World Journal of Surgery

, 33:630 | Cite as

Microarray Analysis of Somatostatin Receptor 5-Regulated Gene Expression Profiles in Murine Pancreas

  • Sanjeet G. Patel
  • Guisheng Zhou
  • Shi-He Liu
  • Min Li
  • Jae-Wook Jeong
  • Francesco J. DeMayo
  • Marie-Claude Gingras
  • Richard A. Gibbs
  • William E. Fisher
  • F. Charles BrunicardiEmail author



We previously demonstrated that somatostatin receptor type 5 (SSTR5) gene ablation results in alterations in insulin secretion and glucose metabolism, accompanied by morphologic alterations in the islets of Langerhans. The underlying mechanism(s) by which SSTR5 exerts its cellular functions remain(s) unknown. We hypothesized that SSTR5 mediates the inhibitory effect of somatostatin (SST) on insulin secretion and islet proliferation by regulating a specific set of pancreatic genes.


To identify SSTR5-regulated pancreatic genes, gene expression microarray analysis was performed on the whole pancreas of 1- and 3-month-old wild-type (WT) and SSTR5 knockout (SSTR5 −/−) male mice. Real-time RT-PCR and immunofluorescence were performed to validate selected differentially expressed genes.


A set of 143 probes were identified to be differentially expressed in the pancreas of 1-month-old SSTR5 −/− mice, 72 of which were downregulated and 71 upregulated. At 3 months of age, SSTR5 gene ablation resulted in downregulation of a set of 30 probes and upregulation of a set of 37 probes. Among these differentially expressed genes, there were 15 and 5 genes that were upregulated and downregulated, respectively, in mice at both 1 and 3 months of age. Three genes, PAP/INGAP, ANG, and TDE1, were selected to be validated by real-time RT-PCR and immunofluorescence.


A specific set of genes linked to a wide range of cellular functions such as islet proliferation, apoptosis, angiogenesis, and tumorigenesis were either upregulated or downregulated in SSTR5-deficient male mice compared with their expression in wild-type mice. Therefore, these genes are potential SSTR5-regulated genes during normal pancreatic development and functional maintenance.


ANG1 Expression Gene Expression Alteration Islet Neogenesis Islet Hyperplasia Islet Cell Proliferation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This project was supported by the National Institutes of Health (NIH) grant NIDDK R01-DK46441, the Elkins Pancreas Center at Baylor College of Medicine, and the generosity of Mr. and Mrs. Walter Hecht. Gratitude is extended to the people working in Dr. Brunicardi’s laboratory for their support and technical assistance. Gratitude is also extended to Katie Elsbury for her editorial assistance and Priscilla Massey for her administrative assistance throughout this project.


