水通道蛋白5在人大肠癌组织中的表达及临床意义
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摘要
目的:检测水通道蛋白5(AQP5)在大肠癌组织中的表达情况,分析其在大肠癌发生、发展及转移过程中的临床意义。
方法:选择2006年11月至2007年12月手术切除后并经病理证实的大肠癌患者30例,采用逆转录聚合酶链反应(RT-PCR),免疫印迹(Western-blot),免疫组织化学的方法检测AQP5在人大肠癌组织和癌旁正常组织中的表达情况。
结果:RT-PCR:在大肠癌组织中均有AQP5 mRNA的表达,AQP5/GAPDH比值为0.42±0.08,而在癌旁正常组织中几乎没有AQP5 mRNA的表达,AQP5/GAPDH比值为0.02±0.00。AQP5与GAPDH灰度值相比后统计分析证实,AQP5 mRNA在大肠癌组织中表达较癌旁正常组织表达明显增多(P<0.05),内参GAPDH的PCR产物在各组中表达无显著性差异(P>0.05)。Western-blot:大肠癌组织标本均有AQP5蛋白表达,AQP5蛋白条带位置为35kD。半定量比较各种组织AQP5蛋白水平,大肠癌组织AQP5/GAPDH为0.74±0.12,癌旁正常组织AQP5/GAPDH为0.01±0.00,蛋白条带灰度值分析表明:大肠癌组织中AQP5蛋白表达量较癌旁正常组织明显增多(P<0.05),内参GAPDH蛋白表达在各组无显著性差异( P > 0.05)。免疫组织化学:AQP5阳性反应呈棕黄色,主要存在于大肠癌组织中肿瘤细胞的细胞膜及细胞浆,而在癌旁正常组织几乎没有表达。AQP5蛋白表达程度与肿瘤分化程度、肿瘤浸润深度、淋巴结转移及TNM分期相关(P<0.05)。
结论:在大肠癌组织中AQP5的高表达,提示整个AQP5在人大肠癌的发生、发展及转移的过程中可能起重要作用。AQP5蛋白表达程度与肿瘤分化程度、肿瘤浸润深度、淋巴结转移及TNM分期相关,或许可以通过AQP5作为干预靶点来抑制大肠癌的生长和转移,为肿瘤的治疗提供一个新的途径。
Objective: To investigate expression of aquaporin5 (AQP5) in human colorectal carcinoma tissues and analyze its clinical significance.
Method: Human colorectal carcinoma tissues were acquired immediately after operation from November 2006 to December 2007. The expression of aquaporin5 in human colorectal carcinoma tissue and paraneoplastic normal tissue was detected by reverse transcription PCR (RT-PCR), Western-blot, Immunohistochemistry.
Results: Findings by RT-PCR indicated that the AQP 5 mRNA expressed in colorectal carcinoma tissues was significantly higher than that expressed in paraneoplastic normal tissues (carcinoma tissues vs. normal tissues: 0.42±0.08 vs. 0.02±0.00, P<0.05). Weston blot showed that the AQP5 protein band was located at 35 kD. Furthermore, the AQP5 protein was significantly higher expressed in colorectal carcinoma tissues compared with paraneoplastic normal tissues (carcinoma tissues vs. normal tissues: 0.74±0.12 vs. 0.01±0.00, P<0.05). Immunohistochemistry showed that the AQP5 was mainly expressed in colorectal carcinoma cell membrane and cytoplasm. However, no AQP5 was detected in paraneoplastic normal tissues. The expression of AQP5 was related with the loss of tumor differentiation, lymph node metastasis and TNM stage (P<0.05).
Conclusion: The overexpression of AQP5 in human colorectal carcinoma tissue plays an important role in colorectal carcinogenesis, progression and metastasis; The expression of AQP5 was related with the loss of tumor differentiation, lymph node metastasis and TNM stage. Furthermore, the AQP5 inhibtors may be regarded as novel targets of anti-cancer therapy.
