思他宁对胃癌细胞株SGC-7901生长调控作用的实验研究
摘要
目的研究生长抑素思他宁在体外对胃癌细胞株SGC-7901生长抑制作用,探讨其作用机制。
方法使用生长抑素思他宁溶液,按不同浓度(10-10mol /L、10-9mol /L、10-8mol /L、10-7mol /L、10-6mol /L)处理对数生长期的胃癌细胞株SGC-7901,倒置显微镜观察细胞生长情况。MTT比色法测量吸光度A值,计算对照组和各实验组细胞的生长抑制率;流式细胞仪对思他宁作用后的SGC-7901细胞进行细胞周期分析,计算细胞凋亡率;免疫细胞化学(SP)法检测肿瘤细胞中VEGF、NFκB蛋白的表达变化;RT-PCR半定量检测SGC-7901细胞VEGF、NFκB mRNA的表达水平。
结果MTT比色法显示思他宁对SGC-7901细胞生长有明显抑制作用,并且随着浓度的增加和作用时间延长而增强,思他宁浓度为10-6mol /L的抑制率最大,约为61.76%;根据流式细胞仪定量分析显示,浓度为10-8mol /L、10-7mol /L、10-6mol /L的思他宁诱导SGC-7901细胞产生的凋亡率分别为15.23%、26.3%、51.27%,与对照组2.28%的凋亡率比较均有显著差异(P<0.05)。思他宁可诱导SGC-7901细胞G0/G1期阻滞,使处于S期的肿瘤细胞逐渐减少,且随着浓度增加作用增强;免疫细胞化学(SP)结果显示,随着不同浓度的思他宁处理48小时后,SGC-7901细胞表达棕黄色颗粒的阳性细胞数减少,染色逐渐变淡。而对照组细胞的VEGF和NFκB蛋白高表达,胞浆内可见大量棕黄色颗粒,染色较深。提示在思他宁作用下SGC-7901细胞内VEGF和NFκB蛋白的表达下降。思他宁干预SGC-7901细胞48小时后,RT-PCR检测结果提示肿瘤细胞VEGF和NFκB mRNA的表达呈浓度依赖性降低。
结论思他宁能够抑制胃癌SGC-7901细胞生长,且呈时间和剂量依赖性。思他宁抗肿瘤的作用机制除已明确的依赖生长抑素受体的抑制作用外,还与下调VEGF和NFκB表达有关。
Objective To study the regulatory effect by Stilamin on human gastric cancer cell line SGC-7901 in vitro,and to explore its possible mechanisms of these effects.
Methods In vitro,exponential phase human gastric cancer cell line SGC-7901 was treated by Stilamin in various concentrations(10-10mol /L、10-9mol /L、10-8mol /L、10-7mol /L、10-6mol /L).Cell morphology changes was observed by optical microscopy.By means of MTT assay,the absorbance value was detected and inhibition rate was calculate. The induction of cell cycle and apoptosis by Stilamin was evaluated by flow cytometry,the expression of VEGF、NFκB protein were analyzed by immunocytochemistry(SP). The expression of VEGF、NFκB mRNA was determined by reverse transcriplase polymerase chain reaction(RT-PCR).
Results MTT assay shows that Stilamin could inhibit the growth of the human gastric cancer cell line SGC-7901,and the inhibitory effect was dose-and-time dependent (P<0.05). The maximum inhibition rate was 61.76% under Stilamin of which dentisy was 10-6mol /L. Quantitative analysis result from DNA bargragh was that cell apoptotic ratio of 10-8mol /L、10-7mol /L、10-6mol /L density was 15.23%、26.3%、51.27%.The difference was significant compared to the control group. Stilamin also induced the cells arrest at G0/G1 stage as the density increased and time prolonged.Morever, cells at S stage descended gradually.SP assay shows that the expression of VEGF and NFκB were downregulated,the number of eumorphism in cell of experiment group was decreased significantly as the density of Stilamin increased after 48h.Many eumorphism could still be seen in cell membrane and emdochylema in cell of control group. The expression of VEGF and NFκB mRNA was determined by reverse transcriplase polymerase chain reaction(RT-PCR).Expression of VEGF and NFκB mRNA was downregulated through ladder strap as the increasing of Stilamin concentration.