  1. 1.
    Brazeau P, Vale W, Burgus R et al (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77–79PubMedCrossRefGoogle Scholar
  2. 2.
    Patel YC (1999) Somatostatin and its receptor family. Front Neuroendocrinol 20:157–198PubMedCrossRefGoogle Scholar
  3. 3.
    Ballian N, Brunicardi FC, Wang XP (2006) Somatostatin and its receptors in the development of the endocrine pancreas. Pancreas 33:1–12PubMedCrossRefGoogle Scholar
  4. 4.
    Ballian N, Hu M, Liu SH et al (2007) Proliferation, hyperplasia, neogenesis, and neoplasia in the islets of Langerhans. Pancreas 35:199–206PubMedCrossRefGoogle Scholar
  5. 5.
    Florio T (2008) Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci 13:822–840PubMedCrossRefGoogle Scholar
  6. 6.
    Wang XP, Norman MA, Brunicardi FC (2005) Somatostatin receptors and autoimmune-mediated diabetes. Diabetes Metab Res Rev 21:15–30PubMedCrossRefGoogle Scholar
  7. 7.
    Moldovan S, De Mayo F, Brunicardi FC (1998) Cloning of the mouse SSTR5 gene. J Surg Res 76:57–60PubMedCrossRefGoogle Scholar
  8. 8.
    Raynor K, O’Carroll AM, Kong H et al (1993) Characterization of cloned somatostatin receptors SSTR4 and SSTR5. Mol Pharmacol 44:385–392PubMedGoogle Scholar
  9. 9.
    Yamada Y, Post SR, Wang K et al (1992) Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci USA 89:251–255PubMedCrossRefGoogle Scholar
  10. 10.
    Yasuda K, Rens-Domiano S, Breder CD et al (1992) Cloning of a novel somatostatin receptor, SSTR3, coupled to adenylylcyclase. J Biol Chem 267:20422–20428PubMedGoogle Scholar
  11. 11.
    Reisine T, Bell GI (1995) Molecular biology of somatostatin receptors. Endocr Rev 16:427–442PubMedGoogle Scholar
  12. 12.
    Pfeiffer M, Koch T, Schroder H et al (2001) Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J Biol Chem 276:14027–14036PubMedGoogle Scholar
  13. 13.
    Rocheville M, Lange DC, Kumar U et al (2000) Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem 275:7862–7869PubMedCrossRefGoogle Scholar
  14. 14.
    Duran-Prado M, Bucharles C, Gonzalez BJ et al (2007) Porcine somatostatin receptor 2 displays typical pharmacological sst2 features but unique dynamics of homodimerization and internalization. Endocrinology 148:411–421PubMedCrossRefGoogle Scholar
  15. 15.
    Peverelli E, Mantovani G, Calebiro D et al (2008) The third intracellular loop of the human somatostatin receptor 5 is crucial for arrestin binding and receptor internalization after somatostatin stimulation. Mol Endocrinol 22:676–688PubMedCrossRefGoogle Scholar
  16. 16.
    Bruno JF, Xu Y, Song J (1993) Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 133:2561–2567PubMedCrossRefGoogle Scholar
  17. 17.
    Panetta R, Greenwood MT, Warszynska A et al (1994) Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. Mol Pharmacol 45:417–427PubMedGoogle Scholar
  18. 18.
    Kreienkamp HJ, Akgun E, Baumeister H et al (1999) Somatostatin receptor subtype 1 modulates basal inhibition of growth hormone release in somatotrophs. FEBS Lett 462:464–466PubMedCrossRefGoogle Scholar
  19. 19.
    Wang XP, Norman M, Yang J et al (2006) Alterations in glucose homeostasis in SSTR1 gene-ablated mice. Mol Cell Endocrinol 247:82–90PubMedCrossRefGoogle Scholar
  20. 20.
    Zheng H, Bailey A, Jiang MH et al (1997) Somatostatin receptor subtype 2 knockout mice are refractory to growth hormone-negative feedback on arcuate neurons. Mol Endocrinol 11:1709–1717PubMedCrossRefGoogle Scholar
  21. 21.
    Strowski MZ, Kohler M, Chen HY et al (2003) Somatostatin receptor subtype 5 regulates insulin secretion and glucose homeostasis. Mol Endocrinol 17:93–106PubMedCrossRefGoogle Scholar
  22. 22.
    Tirone TA, Norman MA, Moldovan S et al (2003) Pancreatic somatostatin inhibits insulin secretion via SSTR-5 in the isolated perfused mouse pancreas model. Pancreas 26:e67–e73PubMedCrossRefGoogle Scholar
  23. 23.
    Wang XP, Norman M, Yang J et al (2005) The effect of global SSTR5 gene ablation on the endocrine pancreas and glucose regulation in aging mice. J Surg Res 129:64–72PubMedCrossRefGoogle Scholar
  24. 24.
    Wang XP, Norman MA, Yang J et al (2004) Double-gene ablation of SSTR1 and SSTR5 results in hyperinsulinemia and improved glucose tolerance in mice. Surgery 136:585–592PubMedCrossRefGoogle Scholar
  25. 25.
    Wang XP, Yang J, Norman MA et al (2005) SSTR5 ablation in islet results in alterations in glucose homeostasis in mice. FEBS Lett 579:3107–3114PubMedCrossRefGoogle Scholar
  26. 26.
    Singh V, Grotzinger C, Nowak KW et al (2007) Somatostatin receptor subtype-2-deficient mice with diet-induced obesity have hyperglycemia, nonfasting hyperglucagonemia, and decreased hepatic glycogen deposition. Endocrinology 148:3887–3899PubMedCrossRefGoogle Scholar