方法:选择2006年11月至2007年12月手术切除后并经病理证实的大肠癌患者30例,采用逆转录聚合酶链反应(RT-PCR),免疫印迹(Western-blot),免疫组织化学的方法检测AQP5在人大肠癌组织和癌旁正常组织中的表达情况。
结果:RT-PCR:在大肠癌组织中均有AQP5 mRNA的表达,AQP5/GAPDH比值为0.42±0.08,而在癌旁正常组织中几乎没有AQP5 mRNA的表达,AQP5/GAPDH比值为0.02±0.00。AQP5与GAPDH灰度值相比后统计分析证实,AQP5 mRNA在大肠癌组织中表达较癌旁正常组织表达明显增多(P<0.05),内参GAPDH的PCR产物在各组中表达无显著性差异(P>0.05)。Western-blot:大肠癌组织标本均有AQP5蛋白表达,AQP5蛋白条带位置为35kD。半定量比较各种组织AQP5蛋白水平,大肠癌组织AQP5/GAPDH为0.74±0.12,癌旁正常组织AQP5/GAPDH为0.01±0.00,蛋白条带灰度值分析表明:大肠癌组织中AQP5蛋白表达量较癌旁正常组织明显增多(P<0.05),内参GAPDH蛋白表达在各组无显著性差异( P > 0.05)。免疫组织化学:AQP5阳性反应呈棕黄色,主要存在于大肠癌组织中肿瘤细胞的细胞膜及细胞浆,而在癌旁正常组织几乎没有表达。AQP5蛋白表达程度与肿瘤分化程度、肿瘤浸润深度、淋巴结转移及TNM分期相关(P<0.05)。
结论:在大肠癌组织中AQP5的高表达,提示整个AQP5在人大肠癌的发生、发展及转移的过程中可能起重要作用。AQP5蛋白表达程度与肿瘤分化程度、肿瘤浸润深度、淋巴结转移及TNM分期相关,或许可以通过AQP5作为干预靶点来抑制大肠癌的生长和转移,为肿瘤的治疗提供一个新的途径。
Objective: To investigate expression of aquaporin5 (AQP5) in human colorectal carcinoma tissues and analyze its clinical significance.
Method: Human colorectal carcinoma tissues were acquired immediately after operation from November 2006 to December 2007. The expression of aquaporin5 in human colorectal carcinoma tissue and paraneoplastic normal tissue was detected by reverse transcription PCR (RT-PCR), Western-blot, Immunohistochemistry.
Results: Findings by RT-PCR indicated that the AQP 5 mRNA expressed in colorectal carcinoma tissues was significantly higher than that expressed in paraneoplastic normal tissues (carcinoma tissues vs. normal tissues: 0.42±0.08 vs. 0.02±0.00, P<0.05). Weston blot showed that the AQP5 protein band was located at 35 kD. Furthermore, the AQP5 protein was significantly higher expressed in colorectal carcinoma tissues compared with paraneoplastic normal tissues (carcinoma tissues vs. normal tissues: 0.74±0.12 vs. 0.01±0.00, P<0.05). Immunohistochemistry showed that the AQP5 was mainly expressed in colorectal carcinoma cell membrane and cytoplasm. However, no AQP5 was detected in paraneoplastic normal tissues. The expression of AQP5 was related with the loss of tumor differentiation, lymph node metastasis and TNM stage (P<0.05).
Conclusion: The overexpression of AQP5 in human colorectal carcinoma tissue plays an important role in colorectal carcinogenesis, progression and metastasis; The expression of AQP5 was related with the loss of tumor differentiation, lymph node metastasis and TNM stage. Furthermore, the AQP5 inhibtors may be regarded as novel targets of anti-cancer therapy.
引文
[1] Sung Koo Kang, Young Kwang Chae, Janghee Woo, et al. Role of Human Aquaporin 5 In Colorectal Carcinogenesis [J]. The American Journal of Pathology, 2008, 173, (2):518-525.
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[2] Yancey SB, Koh K, Chung J, et al. Expression of the gene for main intrinsic polypeptide(MIP):separate spatial distributions of MIP and beta-crystallin gene transcripts in rat lens development [J]. Journal of cell biology, 1988, 106(3): 705-714.
[3] Magni F,Sarto C,Ticozzi D,et al. Proteomic knowledge of human aquaporins [J]. Proteomics, 2006, 6(20): 5637-5649.
[4] Agre P,Kozono D. Aquaporin water channels: molecular mechanisms for human disease s [J]. FEBS Lett,2003,555(1): 72-78.
[5] Verkman AS. More than just water channels: unexpected cellular roles of aquaporins [J]. J Cell Sci, 2005, 118: 3225-3232.
[6] Verkman AS, Hara-Chikuma M, Papadopoulos MC. Aquaporins-new players in cancer biology [J]. J Mol Med, 2008, 86(5): 523-529.
[7] Kozono D,Masato Y,King LS,et.Aquaporin water channels;atomic structure and molecular dynamics meel clinical medicine [J]. J Clin Invest, 2002, 109: 1395-1399.
[8] Krane CM,Towne JE, Menon AG .Cloning and characterization ofmurine AQP5;evidence for a conserved aquaporin gene cluster[J]. Mamm Genome, 1999, 10(5): 498-505.
[9] Matsuzaki T, Tajika Y, Ablimit A, et al. Aquaporins in the digestive system [J]. Med Electorn Micorsc, 2004, 37(2):71-80.
