HERG蛋白与胃癌恶性生物学行为关系及相应调控机制的研究
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摘要
钾离子通道和相应的电流在多种生理现象中发挥重要作用,新近的一些研究提示某些钾通道与恶性肿瘤的发生发展有关。其中电压门控钾通道(Voltage-gated potassium channels,Kv)与肿瘤的关系更成为研究的热点。本研究所的前期研究发现,在胃癌细胞存在延迟整流性钾电流,该电流与胃癌细胞的增殖有关,并受到环氧合酶—2(Cyclooxygenase-2,COX-2)的调控。人eag相关基因(human ether-a-go-go-related gene,herg)编码的HERG蛋白为延迟整流性钾通道的α亚单位,国外已有研究发现HERG蛋白在多种肿瘤细胞中高表达。本研究试图阐明HERG蛋白与胃癌恶性生物学行为的关系及可能的调控机制。
目的:分析HERG蛋白在胃癌组织和细胞中的表达及意义;研究HERG蛋白和电流对胃癌细胞恶性生物学行为的影响;探讨COX—2对HERG电流的影响和相应的调控机制。
方法:(1)采用免疫组织化学方法研究HERG蛋白在胃癌组织和正常胃组织中的表达情况,并分析HERG蛋白与胃癌患者临床病理资料之间的关系。(2)采用RT—PCR和Western blot方法检测胃癌细胞和永生
Potassium channels and currents play important roles in many physiological functions. Recent studies indicated that some potassium channels were associated with carcinogenesis. Some researchers have focused the relationship between voltage-gated potassium channel and tumor. Our previous studies showed that delayed rectifier potassium currents existed in human gastric cancer cells and the currents were related to the growth of gastric cancer cells. The currents in gastric cancer cells were influenced by COX-2, although the specific mechanism was unclear. Human ether-a-go-go-related gene (herg) encoding a subunit of delayed rectifier potassium channel has been indicated with involvement in tumor cell growth and death. The purpose of the present study is to investigate the role of HERG protein in carcinogenesis of gastric cancer cells and related mechanisms.[Objectives]: 1. To investigate the expression of HERG protein in gastric cancer tissue and cells and analyze the relationship between the expression of HERG protein and the clinicopathological characteristics of patients with gastric cancer; 2. To explore the effects of HERG protein on malicious biological behavior of gastric cancer cells; 3. To
elucidate the signal transduction pathway, by which COX-2 regulates delayed rectifier potassium currents in gastric cancer cells.[Methods]: [1] The expression of HERG protein in gastric cancer and normal gastric tissues was investigated by immunohistochemistry and the relationship between the HERG expression and clinicopathological characteristics was statistically analyzed. [2] The expressions of HERG mRNA and protein in gastric cancer cells and immortalized gastric epithelial cells were measured by RT-PCR and Western blot, respectively. [3] The whole cell configuration of the patch-clamp technique was employed to record the potassium currents in various cells. [4] HERG-siRNA vector was constructed and transfected into gastric cancer cells, followed by screening and verifying. [5] After interfereing with HERG current and protein by HERG blocker and HERG-siRNA, the growth curve of gastric cancer cells was drawn by MTT method; the ability of clone formation of gastric cancer cells was studied by clone formation assay; the cell cycle distribution of gastric cancer cells was investigated by Flow cytometry; Flow cytometry with Annexin V/PI staining was used to assess apoptosis of gastric cancer cells; the ultrastructure of gastric cancer cells was studied under transmission electron microscope. [6] Transwell invasion assay and tumorigenesis in nude mice were used to determine the effect of HERG-siRNA on the invasiveness and tumorigenicity of gastric cancer cells, respectively. [7] The HERG protein and current in gastric cancer cells transfected with or without COX-2 antisense vector were measured by Western blot and patch-clamp, respectively. [8] cAMP concentration in gastric cancer cells transfected with or without COX-2 antisense vector was measured by ELISA. [9] Construction of mutant of HERG without cAMP-binding domain was completed by PCR and the mutant was transfected into gastric cancer cells. [10] The impact of COX-2 inhibitor and PGE2 on HERG current in gastric cancer cells transfected with or without mutant of HERG without cAMP-binding domain was
investigated by patch clamp. [11] The effects of agonist and antagonist of cAMP and inhibitor of PKA on HERG current in gastric cancer cells transfected with or without HERG mutant were observed by patch clamp.[Results]: (1) Compared with normal gastric tissues, HERG protein was highly expressed in gastric cancer tissues and the expression of HERG protein was associated with differentiation, TNM stage and lymph node metastasis of gastric cancer (P<0.05). (2) HERG mRNA and protein were positively expressed in four gastric cancer cell lines but negative in immortalized gastric epithelial cell line. (3) HERG current was detected in gastric cancer cell, whereas there was no HERG current in immortalized gastric epithelial cell. (4) Both HERG blocker and HERG-siRNA inhibited proliferation of gastric cancer cells; reduced clone formation ability of gastric cancer cells (P<0.05); inhibited gastric cancer cells entering into S phage from G1 phage; induced apoptosis in gastric cancer cells and there were typical changes of apoptosis under transmission electron microscope. Gastric cancer cells transfected with HERG-siRNA vector presented lower proliferative index. The invasiveness and tumorigenicity of gastric cancer cells were reduced when HERG protein was inhibited (P<0.05). (5) Transfection with COX-2 antisense vector did not alter the expression of HERG protein, but it diminished the amplitude of HERG current in gastric cancer cells (P<0.05). (6) The cAMP concentration in gastric cancer cells transfected with COX-2 antisense vector was lower than that in parental gastric cancer cells (P<0.05). (7) COX-2 inhibitor and PGE2 had influence on the HERG currents in gastric cancer cells. COX-2 inhibitor reduced the amplitude of HERG current in gastric cancer cells and PGE2 enhanced the amplitude. However, in gastric cancer cells transfected with HERG mutant deleting cAMP-binding domain, both COX-2 inhibitor and PGE2 did not show significantly negative or positive effects on HERG current. (8) cAMP agonist enhanced the