  27. 27.
    Reubi JC, Horisberger U, Essed CE et al (1988) Absence of somatostatin receptors in human exocrine pancreatic adenocarcinomas. Gastroenterology 95:760–763PubMedGoogle Scholar
  28. 28.
    Player A, Gillespie J, Fujii T et al (2003) Identification of TDE2 gene and its expression in non-small cell lung cancer. Int J Cancer 107:238–243PubMedCrossRefGoogle Scholar
  29. 29.
    Rosenberg L, Lipsett M, Yoon JW et al (2004) A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6 J mice. Ann Surg 240:875–884PubMedCrossRefGoogle Scholar
  30. 30.
    Zatelli MC, Tagliati F, Taylor JE et al (2001) Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line. J Clin Endocrinol Metab 86:2161–2169PubMedCrossRefGoogle Scholar
  31. 31.
    Qiu Z, Huang C, Sun J et al (2007) RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci 98:1099–1106PubMedCrossRefGoogle Scholar
  32. 32.
    Schadt EE, Li C, Ellis B et al (2001) Feature extraction and normalization algorithms for high-density oligonucleotide gene expression array data. J Cell Biochem Suppl 37:120–125PubMedCrossRefGoogle Scholar
  33. 33.
    Li C, Wong WH (2001) Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 98:31–36PubMedCrossRefGoogle Scholar
  34. 34.
    Jeong JW, Kwak I, Lee KY et al (2006) The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism. Mol Endocrinol 20:1138–1152PubMedCrossRefGoogle Scholar
  35. 35.
    Bernard C, Berthault MF, Saulnier C et al (1999) Neogenesis vs. apoptosis as main components of pancreatic beta cell mass changes in glucose-infused normal and mildly diabetic adult rats. FASEB J 13:1195–1205PubMedGoogle Scholar
  36. 36.
    Bernard-Kargar C, Ktorza A (2001) Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes 50:S30–S35PubMedCrossRefGoogle Scholar
  37. 37.
    Vincent M, Guz Y, Rozenberg M et al (2003) Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Endocrinology 144:4061–4069PubMedCrossRefGoogle Scholar
  38. 38.
    Rafaeloff R, Pittenger GL, Barlow SW et al (1997) Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters. J Clin Invest 99:2100–2109PubMedCrossRefGoogle Scholar
  39. 39.
    Ortiz EM, Dusetti NJ, Vasseur S et al (1998) The pancreatitis-associated protein is induced by free radicals in AR4-2 J cells and confers cell resistance to apoptosis. Gastroenterology 114:808–816PubMedCrossRefGoogle Scholar
  40. 40.
    Bossolasco M, Veillette F, Bertrand R et al (2006) Human TDE1, a TDE1/TMS family member, inhibits apoptosis in vitro and stimulates in vivo tumorigenesis. Oncogene 25:4549–4558PubMedCrossRefGoogle Scholar
  41. 41.
    Vaccaro MI, Calvo EL, Suburo AM et al (2000) Lipopolysaccharide directly affects pancreatic acinar cells: implications on acute pancreatitis pathophysiology. Dig Dis Sci 45:915–926PubMedCrossRefGoogle Scholar
  42. 42.
    Del Zotto H, Borelli MI, Flores L et al (2004) Islet neogenesis: an apparent key component of long-term pancreas adaptation to increased insulin demand. J Endocrinol 183:321–330PubMedCrossRefGoogle Scholar
  43. 43.
    Folch-Puy E, Granell S, Dagorn JC et al (2006) Pancreatitis-associated protein I suppresses NF-kappa B activation through a JAK/STAT-mediated mechanism in epithelial cells. J Immunol 176:3774–3779PubMedGoogle Scholar
  44. 44.
    Hamblet NS, Shi W, Vinik AI et al (2008) The Reg family member INGAP is a marker of endocrine patterning in the embryonic pancreas. Pancreas 36:1–9PubMedCrossRefGoogle Scholar
  45. 45.
    Feanny MA, Fagan SP, Ballian N et al (2008) PDX-1 expression is associated with islet proliferation in vitro and in vivo. J Surg Res 144:8–16PubMedCrossRefGoogle Scholar
  46. 46.
    Liu S, Ballian N, Belagui NS et al (2008) PDX-1 acts as a potential molecular target for treatment of human pancreatic cancer. Pancreas 37:210–220PubMedCrossRefGoogle Scholar
  47. 47.
    Grossman TR, Luque JM, Nelson N (2000) Identification of a ubiquitous family of membrane proteins and their expression in mouse brain. J Exp Biol 203:447–457PubMedGoogle Scholar
  48. 48.
    Aoki S, Su Q, Li H et al (2002) Identification of an axotomy-induced glycosylated protein, AIGP1, possibly involved in cell death triggered by endoplasmic reticulum-Golgi stress. J Neurosci 22:10751–10760PubMedGoogle Scholar
  49. 49.
    Inuzuka M, Hayakawa M, Ingi T (2005) Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis. J Biol Chem 280:35776–35783PubMedCrossRefGoogle Scholar
  50. 50.
    Lebel M, Mes-Masson AM (1994) Sequence analysis of a novel cDNA which is overexpressed in testicular tumors from polyomavirus large T-antigen transgenic mice. DNA Seq 5:31–39PubMedCrossRefGoogle Scholar
  51. 51.