Conclusion: In a dose-and-time dependent manner, Stilamin could control the growth and apoptosis of the human gastric cancer cell line SGC-7901, and besides the definited effect that depend on the somatostatin receptor,Stilamin maybe can resist on tumors with the possible mechanism which can downregulating the expression of VEGF and NFκB.
方法使用生长抑素思他宁溶液,按不同浓度(10-10mol /L、10-9mol /L、10-8mol /L、10-7mol /L、10-6mol /L)处理对数生长期的胃癌细胞株SGC-7901,倒置显微镜观察细胞生长情况。MTT比色法测量吸光度A值,计算对照组和各实验组细胞的生长抑制率;流式细胞仪对思他宁作用后的SGC-7901细胞进行细胞周期分析,计算细胞凋亡率;免疫细胞化学(SP)法检测肿瘤细胞中VEGF、NFκB蛋白的表达变化;RT-PCR半定量检测SGC-7901细胞VEGF、NFκB mRNA的表达水平。
结果MTT比色法显示思他宁对SGC-7901细胞生长有明显抑制作用,并且随着浓度的增加和作用时间延长而增强,思他宁浓度为10-6mol /L的抑制率最大,约为61.76%;根据流式细胞仪定量分析显示,浓度为10-8mol /L、10-7mol /L、10-6mol /L的思他宁诱导SGC-7901细胞产生的凋亡率分别为15.23%、26.3%、51.27%,与对照组2.28%的凋亡率比较均有显著差异(P<0.05)。思他宁可诱导SGC-7901细胞G0/G1期阻滞,使处于S期的肿瘤细胞逐渐减少,且随着浓度增加作用增强;免疫细胞化学(SP)结果显示,随着不同浓度的思他宁处理48小时后,SGC-7901细胞表达棕黄色颗粒的阳性细胞数减少,染色逐渐变淡。而对照组细胞的VEGF和NFκB蛋白高表达,胞浆内可见大量棕黄色颗粒,染色较深。提示在思他宁作用下SGC-7901细胞内VEGF和NFκB蛋白的表达下降。思他宁干预SGC-7901细胞48小时后,RT-PCR检测结果提示肿瘤细胞VEGF和NFκB mRNA的表达呈浓度依赖性降低。
结论思他宁能够抑制胃癌SGC-7901细胞生长,且呈时间和剂量依赖性。思他宁抗肿瘤的作用机制除已明确的依赖生长抑素受体的抑制作用外,还与下调VEGF和NFκB表达有关。
Objective To study the regulatory effect by Stilamin on human gastric cancer cell line SGC-7901 in vitro,and to explore its possible mechanisms of these effects.
Methods In vitro,exponential phase human gastric cancer cell line SGC-7901 was treated by Stilamin in various concentrations(10-10mol /L、10-9mol /L、10-8mol /L、10-7mol /L、10-6mol /L).Cell morphology changes was observed by optical microscopy.By means of MTT assay,the absorbance value was detected and inhibition rate was calculate. The induction of cell cycle and apoptosis by Stilamin was evaluated by flow cytometry,the expression of VEGF、NFκB protein were analyzed by immunocytochemistry(SP). The expression of VEGF、NFκB mRNA was determined by reverse transcriplase polymerase chain reaction(RT-PCR).
Results MTT assay shows that Stilamin could inhibit the growth of the human gastric cancer cell line SGC-7901,and the inhibitory effect was dose-and-time dependent (P<0.05). The maximum inhibition rate was 61.76% under Stilamin of which dentisy was 10-6mol /L. Quantitative analysis result from DNA bargragh was that cell apoptotic ratio of 10-8mol /L、10-7mol /L、10-6mol /L density was 15.23%、26.3%、51.27%.The difference was significant compared to the control group. Stilamin also induced the cells arrest at G0/G1 stage as the density increased and time prolonged.Morever, cells at S stage descended gradually.SP assay shows that the expression of VEGF and NFκB were downregulated,the number of eumorphism in cell of experiment group was decreased significantly as the density of Stilamin increased after 48h.Many eumorphism could still be seen in cell membrane and emdochylema in cell of control group. The expression of VEGF and NFκB mRNA was determined by reverse transcriplase polymerase chain reaction(RT-PCR).Expression of VEGF and NFκB mRNA was downregulated through ladder strap as the increasing of Stilamin concentration.
