大肠腺癌中鞘氨醇激酶-1与1-磷酸鞘氨醇受体mRNA和蛋白表达的研究
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摘要
目的：检测鞘氨醇激酶1(SphK1)及1-磷酸鞘氨醇(S1P)受体(S1P1,2,3)在正常大肠组织、大肠腺瘤、大肠腺癌、伴有远处转移的大肠腺癌组织中的表达情况,探讨SphK1/S1P通路在大肠癌发生发展中的可能作用及其临床意义。
方法：收集人大肠腺癌组织标本24例、大肠腺瘤组织标本12例、正常大肠组织标本12例。应用RT-PCR方法检测各组织标本中SphK1与S1P1,2,3 mRNA表达水平。应用Western Blot方法检测各组织标本SphK1与1-磷酸鞘氨醇受体1(S1P1)的蛋白表达。
结果：SphKl mRNA、SI P1 mRNA1 S1P2mRNA1 S1P3mRNA的表达在伴有远处转移的大肠腺癌组织、无远处转移的大肠腺癌、大肠腺瘤、正常大肠组织呈依次递减趋势,各组间比较均有显著的统计学差异(p<0.01)。与此相似,SphK1与S1P1蛋白在各组中的表达亦与其mRNA表达一致,呈现从高到低表达的趋势。大肠腺癌SphK1 mRNA表达量的多少与患者的年龄、性别、部位无关,而与浸润深度及淋巴结转移有关。
结论：SphKl及其底物的受体表达异常可能参与了大肠肿瘤的发生发展。
Objective:Analyze the expression of sphingosine kinases 1(SphKl) and sphingosine-1-phosphate (SIP) receptors (SIP1,2,3) in tissues of normal colon, colorectal adenoma, colorectal adenocarcinoma, colorectal adenocarcinoma with distant metastasis and approach the possible role of SphK/S1P pathway in colorectal cancer development and progression and its clinical significance.
Methods:Randomly collect 12 normal colon tissues,12 colorectal adenoma tissues,12 colorectal adenocarcinoma tissues and 12 tissues of colorectal adenocarcinoma with distant metastasis. The expressions of SphKl, S1P1, S1P2, S1P3 mRNA in tissues were detected by RT-PCR. The protein expressions of SphKl, S1 P1 were evaluated by Western blot.
Results:The expression of SphKl, S1P1, S1P2, S1P3 mRNA in colorectal adenocarcinoma with distant metastasis group, colorectal adenocarcinoma group, colorectal adenoma group, normal colon group is showed a decreasing trend in turn, and between groups the differences were significantly. Similarly, the protein expressions of SphK1, S1P1 in the 4 groups are consistent with their mRNA expression, showed a trend from high to low. The expression of SphKl mRNA is associated with the depth of invasion and the level of lymph node metastasis, while it is unrelated with patient's age, sex and the location of colorectal adenocarcinoma.
Conclusions:The abnormal expression of SphK1 and S1P receptors may be involved in colorectal tumor occurrence and development.
方法：收集人大肠腺癌组织标本24例、大肠腺瘤组织标本12例、正常大肠组织标本12例。应用RT-PCR方法检测各组织标本中SphK1与S1P1,2,3 mRNA表达水平。应用Western Blot方法检测各组织标本SphK1与1-磷酸鞘氨醇受体1(S1P1)的蛋白表达。
结果：SphKl mRNA、SI P1 mRNA1 S1P2mRNA1 S1P3mRNA的表达在伴有远处转移的大肠腺癌组织、无远处转移的大肠腺癌、大肠腺瘤、正常大肠组织呈依次递减趋势,各组间比较均有显著的统计学差异(p<0.01)。与此相似,SphK1与S1P1蛋白在各组中的表达亦与其mRNA表达一致,呈现从高到低表达的趋势。大肠腺癌SphK1 mRNA表达量的多少与患者的年龄、性别、部位无关,而与浸润深度及淋巴结转移有关。
结论：SphKl及其底物的受体表达异常可能参与了大肠肿瘤的发生发展。
Objective:Analyze the expression of sphingosine kinases 1(SphKl) and sphingosine-1-phosphate (SIP) receptors (SIP1,2,3) in tissues of normal colon, colorectal adenoma, colorectal adenocarcinoma, colorectal adenocarcinoma with distant metastasis and approach the possible role of SphK/S1P pathway in colorectal cancer development and progression and its clinical significance.
Methods:Randomly collect 12 normal colon tissues,12 colorectal adenoma tissues,12 colorectal adenocarcinoma tissues and 12 tissues of colorectal adenocarcinoma with distant metastasis. The expressions of SphKl, S1P1, S1P2, S1P3 mRNA in tissues were detected by RT-PCR. The protein expressions of SphKl, S1 P1 were evaluated by Western blot.
