Water Channel Protein-1 (AQP-1) In Colorectal Carcinoma Tissue Of Expression And Its Relationship With Tumor Angiogenesis

Objective: Water is the main ingredient in the cellular and intercellular spaces, and all life activities are in water environment, digestion, breathing, circulation, temperature regulation, eliminate toxins and nerve homeostasis and other activities in the body are present across the cell membrane transport of water. Water channel protein (aquaporins, AQPs) are water channel protein specificity, exist in plants and animals and microbes, mediated free water rapidly across the passive biological membrane, is the main way of water in and out of the cell. So far, the cloned mammalian aquaporins have 13 family members (AQP0-12), their gene structure, gene expression, chromosomal localization, protein structure, tissue distribution and physiological function have been more extensively studied.Further research shows that, to satisfy the rapid proliferation, division and the need for invasion and metastasis, tumor cell enzyme activity and expression of a series of changes, the basic structure of cell components such as proteins, lipids and nucleic acid synthesis enhanced, the basic nucleic acid synthesis raw materials--significantly strengthened the biosynthesis of nucleotides, as well as protein expression or protein activity have a pedigree to change. Meanwhile the invasion of tumor cells and access to the surrounding matrix blood vessels, lymphatic vessels of its size and shape need to be changed. The tumor cells are all these activities without water environment and participation, more than normal cell tumor cells need water molecules rapidly across the membrane. With the deepening of the research, the researchers found that water channel protein in some pathological process, especially in certain malignant tumor of existence, and thus expressing abnormal protein in the water channel, tumor occurrence, development, and the formation of blood vessels may play an important role in the process, it has become a hotspot.Colorectal cancer is one of the most common malignancy. In North America and Europe, colorectal cancer has risen to No.2. Common malignant tumors, in China occupies the first three to four.Statistics show that in urban areas the incidence of colorectal cancer ranks the first four, and in major cities such as Beijing and Shanghai, the incidence rate has increased to 2-3, already close to developed western countries colorectal cancer morbidity.The current treatments of colorectal cancer mainly include surgery, radiotherapy and chemotherapy, the treatments not only have therapeutic effect on tumor cells, also affect non-tumor tissues, resulting in serious toxicity. Targeted therapy for tumor genesis and development of abnormal cell signaling channel, and therefore the impact of small non-tumor tissue. I believe the near future molecular targeted therapy will become the primary means of treatment of colorectal cancer in one.Tumor angiogenesis (angiogenesis), or blood or bone marrow-derived endothelial progenitor cells to form new blood vessels in tumor growth and development has an important role in. Tumor growth and proliferation are dependent on the growth of its surrounding vessels and foreign invasion. New tumor blood vessels for the tumor to provide the necessary oxygen metabolism and nutrition. So that rapid tumor growth. VEGF/VEGFR pathway is the major tumor angiogenesis pathway. Studies have shown, AQP-1 could promote cell migration. Endothelial cell migration is essential in the process of angiogenesis. Therefore, AQP-1 in tumor angiogenesis may be through the promotion of endothelial cell migration completed.Water channel protein (aquaporins, AQPs) are small molecule hydrophobic inner membrane protein family, now found 13 species. Recent studies show that, AQPs involved in a number of important physiological mammalian pathological processes, such as urine concentration, the formation of brain edema, intraocular pressure regulation, lipid metabolism, exocrine gland secretion, and tumor angiogenesis. AQP-1 is Agre, who in 1992 discovered the first time from the first red cell membrane water channel protein, and therefore get the 2003 Nobel Prize in Chemistry. AQP-1 is the major water channel of red cell membrane. Formerly known as channel forming transmembrane protein (Channel forming integral protein, CHIP28), the protein molecule containing 269 amino acids.AQP-1 is closely related with tumor angiogenesis and metastasis in many tumor microvascular endothelial cells. The lack of AQP-1 in mouse tumor angiogenesis and endothelial cell migration was impaired. Compared with wild-type mice, AQP-1 knockout mice implanted tumor growth slowed down, tissue showed reduced tumor microvessel density, necrotic tissue region larger. In primary cultured aortic endothelial cells, further analysis confirmed the lack of AQP-1 in endothelial cell migration rate significantly slower. The reason may be the cell membrane in the migration of short-lived when a prominent. The process requires rapid local transmembrane ion and water transport, the lack of AQP-1-mediated rapid water transport, can not form prominent membrane, cell migration rate will be slowed down. Another study has showed that inhibition of AQP-1 may reduce the number of tumor metastasis. Therefore, the inhibition of AQP-1 can delay tumor angiogenesis and prevent tumor metastasis.Endo et al have found AQP-1 highly expressed in tumor tissue that could be involved in the role of tumor angiogenesis. Saadoun et al have found that, AQP-1 plays an important role on cancer growth and metastasis. Therefore, regulating