Conclusion: In a dose-and-time dependent manner, Stilamin could control the growth and apoptosis of the human gastric cancer cell line SGC-7901, and besides the definited effect that depend on the somatostatin receptor,Stilamin maybe can resist on tumors with the possible mechanism which can downregulating the expression of VEGF and NFκB.
引文
1. Guillermet-Guibert J,Lahlou H,Cordelier P,et al.Physiology of somatostatin receptors〔J〕.J Endocrinol Invest ,2005 ,28 (11 Suppl) :5.
2. Wang CH,Tang CW,Liu CL,et al. Inhibitory effect of octreotide on gastric cancer growth via MAPK pathway[J] . World J Gastroenterol,2003,9 (9) :1904 -1908.
3. Rayet B,Gelinas C. Aberrant rel/ nfkb genes and activity in human cancer. Oncogene,1999,18 (49) :6938-6947.
4. McMahonG.VEGF receptor signaling in tumor angiogenesis [J].O ncologist,2000,5 (suppl1): 3-10.
5. Qin Pan,Ding Guo Li,Han Ming Lu,et al.Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cell〔sJ〕. World J Gastroenterol ,2004 ,10 (7) :1015.
6. Reisine T, Bell GI. Molecular biology of somatostatin receptors [ J ]. Endocr Rev, 1995, 16 (4) : 93-96.
7. Li M ,Zhang R ,Li F ,et al. Transfection of SSTR1 and SSTR2 inhibits Panc1 cell proliferation and renders Panc1 cells responsive to somatostatin analogue〔J〕.J Am Coll Surg,2005,201 (4) : 571.
8. Li M,Fisher WE,Kim HJ,etal.Somatostatin,somatostatin receptors,and pancreatic cancer〔J〕. World J Surg ,2005 ,29 (3) : 293.
9. Bousquet C,Puente E,Buscail L,et al.Antiproliferative effect of somatostatin and analogs〔J〕.Chemotherapy ,2001 ,47:30.
10. LeeJU,Hosotani R,Wada M,et al.Antiproliferativeactivityin duced by the somatostatin analogue ,TT-232 ,in human pancreatic cancer cell〔sJ〕. EurCancer ,2002 ,38 (11) :1526.
11. Hall GH,Turnbull LW,Richmond I,et al.Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumors〔J〕.Br J Cancer ,2002 ,87 (1) :86.
12. Guillermet J ,Saint Laurent N ,Rochaix P ,et al. Somatostatin receptor subtype sensitizes human pancreatic cancer cells to death Ligand induced apoptosis〔J〕. Proc Natl Acad Sci USA ,2003 ,100 (1) :155.
13. Chatzistamou I , Schally AV , Varga JL , et al . Antagonists of growth hormone-releasing hormone and somatosatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice〔J〕.J Clin Endocrinol Metab ,2001 ,86 (5) :2144.
14. Wang C , Tang C , Inhibition of human gastric cancer metastasis by octreotide in vitro and in vivo〔J〕. China phearm Med Instrum. 2002 ,10 :82 (1) :19.
15. McMahonG. VEGFreceptorsignalingintumorangiogenesis[J]. O ncologist, 2000, 5 (suppl1): 3-10.
16. Steták1 A ,Lankenau A ,Vántus T ,et al. The Antitumor Somatostatin Analogue TT-232 Induces Cell Cycle Arrest through PKC and C-Src〔J〕.Biochem Biophys Res Commun,2001,285 (2): 483.
17. Teijeiro R,Rios R,CostoyaJA,et al.Activation of human somatostatin receptor promotes apoptosis through a mechanism that is independent from induction of p53〔J〕. Cell Physiol Biochem ,2002 ,12 (1) :31.
