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Ghrelin Expression in Islet Cell Tumors: Augmented Expression of Ghrelin in a Case of Glucagonoma with Multiple Endocrine Neoplasm Type I

Departments of Medicine and Clinical Science (H.I., K.H., C.S., J.F., T.T., K.T., Y.O., T.H., G.I., T.A., K.N.) and Surgery and Surgical Basic Science (R.D., I.K., M.I.), Kyoto University Graduate School of Medicine, Kyoto 606-8507; Department of Life Science (K.H.), Kyoto University Graduate School of Human and Environmental Studies, Kyoto 606-8501; Department of Diabetes and Endocrinology (H.N.), Osaka Saiseikai Nakatsu Hospital, Osaka 530-0012; and Department of Biochemistry (H.H., M.K., K.K.), National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Kiminori Hosoda, M.D., Ph.D., Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: kh{at}kuhp.kyooto-u.ac.jp.

Abstract

Ghrelin is a 28-amino acid peptide that regulates GH release together with GHRH and somatostatin. The expression of ghrelin has been detected in the stomach, small intestine, hypothalamus, pituitary gland, kidney, placenta, and testis. Recently it was reported that ghrelin is present in pancreatic -cells and that it stimulates insulin secretion. In this study, we examined the ghrelin expression in two cases of glucagonoma and two cases of insulinoma by Northern blot analysis and immunohistochemistry. Ghrelin expression was identified in a case of glucagonoma associated with multiple endocrine neoplasm type I both by Northern blot analysis using total RNA and by immunohistochemistry, although the plasma ghrelin level was not elevated. This is the first case of tumor in which ghrelin gene expression was detected by Northern blot analysis using total RNA.

GHRELIN IS A 28-AMINO acid peptide with unique modification of acylation, which is essential for its biological action (1). Ghrelin was identified in rat stomach as an endogenous ligand for an orphan receptor, which has been so far called GH secretagogue receptor (1). Ghrelin expression is detected in the gastric oxyntic gland, intestine, hypothalamus, pituitary gland, kidney, placenta, and testis (2, 3, 4, 5, 6). Ghrelin is involved in the regulation of GH release, food intake, gastric acid secretion, gastric motility, blood pressure, and cardiac output (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21).

The ghrelin gene expression has been reported in pituitary adenoma, thyroid tumor, and pancreatic and gastrointestinal endocrine tumors (5, 22, 23, 24, 25). The ghrelin gene expression was detected not by Northern blot analysis but by RT-PCR in these reports. Recently Date et al. (26) reported that ghrelin was present in -cells of normal pancreatic islet. Therefore, we examined the ghrelin expression in four cases of islet tumors including two cases of glucagonoma and two cases of insulinoma by Northern blot analysis, RT-PCR, and immunohistochemistry.

Subjects and Methods

Subjects

We studied four cases of islet cell tumors consisting of two cases of glucagonoma and two cases of insulinoma. The diagnoses of glucagonoma and insulinoma were made by abdominal computed tomographic analysis and inappropriate elevation of serum glucagon or insulin level. Among them, one case of glucagonoma and one case of insulinoma were with multiple endocrine neoplasm type I (MEN I). These two patients had family histories of MEN I. All four patients underwent tumoral nucleation. Normal portion of stomach and pancreas of patients with gastric and pancreatic cancers obtained at surgery were used as control samples. The studies conform to the policy of the ethical committee on human research of Kyoto University Graduate School of Medicine. Informed consent was obtained from all subjects.

Methods

Northern blot analysis and RT-PCR. When samples were obtained at surgery, they were immediately frozen in liquid nitrogen and stored at -80 C until use. Total RNA was extracted from tumor samples with TRIZOL reagent (Invitrogen, Carlsbad, CA) (27). Filters containing 20 µg total RNA were prepared (27). The density of 18S rRNA stained with ethidium bromide was used to monitor the amount of total RNA in each lane (27). Northern blot analyses were performed as described previously (27), using the full length of human preproghrelin cDNA and human ß-actin cDNA (CLONTECH Laboratories, Inc., Palo Alto, CA) as a probe. As a positive control, RNA from the normal part of the stomach with gastric cancer was used. RT-PCR was performed with oligo (dT)₁₅ primer and SuperScript II reverse transcriptase (Invitrogen). The following primers were used: human preproghrelin sense, 5'-AAGGAGTCGAAGAAGCCACCA-3'; antisense, 5'-GCCAGATGAGCGCTTCTAAACTTA-3'. The annealing temperature was 58 C and cycles of PCR were 40.

Immunohistochemistry. The surgical specimen was fixed in 10% formalin and embedded in paraffin blocks. Formalin-fixed, paraffin-embedded tissue sections were immunostained using the avidin-biotin peroxidase complex method (Vectastain ABC Elite kit; Vector Laboratories, Burlingame, CA). Deparaffinized and rehydrated sections were pretreated with 0.3% hydrogen peroxide for 30 min and 10% normal goat serum for 30 min. Then, sections were incubated for 16 h at 4 C with antighrelin (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) antiserum (1) at 1:1000 final dilution, or antiglucagon antiserum (DAKO Corp., Glostrup, Denmark) at 1:500 dilution. Nonimmune rabbit serum was used for negative controls. Incubation with biotinylated goat antirabbit immunoglobulin (1:250) was carried out for 40 min and with avidin-biotin horseradish peroxidase complex for 50 min. To visualize the peroxidase activities in sections, diaminobenzidine tetrahydrochloride was used.