[10] Smith KJ,Siddiqui AA,Midica LA , et al.Interferon-a upregulatesgene expression of Aquaporins-5 in human parotid glands [J]. J Interferon Cytokine Res, 1999,19: 929-935.
[11] Ishikawa Y, Skowronski MT, Inoue N, et al. Alpha adrenoceptor- induced trafficking of aquaporin-5 to the apical plasma membrane of rat parotid cells [J]. Biochem Biophys Res Commum, 1999,265(1): 94-100.
[12] Mobasheri A, Airley R, Hewitt SM, et al. Heterogeneous expressionof the aquaporin 1 (AQP1) water channel in tumors of the prostate,breast, ovary, colon and lung: a study using high density multiple human tumor tissue microarrays [J]. Int J Oncol, 2005, 26(5): 1149-1158.
[13] Xiang Y, Ma B , Li T , et al. Acetazolamide suppresses tumor metastasis and related protein expression in mice bearing Lewis lung carcinoma [J]. Acta Pharmacol Sin, 2002, 23: 745-751.
[14] Yang J H, Shi YF, Cheng Q, et al . Expression and localization of aquaporin 5 in the epithelial ovarian tumor [J]. Gynecol Oncol ,2006, 100: 294-299.
[15] Oshio K, Binder DK, Liang Y, et al . Expression of the Aquaporin-1water channel in human glial tumors [J]. Neurosurgery, 2005, 56(2): 375-381.
[16] Oshio K, Binder DK, Bollen A, et al. Aquaporin-1 expression in human glial tumors suggest s a potential novel therapeutic target for tumor-associated edema[J]. Acta Neurochir Suppl, 2003, 86: 499-502.
[17] Saadoun S, Papadopoulos MC, Davies DC, et al. Increased aquaporin 1 water channel expression in human brain tumours [J]. Br J Cancer, 2002, 87(6): 621-623.
[18] Woo J, Lee J, Kim MS,et al. The effect of aquaporin 5 overexpression on the Ras signaling pathway [J]. Biochem Biophys Res Commun. 2008, 367(2): 291-298.
[19] Woo J, Lee J, Chae YK,et al. Overexpression of AQP5, a putative oncogene,promotes cell growth and transformation [J]. Cancer Lett, 2008, 264(1): 54-62.
[20] Kang SK, Chae YK, Woo J, et al. Role of human aquaporin 5 in colorectal carcinogenesis [J]. Am J Pathol, 2008, 173(2): 518-525.
[21] Saadoun S,Papadopoulos MC, Hara-Chikuma M,et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption [J]. Nature, 2005, 434(6): 786-792.
[22] Hara M, Ma T, Verkman AS. Selectively reduced glycerol in skin of aquaporin-3 deficient mice may account for impaired skin hydration,elasticity, and barrier recovery [J]. J Biol Chem, 2002, 277(11): 46616-46621.
[23] Hara M, Verkman AS. Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice [J]. Proc Natl Acad Sci U S A, 2003, 100(10): 7360-7365.
[24] Hara-Chikuma M, Verkman AS. Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption [J]. Mol Cell Biol, 2008, 28(3):326-333.
[25] Fischer H, Stenling R, Rubio C, et al. Differential expressionof aquaporin 8 in human colonic epithelial cells andcolorectal tumors [J]. BMC Physiology, 2001, 1(1): 1-8.
[26] Zhang R, Skach W, Hasegawa H, et al. Cloning, functional analysis and cell localization of a kidney proximal tubule water transpoter homologou to CHIP 28 [J]. J Cell Biol, 1993, 120(2): 359-369.
[27] Ma B, Xiang Y, Li T,et al. Inhibitory effect of topiramate on Lewis lung carcinoma metastasis and its relation with AQP1 water channel[J]. Acta Pharmacol Sin, 2004, 25(1): 54-60.
[28] Xiang Y, Ma B, Li T, et al. Acetazolamide suppresses tumor metastasis and related protein expression in mice bearing Lewis lung carcinoma [J]. Acta Pharmacol Sin, 2002, 23(8): 745-751.
[29] Nicchia GP, Frigeri A, Liuzzi GM, et al. Inhibition of aquaporin-4expression in astrocytes by RNAi determines alteration in cell morphology, growth,and water transport and induces changes in ischemia-related genes [J]. FASEB J, 2003, 17(11): 1508-1510.
[30] Bissell MJ. Tumor plasticity allows vasculogenic mimicry, a novel form of angiogenic switch. A rose by any other name [J]. Am Pat hol, 1999, 155: 675-677.
[31] Yasui M. Molecular mechanisms and drug development in aquaporin water channel diseases: structure and function of aquaporins [J]. Pharmacol Sci , 2004 , 96: 260-263.
[32] Agre P, Cart ron J P. Molecular biology of the Rh antigens [J]. Blood, 1991, 78: 551-563.
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