18. Hanahan D ,Weinberg RA. The hallmarks of cancer. Cell ,2000 ,100(1) : 57.
19. Mercurio F ,Manning AM. NF -kappa B as a primary regulator of the stress response. Oncogene ,1999 ,18 (45) :6163 -6171.
20. Jo H,ZhangR,ZhangH,etal. NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene,2000 ,19 (7) :841 -849.
21. Miyazaki M,Mizuta Y,Takeshima F,et al. Expression of nuclear factor -kappa B in helicobacter pylori -infected gastric mucosa detected with southwesternhisto-chemistry. ScandJ Gastroenterol,2000,35 (3):247-254.
22. Buscail L ,Vernejoul F ,Faure P ,et al . Regulation of cell proliferation by somatostatin〔J〕. Ann Endocrinol ( Paris) ,2002 ,63 (2 Pt type expression〔J〕. Head Neck ,2006 ,28 (4) :305.
1. Guillermet-Guibert J ,Lahlou H ,Cordelier P ,et al. Physiology of somatostatin receptors〔J〕.J Endocrinol Invest ,2005 ,28 (11 Suppl) :5.
2. Slooter GD , Mearadji A , Breeman WAP. Somatostatin receptor imaging , therapy and new strategies in patients with neuroendocrine tumours [J ] . Br J Surg ,2001 ,88 :31 -40.
3. TenBokumAM, RosmalenJG, HoflandLJ, et al.Tissuedistribution ofoctreotide binding receptors in normal mice and strains prone to autoimmunity〔J〕. Nucl Med Commun ,2002 ,23 (10) : 1009.
4. Ferone D ,Pivonello R ,Van Hagen PM ,et al. Quantitative and function expression of somatostatin receptor subtypes in human thymocytes〔J〕. Am J Physiol Endocrinol Metab ,2002 ,283 (5) : E1056. type expression〔J〕. Head Neck ,2006 ,28 (4) :305.
5. Li M ,Zhang R ,Li F ,et al. Transfection of SSTR1 and SSTR2 inhibits Panc1 cell proliferation and renders Panc1 cells responsive to somatostatin analogue〔J〕.J Am Coll Surg,2005,201 (4) : 571.
6. Li M,Fisher WE,Kim HJ,etal.Somatostatin,somatostatin receptors,and pancreatic cancer〔J〕. World J Surg ,2005 ,29 (3) : 293.
7. 王春晖等.奥曲肽抑制胃癌生长的实验研究[J].胃肠病学,2002,7:158 -162.
8. Qin Pan,Ding Guo Li,Han Ming Lu,et al.Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cell〔sJ〕. World J Gastroenterol ,2004 ,10 (7) :1015.
9. Bousquet C,Puente E,Buscail L,et al.Antiproliferative effect of somatostatin and analogs〔J〕.Chemotherapy ,2001 ,47:30.
10. LeeJU,Hosotani R,Wada M,et al.Antiproliferativeactivityin duced by the somatostatin analogue ,TT2232 ,in human pancreatic cancer cells〔J〕. Eur Cancer ,2002 ,38 (11) :1526.
11. Hall GH,Turnbull LW,Richmond I,et al.Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumors〔J〕.Br J Cancer ,2002 ,87 (1) :86.
12. Guillermet J ,Saint Laurent N ,Rochaix P ,et al. Somatostatin receptor subtype sensitizes human pancreatic cancer cells to death Ligandinduced apoptosis〔J〕. Proc Natl Acad Sci USA ,2003 ,100 (1) :155.
13. Wang CH,Tang CW,Liu CL,et al. Inhibitory effect of octreotide on gastric cancer growth via MAPK pathway[J ] . World J Gastroenterol,2003,9 (9) :1904 -1908.
14. Chatzistamou I , Schally AV , Varga JL , et al . Antagonists of growth hormone-releasing hormone and somatosatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice〔J〕.J Clin Endocrinol Metab ,2001 ,86 (5) :2144.
15. Wang C , Tang C , Inhibition of human gastric cancer metastasis by octreotide in vitro and in vivo〔J〕. China phearm Med Instrum. 2002 ,10 :82 (1) :19.