目的:分析HERG蛋白在胃癌组织和细胞中的表达及意义;研究HERG蛋白和电流对胃癌细胞恶性生物学行为的影响;探讨COX—2对HERG电流的影响和相应的调控机制。
方法:(1)采用免疫组织化学方法研究HERG蛋白在胃癌组织和正常胃组织中的表达情况,并分析HERG蛋白与胃癌患者临床病理资料之间的关系。(2)采用RT—PCR和Western blot方法检测胃癌细胞和永生
Potassium channels and currents play important roles in many physiological functions. Recent studies indicated that some potassium channels were associated with carcinogenesis. Some researchers have focused the relationship between voltage-gated potassium channel and tumor. Our previous studies showed that delayed rectifier potassium currents existed in human gastric cancer cells and the currents were related to the growth of gastric cancer cells. The currents in gastric cancer cells were influenced by COX-2, although the specific mechanism was unclear. Human ether-a-go-go-related gene (herg) encoding a subunit of delayed rectifier potassium channel has been indicated with involvement in tumor cell growth and death. The purpose of the present study is to investigate the role of HERG protein in carcinogenesis of gastric cancer cells and related mechanisms.[Objectives]: 1. To investigate the expression of HERG protein in gastric cancer tissue and cells and analyze the relationship between the expression of HERG protein and the clinicopathological characteristics of patients with gastric cancer; 2. To explore the effects of HERG protein on malicious biological behavior of gastric cancer cells; 3. To
elucidate the signal transduction pathway, by which COX-2 regulates delayed rectifier potassium currents in gastric cancer cells.[Methods]: [1] The expression of HERG protein in gastric cancer and normal gastric tissues was investigated by immunohistochemistry and the relationship between the HERG expression and clinicopathological characteristics was statistically analyzed. [2] The expressions of HERG mRNA and protein in gastric cancer cells and immortalized gastric epithelial cells were measured by RT-PCR and Western blot, respectively. [3] The whole cell configuration of the patch-clamp technique was employed to record the potassium currents in various cells. [4] HERG-siRNA vector was constructed and transfected into gastric cancer cells, followed by screening and verifying. [5] After interfereing with HERG current and protein by HERG blocker and HERG-siRNA, the growth curve of gastric cancer cells was drawn by MTT method; the ability of clone formation of gastric cancer cells was studied by clone formation assay; the cell cycle distribution of gastric cancer cells was investigated by Flow cytometry; Flow cytometry with Annexin V/PI staining was used to assess apoptosis of gastric cancer cells; the ultrastructure of gastric cancer cells was studied under transmission electron microscope. [6] Transwell invasion assay and tumorigenesis in nude mice were used to determine the effect of HERG-siRNA on the invasiveness and tumorigenicity of gastric cancer cells, respectively. [7] The HERG protein and current in gastric cancer cells transfected with or without COX-2 antisense vector were measured by Western blot and patch-clamp, respectively. [8] cAMP concentration in gastric cancer cells transfected with or without COX-2 antisense vector was measured by ELISA. [9] Construction of mutant of HERG without cAMP-binding domain was completed by PCR and the mutant was transfected into gastric cancer cells. [10] The impact of COX-2 inhibitor and PGE2 on HERG current in gastric cancer cells transfected with or without mutant of HERG without cAMP-binding domain was
investigated by patch clamp. [11] The effects of agonist and antagonist of cAMP and inhibitor of PKA on HERG current in gastric cancer cells transfected with or without HERG mutant were observed by patch clamp.[Results]: (1) Compared with normal gastric tissues, HERG protein was highly expressed in gastric cancer tissues and the expression of HERG protein was associated with differentiation, TNM stage and lymph node metastasis of gastric cancer (P<0.05). (2) HERG mRNA and protein were positively expressed in four gastric cancer cell lines but negative in immortalized gastric epithelial cell line. (3) HERG current was detected in gastric cancer cell, whereas there was no HERG current in immortalized gastric epithelial cell. (4) Both HERG blocker and HERG-siRNA inhibited proliferation of gastric cancer cells; reduced clone formation ability of gastric cancer cells (P<0.05); inhibited gastric cancer cells entering into S phage from G1 phage; induced apoptosis in gastric cancer cells and there were typical changes of apoptosis under transmission electron microscope. Gastric cancer cells transfected with HERG-siRNA vector presented lower proliferative index. The invasiveness and tumorigenicity of gastric cancer cells were reduced when HERG protein was inhibited (P<0.05). (5) Transfection with COX-2 antisense vector did not alter the expression of HERG protein, but it diminished the amplitude of HERG current in gastric cancer cells (P<0.05). (6) The cAMP concentration in gastric cancer cells transfected with COX-2 antisense vector was lower than that in parental gastric cancer cells (P<0.05). (7) COX-2 inhibitor and PGE2 had influence on the HERG currents in gastric cancer cells. COX-2 inhibitor reduced the amplitude of HERG current in gastric cancer cells and PGE2 enhanced the amplitude. However, in gastric cancer cells transfected with HERG mutant deleting cAMP-binding domain, both COX-2 inhibitor and PGE2 did not show significantly negative or positive effects on HERG current. (8) cAMP agonist enhanced the
引文
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