the expression of AQP-1 has a broad treatment of drug application. Although there is no AQP-1 effective regulator was found, the protein is still a potential drug target, this study hopes to prove the role of the target to bring hope.Methods: 1 AQP-1 expressions of 30 cases of colorectal carcinoma were detected by immunohistochemistry and RT-PCR,and analyzes the clinical data of colorectal cancer including age, sex, tumor size, infiltration depth, differentiation degree, lymph node metastasis and tumor stage of the correlation between.2 AQP-1,VEGF,CD34 expressions of 30 cases of colorectal carcinoma were detected by immunohistochemistry, microessel-density was calculated, and analysis of their relevance.3 The human colon carcinoma HT-29 cells were injected subcutaneously in nude mice to establish xenograft model, 16 days later, the nude mice were randomly divided into two groups: blank control group, acetazolamide (40mg/kg/d). In every three days of grace measurement of tumor volume, administered 21 days after the execution of nude mice transplanted tumor tissues were cut detection of AQP-1,VEGF and CD34 protein, AQP-1mRNA expression,then and analysis of their relevance.Results: 1 AQP-1, mainly in colorectal cancer tissues showed high expression of pulp cells, and in cancer tissues of normal cells, plasma showed low expression. Immunohistochemical score (IHS) were: colorectal cancer 3.17±2.23, normal intestinal epithelium 1.07±1.01, the difference was statistically significant (F=4.83, P<0.0001). AQP-1mRNA expression of adjacent tissues was 0.52±0.29, colorectal cancer was 1.26±0.27, difference between the two groups was statistically significant (P<0.01). AQP-1 expression and age, gender, tumor size, invasive depth and degree of differentiation was not related (P>0.05), and tumor Duke's stage, lymph node metastasis was related (P<0.05).2 AQP-1, VEGF, and CD34 to varying degrees, expressed in cancer tissues and adjacent, the difference between the two groups was significant meaning. AQP-1 and VEGF in colorectal cancer tissues were positively correlated (rs = 0.482, P<0.01), suggest AQP-1 and VEGF expression in colorectal cancer in the interaction and participation in the incidence of colorectal cancer and end development and tumor angiogenesis may be used to reflect the biological behavior of colorectal cancer and objective reference; AQP-1 and MVD in colorectal cancer tissues were positively correlated (rs = 0.510, P<0.01), shows AQP-1 in colorectal cancer angiogenesis plays a very important role, and in tumor growth, metastasis.Angiogenesis has to provide the necessary material base and the transfer channel, AQP-1 in colorectal cancer occurrence and development of play to promote cancer cell growth, metastasis, and with angiogenesis.3 Through the establishment of human colon cancer xenograft model in nude mice subcutaneously, and then water channel protein inhibitor acetazolamide gavage treatment, two groups of tumor size, tumor weight difference was statistically significant (P<0.01). And calculate tumor inhibition rate of 88.28%. Experimental group compared with the control group of water channel protein-1 protein and mRNA expression was significantly reduced, AQP-1 protein expression: experimental group was 0.5344±0.2535, the control group was 0.8156±0.1954 (P=0.0121<0.05); The expression of AQP-1mRNA: the test group was 0.52±0.29 in the control group was 1.26±0.27 (P<0.001). Two groups of nude mice bearing human colon cancer xenografts AQP-1, VEGF and CD34 expression between the experimental group differences and AQP-1, VEGF and CD34 correlation analysis confirmed that, AQP-1, VEGF and CD34 expression to varying degrees in the control group and the experimental group, the difference between the two groups IHS score significant meaning (P <0.05), AQP-1 and VEGF, AQP-1 and CD34, CD34 and VEGF expression in the experimental group were positively correlated (rs = 0.398,0.583,0.439;P <0.01), prompted acetazolamide on AQP-1 inhibition and tumor angiogenesis is closely related to acetazolamide may inhibit tumor angiogenesis on the inhibition of tumor growth.Conclusions: 1 AQP-1, mainly in colorectal cancer tissues showed high expression of pulp cells, and in cancer tissues of normal cells, plasma showed low expression. AQP-1 in colorectal cancer tissues with high expression and tumor grade and lymph node metastasis are closely related. Confirmed that AQP-1 in cancer occurrence and development play an important role. AQP-1 in-depth study is beneficial to future research the pathogenesis of colorectal cancer to guide clinical diagnosis and prognosis.2 AQP-1 and VEGF, CD34 expression to varying degrees in cancer tissue and cancer tissue, correlation analysis of the meaning of significant, indicating AQP-1 and angiogenesis of colorectal cancer are closely related, AQP-1 in rectal cancer, from the development process to promote cancer cell growth, metastasis and with angiogenesis. AQP-1 may be targeted as a colorectal cancer therapeutic target.3 AQP inhibitor acetazolamide significantly inhibit the growth of colon cancer xenografts in nude mice, tumor growth is slow. AQP-1 and VEGF, AQP-1 and CD34, CD34 and VEGF expression in the experimental group were positively correlated (rs=0.398,0.583,0.439;P<0.01),prompted acetazolamide on AQP-1 inhibition and tumor angiogenesis is closely related to acetazolamide may inhibit tumor angiogenesis on the inhibition of tumor growth. Acetazolamide may be by inhibiting AQP-1-mediated water transport, and inhibiting tumor angiogenesis in tumor growth inhibition of colorectal cancer, as a new target for the treatment shows good prospects.