16. Buscail L ,Vernejoul F ,Faure P ,et al . Regulation of cell proliferation by somatostatin〔J〕. Ann Endocrinol ( Paris) ,2002 ,63 (2 Pt 3550·
17. Steták1 A ,Lankenau A ,Vántus T ,et al. The Antitumor Somatostatin Analogue TT-232 Induces Cell Cycle Arrest through PKC and C-Src〔J〕.Biochem Biophys Res Commun,2001,285 (2): 483.
18. Teijeiro R,Rios R,CostoyaJA,et al.Activation of human somatostatin receptor promotes apoptosis through a mechanism that is independent from induction of p53〔J〕. Cell Physiol Biochem ,2002 ,12 (1) :31.
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2. Wang CH,Tang CW,Liu CL,et al. Inhibitory effect of octreotide on gastric cancer growth via MAPK pathway[J] . World J Gastroenterol,2003,9 (9) :1904 -1908.
3. Rayet B,Gelinas C. Aberrant rel/ nfkb genes and activity in human cancer. Oncogene,1999,18 (49) :6938-6947.
4. McMahonG.VEGF receptor signaling in tumor angiogenesis [J].O ncologist,2000,5 (suppl1): 3-10.
5. Qin Pan,Ding Guo Li,Han Ming Lu,et al.Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cell〔sJ〕. World J Gastroenterol ,2004 ,10 (7) :1015.
6. Reisine T, Bell GI. Molecular biology of somatostatin receptors [ J ]. Endocr Rev, 1995, 16 (4) : 93-96.
7. Li M ,Zhang R ,Li F ,et al. Transfection of SSTR1 and SSTR2 inhibits Panc1 cell proliferation and renders Panc1 cells responsive to somatostatin analogue〔J〕.J Am Coll Surg,2005,201 (4) : 571.
8. Li M,Fisher WE,Kim HJ,etal.Somatostatin,somatostatin receptors,and pancreatic cancer〔J〕. World J Surg ,2005 ,29 (3) : 293.
9. Bousquet C,Puente E,Buscail L,et al.Antiproliferative effect of somatostatin and analogs〔J〕.Chemotherapy ,2001 ,47:30.
10. LeeJU,Hosotani R,Wada M,et al.Antiproliferativeactivityin duced by the somatostatin analogue ,TT-232 ,in human pancreatic cancer cell〔sJ〕. EurCancer ,2002 ,38 (11) :1526.
11. Hall GH,Turnbull LW,Richmond I,et al.Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumors〔J〕.Br J Cancer ,2002 ,87 (1) :86.
12. Guillermet J ,Saint Laurent N ,Rochaix P ,et al. Somatostatin receptor subtype sensitizes human pancreatic cancer cells to death Ligand induced apoptosis〔J〕. Proc Natl Acad Sci USA ,2003 ,100 (1) :155.
13. Chatzistamou I , Schally AV , Varga JL , et al . Antagonists of growth hormone-releasing hormone and somatosatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice〔J〕.J Clin Endocrinol Metab ,2001 ,86 (5) :2144.
14. Wang C , Tang C , Inhibition of human gastric cancer metastasis by octreotide in vitro and in vivo〔J〕. China phearm Med Instrum. 2002 ,10 :82 (1) :19.
15. McMahonG. VEGFreceptorsignalingintumorangiogenesis[J]. O ncologist, 2000, 5 (suppl1): 3-10.
16. Steták1 A ,Lankenau A ,Vántus T ,et al. The Antitumor Somatostatin Analogue TT-232 Induces Cell Cycle Arrest through PKC and C-Src〔J〕.Biochem Biophys Res Commun,2001,285 (2): 483.
17. Teijeiro R,Rios R,CostoyaJA,et al.Activation of human somatostatin receptor promotes apoptosis through a mechanism that is independent from induction of p53〔J〕. Cell Physiol Biochem ,2002 ,12 (1) :31.
18. Hanahan D ,Weinberg RA. The hallmarks of cancer. Cell ,2000 ,100(1) : 57.
19. Mercurio F ,Manning AM. NF -kappa B as a primary regulator of the stress response. Oncogene ,1999 ,18 (45) :6163 -6171.