Results:The expression of SphKl, S1P1, S1P2, S1P3 mRNA in colorectal adenocarcinoma with distant metastasis group, colorectal adenocarcinoma group, colorectal adenoma group, normal colon group is showed a decreasing trend in turn, and between groups the differences were significantly. Similarly, the protein expressions of SphK1, S1P1 in the 4 groups are consistent with their mRNA expression, showed a trend from high to low. The expression of SphKl mRNA is associated with the depth of invasion and the level of lymph node metastasis, while it is unrelated with patient's age, sex and the location of colorectal adenocarcinoma.
Conclusions:The abnormal expression of SphK1 and S1P receptors may be involved in colorectal tumor occurrence and development.
引文
1. Taha Ta, Hannun YA, Obeid LM. Sphingosine kinase:biochemical and cellular regulation and role in disease. Biochem Mol Biol,2006, 39(2):113-131
2. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
3. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta,2006, 1758(12):2016-2026
4. Leclercq TM, Pitson SM. Cellular signalling by sphingosine kinase and sphingosine 1-phosphate. IUBMB Life,2006,58(8):467-472
5. Pyne S, Lee SC, Long J, et al. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal,2009,21(1):14-21
6. Jo SK, Bajwa A, Awad AS, et al. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int, 2008,73(11):1220-1230
7. Limaye V. The role of sphingosine kinase and sphingosine-1-phosphate in the regulation of endothelial cell biology. Endothelium,2008,15(3):101-112
8. Young N, Van Brocklyn JR. Signal transduction of sphingosine-1-phosphate G protein-coupled receptors. Scientific World Journal,2006,6:946-966
9. von Wenckstern H, Zimmermann K, Kleuser B. The role of the lysophospholipid sphingosine 1-phosphate in immune cell biology. Arch Immunol Ther Exp (Warsz),2006,54(4):239-251
10. Alemany R, van Koppen CJ, Danneberg K, et al. Regulation and functional roles of sphingosine kinases. Naunyn Schmiedebergs Arch Pharmacol,2007, 374(5-6):413-428
11. Bryan L, Kordula T, Spiegel S, et al. Regulation and functions of sphingosine kinases in the brain. Biochim Biophys Acta,2008,1781(9): 459-466
12. Shida D, Takabe K, Kapitonov D, et al. Targeting SphK1 as a new strategy against cancer. Curr Drug Targets,2008,9(8):662-673
13.Taha TA, Hannun YA, Obeid LM. Sphingosine kinase:biochemical and cellular regulation and role in disease. J Biochem Mol Biol,2006, 39(2):113-131
14. Bergelin N, Blom T, Heikkila J, et al. Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology,2009,150(5):2055-2063
15. Shida D, Takabe K, Kapitonov D, et al. Targeting SphKl as a new strategy against cancer. Curr Drug Targets,2008,9(8):662-673
16. McDonald RA, Pyne S, Pyne NJ, et al. The sphingosine kinase inhibitor N,N-dimethylsphingosine inhibits neointimal hyperplasia. Br J Pharmacol, 2010,159(3):543-553
17. Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res,2009, 15(4):1393-1399
18. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
19. Knapp P, Baranowski M, Knapp M. Altered sphingolipid metabolism in human endometrial cancer. Prostaglandins &Other Lipid Mediators,2010, 92(1-4):62-66
20. Kohno M, M onloi M, Oo M L, et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol,2006, 26(19):7211-7223
21.孙慧燕,段海峰,贾向旭等.IL-6对多发性骨髓瘤细胞鞘氨醇激酶的激活作用.军事医学科学院院刊,2004,28(2)：130-132
22. Yamashita H, Kitayama J, Shida D, et al. Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells:differential regulation on the migration and proliferation. J Surg Res,2006,130(1):80-87
23. Dayon A, Brizuela L, Martin C, et al. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival. PLoS One,2009, 4(11):e8048
24. Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme:roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol,2005,64(8):695-705
25. Anliker B, Chun J. Lysophospholipid G protein-coupled receptors. J Biol Chem,2004,279(20):20555-20558
1. Alemany R, van Koppen CJ, Danneberg K, et al. Regulation and functional roles of sphingosine kinases. Naunyn Sebmiedebergs Arch Pharmacol,2007, 374(5-6):413-428
2. Oliver A, Kohama T, Tu Z, et al. Purification and characterization of rat kidney sphingosine kinase. J Biol Chem,1998,273(20):12576-12583
3. Kohama T, Olivera A, Edsall L, et al. Molecular cloning and functional characterization ofmurine sphingosine kinase. J Biol Chem,1998,273(37): 23722-23728
4. Nava VE, Lacana E, Poulton S, et al. Functional characterization of human sphingosine kinase 1. FEBS Lett,2000,473(1):81-84
5. Pitson SM, Dandrea RJ, Vandeleur L, et al. Human sphingosine kinase: purification,molecular cloning and characterization of the native and recombinant enzymes. Biochem J,2000,350(2):429-441
6. Liu H, SugiuraM, Nava VE, et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. Biol Chem,2000,275 (26):19513-19520