    Bossolasco M, Lebel M, Lemieux N et al (1999) The human TDE gene homologue: localization to 20q13.1-13.3 and variable expression in human tumor cell lines and tissue. Mol Carcinog 26:189–200PubMedCrossRefGoogle Scholar
  52. 52.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedGoogle Scholar
  53. 53.
    Folkman J, Watson K, Ingber D et al (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61PubMedCrossRefGoogle Scholar
  54. 54.
    Folkman J (1986) How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res 46:467–473PubMedGoogle Scholar
  55. 55.
    Blood CH, Zetter BR (1990) Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta 1032:89–118PubMedGoogle Scholar
  56. 56.
    Fett JW, Strydom DJ, Lobb RR et al (1985) Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24:5480–5486PubMedCrossRefGoogle Scholar
  57. 57.
    Li D, Bell J, Brown A et al (1994) The observation of angiogenin and basic fibroblast growth factor gene expression in human colonic adenocarcinomas, gastric adenocarcinomas, and hepatocellular carcinomas. J Pathol 172:171–175PubMedCrossRefGoogle Scholar
  58. 58.
    Montero S, Guzman C, Cortes-Funes H et al (1998) Angiogenin expression and prognosis in primary breast carcinoma. Clin Cancer Res 4:2161–2168PubMedGoogle Scholar
  59. 59.
    Majumder PK, Yeh JJ, George DJ et al (2003) Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci USA 100:7841–7846PubMedCrossRefGoogle Scholar
  60. 60.
    Chopra V, Dinh TV, Hannigan EV (1998) Circulating serum levels of cytokines and angiogenic factors in patients with cervical cancer. Cancer Invest 16:152–159PubMedCrossRefGoogle Scholar
  61. 61.
    Shimoyama S, Shimizu N, Tsuji E et al (2002) Distribution of angiogenin and its gene message in colorectal cancer patients and their clinical relevance. Anticancer Res 22:1045–1052PubMedGoogle Scholar
  62. 62.
    Chopra V, Dinh TV, Hannigan EV (1997) Serum levels of interleukins, growth factors and angiogenin in patients with endometrial cancer. J Cancer Res Clin Oncol 123:167–172PubMedGoogle Scholar
  63. 63.
    Shimoyama S, Kaminishi M (2000) Increased angiogenin expression in gastric cancer correlated with cancer progression. J Cancer Res Clin Oncol 126:468–474PubMedCrossRefGoogle Scholar
  64. 64.
    Wechsel HW, Bichler KH, Feil G et al (1999) Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res 19:1537–1540PubMedGoogle Scholar
  65. 65.
    Barton DP, Cai A, Wendt K et al (1997) Angiogenic protein expression in advanced epithelial ovarian cancer. Clin Cancer Res 3:1579–1586PubMedGoogle Scholar
  66. 66.
    Shimoyama S, Gansauge F, Gansauge S et al (1996) Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness. Cancer Res 56:2703–2706PubMedGoogle Scholar
  67. 67.
    Miyake H, Hara I, Yamanaka K et al (1999) Increased angiogenin expression in the tumor tissue and serum of urothelial carcinoma patients is related to disease progression and recurrence. Cancer 86:316–324PubMedCrossRefGoogle Scholar
  68. 68.
    Maeda K, Nomata K, Noguchi M et al (2001) Angiogenin expression in superficial bladder cancer. Hinyokika Kiyo 47:547–552PubMedGoogle Scholar
  69. 69.
    Eberle K, Oberpichler A, Trantakis C et al (2000) The expression of angiogenin in tissue samples of different brain tumours and cultured glioma cells. Anticancer Res 20:1679–1684PubMedGoogle Scholar
  70. 70.
    Verstovsek S, Kantarjian H, Aguayo A et al (2001) Significance of angiogenin plasma concentrations in patients with acute myeloid leukaemia and advanced myelodysplastic syndrome. Br J Haematol 114:290–295PubMedCrossRefGoogle Scholar
  71. 71.
    Park YW, Kim SM, Min BG et al (2002) Lymphangioma involving the mandible: immunohistochemical expressions for the lymphatic proliferation. J Oral Pathol Med 31:280–283PubMedCrossRefGoogle Scholar
  72. 72.
    Hartmann A, Kunz M, Kostlin S et al (1999) Hypoxia-induced up-regulation of angiogenin in human malignant melanoma. Cancer Res 59:1578–1583PubMedGoogle Scholar
  73. 73.
    Skoldenberg EG, Christiansson J, Sandstedt B et al (2008) Angiogenesis and angiogenic growth factors in Wilms tumor. J Urol 165:2274–2279CrossRefGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2009

Authors and Affiliations

  • Sanjeet G. Patel
    • 1
  • Guisheng Zhou
    • 1
  • Shi-He Liu
    • 1
  • Min Li
    • 1
  • Jae-Wook Jeong
    • 2
  • Francesco J. DeMayo
    • 2
  • Marie-Claude Gingras
    • 3
  • Richard A. Gibbs
    • 3
  • William E. Fisher
    • 1
  • F. Charles Brunicardi
    • 1
    Email author
  1. 1.The Michael E. DeBakey Department of SurgeryBaylor College of MedicineHoustonUSA
  2. 2.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA
  3. 3.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA

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