20. Jo H,ZhangR,ZhangH,etal. NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene,2000 ,19 (7) :841 -849.
21. Miyazaki M,Mizuta Y,Takeshima F,et al. Expression of nuclear factor -kappa B in helicobacter pylori -infected gastric mucosa detected with southwesternhisto-chemistry. ScandJ Gastroenterol,2000,35 (3):247-254.
22. Buscail L ,Vernejoul F ,Faure P ,et al . Regulation of cell proliferation by somatostatin〔J〕. Ann Endocrinol ( Paris) ,2002 ,63 (2 Pt type expression〔J〕. Head Neck ,2006 ,28 (4) :305.
1. Guillermet-Guibert J ,Lahlou H ,Cordelier P ,et al. Physiology of somatostatin receptors〔J〕.J Endocrinol Invest ,2005 ,28 (11 Suppl) :5.
2. Slooter GD , Mearadji A , Breeman WAP. Somatostatin receptor imaging , therapy and new strategies in patients with neuroendocrine tumours [J ] . Br J Surg ,2001 ,88 :31 -40.
3. TenBokumAM, RosmalenJG, HoflandLJ, et al.Tissuedistribution ofoctreotide binding receptors in normal mice and strains prone to autoimmunity〔J〕. Nucl Med Commun ,2002 ,23 (10) : 1009.
4. Ferone D ,Pivonello R ,Van Hagen PM ,et al. Quantitative and function expression of somatostatin receptor subtypes in human thymocytes〔J〕. Am J Physiol Endocrinol Metab ,2002 ,283 (5) : E1056. type expression〔J〕. Head Neck ,2006 ,28 (4) :305.
5. Li M ,Zhang R ,Li F ,et al. Transfection of SSTR1 and SSTR2 inhibits Panc1 cell proliferation and renders Panc1 cells responsive to somatostatin analogue〔J〕.J Am Coll Surg,2005,201 (4) : 571.
6. Li M,Fisher WE,Kim HJ,etal.Somatostatin,somatostatin receptors,and pancreatic cancer〔J〕. World J Surg ,2005 ,29 (3) : 293.
7. 王春晖等.奥曲肽抑制胃癌生长的实验研究[J].胃肠病学,2002,7:158 -162.
8. Qin Pan,Ding Guo Li,Han Ming Lu,et al.Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cell〔sJ〕. World J Gastroenterol ,2004 ,10 (7) :1015.
9. Bousquet C,Puente E,Buscail L,et al.Antiproliferative effect of somatostatin and analogs〔J〕.Chemotherapy ,2001 ,47:30.
10. LeeJU,Hosotani R,Wada M,et al.Antiproliferativeactivityin duced by the somatostatin analogue ,TT2232 ,in human pancreatic cancer cells〔J〕. Eur Cancer ,2002 ,38 (11) :1526.
11. Hall GH,Turnbull LW,Richmond I,et al.Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumors〔J〕.Br J Cancer ,2002 ,87 (1) :86.
12. Guillermet J ,Saint Laurent N ,Rochaix P ,et al. Somatostatin receptor subtype sensitizes human pancreatic cancer cells to death Ligandinduced apoptosis〔J〕. Proc Natl Acad Sci USA ,2003 ,100 (1) :155.
13. Wang CH,Tang CW,Liu CL,et al. Inhibitory effect of octreotide on gastric cancer growth via MAPK pathway[J ] . World J Gastroenterol,2003,9 (9) :1904 -1908.
14. Chatzistamou I , Schally AV , Varga JL , et al . Antagonists of growth hormone-releasing hormone and somatosatin analog RC-160 inhibit the growth of the OV-1063 human epithelial ovarian cancer cell line xenografted into nude mice〔J〕.J Clin Endocrinol Metab ,2001 ,86 (5) :2144.
15. Wang C , Tang C , Inhibition of human gastric cancer metastasis by octreotide in vitro and in vivo〔J〕. China phearm Med Instrum. 2002 ,10 :82 (1) :19.
16. Buscail L ,Vernejoul F ,Faure P ,et al . Regulation of cell proliferation by somatostatin〔J〕. Ann Endocrinol ( Paris) ,2002 ,63 (2 Pt 3550·
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