7. Murate T, Banno Y, T-Koizumi K, et al. Cell type-specific localization of sphingosine kinase-la in human tissues. J Histochem Cytochem,2001, 49(7):845-855
8. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta,2006,1758 (12):2016-2026
9. Pyne S, Lee SC, Long J, et al. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal,2009,21(1):14-21
10. Taha TA, Kitatani K, El-Alwani M, et al. Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death:modulation of sphingolipid levels and the induction of apoptosis. FASEB J,2006, 20(3):482-484
11.Pitson SM, Xia P, Leclercq TM, et al. Phosphorylation dependent translocation of sphingosine kinase to the plasma merebrane drives its oncogenic signaling. J Exp Med,2005,201(1):49-54
12. Bergelin N, Blom T, Heikkila J, et al. Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology,2009,150(5):2055-2063
13. Pitson SM, Moretti PA, Zebol JR, et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J,2003,22(20):5491-5500
14. Vera K-K, SY, Tina R, et al. Stable knock-down of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells. Arterioscler Thromb Vasc Biol,2005,25(3):546-552
15. Heo K, Park KA, Kim YH, et al. Sphingosine 1-phosphate induces vascular endothelial growth factor expression in endothelial cells. BMB Rep,2009, 42(10):685-90
16. M izugishi K, Yamashita T, Olivera A, et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol,2005, 25(24):11113-11121
17. Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res,2009, 15(4):1393-1399
18. Yamashita H, Kitayama J, Shida D, et al. Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells:differential regulation on the migration and proliferation. J Surg Res,2006,130(1):80-87
19. Shida D, Fang X, Kordula T, et al. Cross-talk between LPA1 and epidermal growth factor receptors mediates up-regulation of sphingosine kinase 1 to promote gastric cancer cell motility and invasion. Cancer Res,2008, 68(16):6569-6577
20. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
21. Kohno M, M onloi M, Oo M L, et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol,2006, 26(19):7211-7223
22. Jordan VC. Selective estrogen receptor modulation:concept and consequences in cancer. Cancer Cel,2004,5(3):207-213
23. Ruckhaberle E, Rody A, Engels K, et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat,2008,112(1):41-52
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30. Young N, Pearl DK, Van Brocklyn JR. Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. Mol Cancer Res,2009,7(1):23-32
31. Paugh BS, Bryan L, Paugh SW, et al. Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem,2009, 284(6):3408-3417
32. Bergelin N, Blom T, Heikkila J, et al. Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Docrinology,2009,150(5):2055-2063
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35. Dayon A, Brizuela L, Martin C, et al. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival. PLoS One,2009, 4(11):e8048
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41. Vadas M, Xia P, McCaughan G, et al. The role of sphingosine kinase 1 in cancer:oncogene or non-oncogene addiction? Biochim Biophys Acta,2008, 1781(9):442-447
42. Knapp P, Baranowski M, Knapp M. Altered sphingolipid metabolism in human endometrial cancer. Prostaglandins Other Lipid Mediators,2010, 92(1-4):62-66
43. Guillermet-Guibert J, Davenne L, Pchejetski D, et al. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther,2009,8(4):809-820
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2. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
3. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta,2006, 1758(12):2016-2026
4. Leclercq TM, Pitson SM. Cellular signalling by sphingosine kinase and sphingosine 1-phosphate. IUBMB Life,2006,58(8):467-472
5. Pyne S, Lee SC, Long J, et al. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal,2009,21(1):14-21
6. Jo SK, Bajwa A, Awad AS, et al. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int, 2008,73(11):1220-1230
7. Limaye V. The role of sphingosine kinase and sphingosine-1-phosphate in the regulation of endothelial cell biology. Endothelium,2008,15(3):101-112
8. Young N, Van Brocklyn JR. Signal transduction of sphingosine-1-phosphate G protein-coupled receptors. Scientific World Journal,2006,6:946-966
9. von Wenckstern H, Zimmermann K, Kleuser B. The role of the lysophospholipid sphingosine 1-phosphate in immune cell biology. Arch Immunol Ther Exp (Warsz),2006,54(4):239-251
10. Alemany R, van Koppen CJ, Danneberg K, et al. Regulation and functional roles of sphingosine kinases. Naunyn Schmiedebergs Arch Pharmacol,2007, 374(5-6):413-428
11. Bryan L, Kordula T, Spiegel S, et al. Regulation and functions of sphingosine kinases in the brain. Biochim Biophys Acta,2008,1781(9): 459-466
