays a critical role in dendritic development and excitatory synapse formation in hippocampal neurons[J].Front Mol Neurosci2017,10:186.
6.Gottfried I,Ehrlich M,Ashery U.The Sla2p/HIP1/HIP1R family:similar structure,similar function in endocytosis?[J].Biochem Soc Trans,2010,38(Pt 1):187-191.
7.Wilbur JD,Hwang PK,Brodsky FM,et al.Accommodation of structural rearrangements in the huntingtin-interacting protein 1coiled-coil domain[J].Acta Crystallogr D Biol Crystallogr,2010,66(Pt3):314-318.
8.Rice MA,Ishteiwy RA,Magani F,et al.The microRNA-23b/-27b cluster suppresses prostate cancer metastasis via Hunting-interacting protein 1-related[J].Oncogene,2016,35(36):4752-4761.
9.Wang J,Yu M,Guo Q,et al.Prognostic significance of huntingtin interacting protein 1 expression on patients with acute myeloid leukemia[J].Sci Rep,2017,7:45960.
10.Hong M,Kim RN,Song JY,et al.HIP1-ALK,a novel fusion protein identified in lung adenocarcinoma[J].J Thorac Oncol,2014,9(3):419-422.
11.张亚斌,孙盈,孙蕾,等.HIP1在食管癌中的表达及其临床意义[J].现代肿瘤医学,2018,26(21):3401-3404.ZHANG Yabin,SUN Ying,SUN Lei,et al.Expression of HIP1 in esophageal squamous cell carcinoma and its clinical significance[J]Journal of Modern Oncology,2018,26(21):3401-3404.
12.Socinski MA,Crowell R,Hensing TE,et al.Treatment of non-small cell lung cancer,stage IV:ACCP evidence-based clinical practice guidelines(2nd edition)[J].Chest,2007,132(3 Suppl):277S-289S.
13.Azzoli CG,Baker S Jr,Temin S,et al.American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer[J].J Clin Oncol,2009,27:6251-6266.
14.Felip E,Gridelli C,Baas P,et al.Metastatic non-small-cell lung cancer:consensus on pathology and molecular tests,first-line,second-line,and third-line therapy:1st ESMO Consensus Conference in Lung Cancer;Lugano 2010[J].Ann Oncol,2011;22:1507-1519.
15.van Klaveren RJ.Lung cancer screening[J].Eur J Cancer,2011,47(Suppl 3):S147-S155.
16.Hsu CY,Lin CH,Jan YH,et al.HIP1 is an early-stage prognostic biomarker of lung adenocarcinoma and suppresses metastasis via Aktmediated EMT[J].Am J Respir Crit Care Med,2016,193(8):869-880.
17.Kao SH,Wang WL,Chen CY,et al.GSK3beta controls epithelialmesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug[J].Oncogene,2014,33:3172-3182.
18.Scanlon CS,Van Tubergen EA,Inglehart RC,et al.Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma[J]J Dent Res,2013,92(2):114-121.
19.Turley EA,Veiseh M,Radisky DC,et al.Mechanisms of disease:epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression?[J].Nat Clin Pract Oncol,2008,5(5):280-290.
20.Denlinger CE,Ikonomidis JS,R eed CE,et al.Epithelial to mesenchymal transition:the doorway to metastasis in human lung cancers[J].J Thorac Cardiovasc Surg,2010,140(3):505-513.
21.Zheng H,Kang Y.Multilayer control of the EMT master regulators[J]Oncogene,2014,33(14):1755-1763.
22.De Craene B,Berx G.Regulatory networks defining EMT during cancer initiation and progression[J].Nat Rev Cancer,2013,13(2):97-110.
23.Yang J,Weinberg RA.Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis[J].Dev Cell,200814(6):818-829.