12. Shida D, Takabe K, Kapitonov D, et al. Targeting SphK1 as a new strategy against cancer. Curr Drug Targets,2008,9(8):662-673
13.Taha TA, Hannun YA, Obeid LM. Sphingosine kinase:biochemical and cellular regulation and role in disease. J Biochem Mol Biol,2006, 39(2):113-131
14. Bergelin N, Blom T, Heikkila J, et al. Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology,2009,150(5):2055-2063
15. Shida D, Takabe K, Kapitonov D, et al. Targeting SphKl as a new strategy against cancer. Curr Drug Targets,2008,9(8):662-673
16. McDonald RA, Pyne S, Pyne NJ, et al. The sphingosine kinase inhibitor N,N-dimethylsphingosine inhibits neointimal hyperplasia. Br J Pharmacol, 2010,159(3):543-553
17. Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res,2009, 15(4):1393-1399
18. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
19. Knapp P, Baranowski M, Knapp M. Altered sphingolipid metabolism in human endometrial cancer. Prostaglandins &Other Lipid Mediators,2010, 92(1-4):62-66
20. Kohno M, M onloi M, Oo M L, et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol,2006, 26(19):7211-7223
21.孙慧燕,段海峰,贾向旭等.IL-6对多发性骨髓瘤细胞鞘氨醇激酶的激活作用.军事医学科学院院刊,2004,28(2)：130-132
22. Yamashita H, Kitayama J, Shida D, et al. Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells:differential regulation on the migration and proliferation. J Surg Res,2006,130(1):80-87
23. Dayon A, Brizuela L, Martin C, et al. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival. PLoS One,2009, 4(11):e8048
24. Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme:roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol,2005,64(8):695-705
25. Anliker B, Chun J. Lysophospholipid G protein-coupled receptors. J Biol Chem,2004,279(20):20555-20558
1. Alemany R, van Koppen CJ, Danneberg K, et al. Regulation and functional roles of sphingosine kinases. Naunyn Sebmiedebergs Arch Pharmacol,2007, 374(5-6):413-428
2. Oliver A, Kohama T, Tu Z, et al. Purification and characterization of rat kidney sphingosine kinase. J Biol Chem,1998,273(20):12576-12583
3. Kohama T, Olivera A, Edsall L, et al. Molecular cloning and functional characterization ofmurine sphingosine kinase. J Biol Chem,1998,273(37): 23722-23728
4. Nava VE, Lacana E, Poulton S, et al. Functional characterization of human sphingosine kinase 1. FEBS Lett,2000,473(1):81-84
5. Pitson SM, Dandrea RJ, Vandeleur L, et al. Human sphingosine kinase: purification,molecular cloning and characterization of the native and recombinant enzymes. Biochem J,2000,350(2):429-441
6. Liu H, SugiuraM, Nava VE, et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. Biol Chem,2000,275 (26):19513-19520
7. Murate T, Banno Y, T-Koizumi K, et al. Cell type-specific localization of sphingosine kinase-la in human tissues. J Histochem Cytochem,2001, 49(7):845-855
8. Hait NC, Oskeritzian CA, Paugh SW, et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta,2006,1758 (12):2016-2026
9. Pyne S, Lee SC, Long J, et al. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal,2009,21(1):14-21
10. Taha TA, Kitatani K, El-Alwani M, et al. Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death:modulation of sphingolipid levels and the induction of apoptosis. FASEB J,2006, 20(3):482-484
11.Pitson SM, Xia P, Leclercq TM, et al. Phosphorylation dependent translocation of sphingosine kinase to the plasma merebrane drives its oncogenic signaling. J Exp Med,2005,201(1):49-54
12. Bergelin N, Blom T, Heikkila J, et al. Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology,2009,150(5):2055-2063
13. Pitson SM, Moretti PA, Zebol JR, et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J,2003,22(20):5491-5500
14. Vera K-K, SY, Tina R, et al. Stable knock-down of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells. Arterioscler Thromb Vasc Biol,2005,25(3):546-552
15. Heo K, Park KA, Kim YH, et al. Sphingosine 1-phosphate induces vascular endothelial growth factor expression in endothelial cells. BMB Rep,2009, 42(10):685-90
16. M izugishi K, Yamashita T, Olivera A, et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol,2005, 25(24):11113-11121
17. Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res,2009, 15(4):1393-1399
18. Yamashita H, Kitayama J, Shida D, et al. Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells:differential regulation on the migration and proliferation. J Surg Res,2006,130(1):80-87
19. Shida D, Fang X, Kordula T, et al. Cross-talk between LPA1 and epidermal growth factor receptors mediates up-regulation of sphingosine kinase 1 to promote gastric cancer cell motility and invasion. Cancer Res,2008, 68(16):6569-6577
20. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J,2006,20(2):386-388
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