Measurements of plasma ghrelin. Blood was withdrawn from antecubital vein, immediately transferred to chilled siliconized glass tubes containing Na₂EDTA (1 mg/ml) and aprotinin (1000 KIU/ml; Ohkura Pharmaceutical, Kyoto, Japan), and centrifuged at 4 C. Plasma was immediately frozen and stored at -20 C until assay. One milliliter of separated plasma was loaded onto a Sep-Pak C18 cartridge (Waters, Milford, MA) preequilibrated with 0.9% NaCl. The cartridge was washed with 3.0 ml 5% CH₃CN/0.1% trifluoroacetic acid and eluted with 3.0 ml 60% CH₃CN/0.1% trifluoroacetic acid. The eluate was evaporated, lyophilized, and dissolved in RIA buffer [50 mM sodium phosphate buffer (pH 7.4), 0.5% BSA, 0.5% Triton X-100, 80 mM NaCl, 25 mM Na₂EDTA, and 0.05% NaN₃]. The RIA was carried out by using [¹²⁵I]-labeled ghrelin and the double antibody method with antighrelin (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) antiserum as described previously (28).

Results and Discussion

We examined the ghrelin gene expression in four cases of islet cell tumors (Table 1) by Northern blot analysis with 20 µg total RNA. Ghrelin mRNA was detected in only patient 1 with glucagonoma with a size of 0.62 kb, which was the same as that in stomach of the control subject (Fig. 1). Ghrelin mRNA level in this tumor was approximately as abundant as that in the antrum of the stomach. The expression of ghrelin mRNA was not detected in patient 2 with glucagonoma, the two patients with insulinoma, or the normal portion of the pancreas by Northern blot analysis with 20 µg total RNA. We confirmed that approximately equal amount of total RNA was assayed in Northern blot hybridization analysis by checking density of 18S rRNA in the gel and signal of ß-actin in each lane (data not shown). The ghrelin gene expression was detected in all cases by RT-PCR as the same size as that in the stomach (Fig. 2). RT-PCR appeared to be able to detect much lower levels of ghrelin mRNA than Northern blot analysis with total RNA of 20 µg. This is supported by our previous observation (23) that the ghrelin gene expression in total human thyroid was not detectable by Northern blot analysis with polyadenylated RNA of 2.5 µg at all but by RT-PCR. There may be biological significance in the ghrelin gene expression of patient 1 with glucagonoma, which was detected by Northern blot analysis with total RNA of 20 µg.

View larger version (82K): [in this window] [in a new window]   Figure 1. Northern blot analysis of four cases of islet cell tumors. A, Ghrelin mRNA expression. Each lane contains 20 µg total RNA. Lane1, Normal antrum; lane 2, normal fundus; lane 3, normal antrum; lane 4, normal fundus; lane 5, normal pancreas; lane 6, patient 1 insulinoma; lane 7, patient 2 insulinoma; lane 8, patient 1 glucagonoma. B, Ghrelin mRNA expression. Lane 1, Normal antrum; lane 2, normal fundus; lane 3, patient 1 glucagonoma; lane 4, patient 2 glucagonoma. C, Glucagon mRNA expression in the same sheet of B. Lane 1, Normal antrum; lane 2, normal fundus; lane 3, patient 1 glucagonoma; lane 4, patient 2 glucagonoma.

View larger version (10K): [in this window] [in a new window]   Figure 2. The ghrelin mRNA expression by RT-PCR. Lane 1, Patient 1 glucagonoma; lane 2, patient 1 glucagonoma RT (-); lane 3, patient 2 glucagonoma; lane 4, patient 2 glucagonoma RT (-); lane 5, patient 1 insulinoma; lane 6, patient 1 insulinoma RT (-); lane 7, patient 2 insulinoma; lane 8, patient 2 insulinoma RT (-).

View larger version (116K): [in this window] [in a new window]   Figure 3. Immunohistochemistry of ghrelin in patient 2 with glucagonoma. A, Ghrelin-like immunoreactivity was observed in nearly all tumor cells in patient 1 glucagonoma. B, Preabsorption of ghrelin reduced ghrelin-like immunoreactivity. C, Glucagon-like immunoreactivity in patient 1 glucagonoma. D, No ghrelin-like immunoreactivity was observed in patient 2 with glucagonoma.

In the present study, ghrelin mRNA was detected in one patient with glucagonoma but not in the second patient with glucagonoma by Northern blot analysis with 20 µg total RNA. In immunohistochemical study, ghrelin-like immunoreactivity was demonstrated in tumor cells of the patient with glucagonoma but not in those of the second patient with glucagonoma (Fig. 3). The mechanism of variation of the ghrelin gene expression between the two patients is unclear at present. It may be explained by association of MEN I with ghrelin production, Because MEN I is noted only in patient 1 but not in patient 2. Alternatively, the discrepancy between two cases of glucagonoma can be explained by the different nature of tumor cells in these two cases of glucagonoma. Patient 1 with glucagonoma is small solitary adenoma without metastasis, and patient 2 with glucagonoma had metastasis to liver, indicating that patient 2 with glucagonoma is less differentiated, compared with patient 1 with glucagonoma, which may explain the difference of ghrelin expression between these patients. Because we studied only two patients with glucagonoma, further study will be needed to elucidate the relationship between production of ghrelin and MEN I.

In this patient 1 with glucagonoma, although the fasting plasma insulin levels were in normal range, insulin hypersecretion was observed in a 75-g oral glucose tolerance test (OGTT) (Table 2). This hypersecretion was not observed after tumor resection. Recently Date et al. (26) reported that ghrelin increases insulin secretion from the isolated rat islets in the presence of 8.3 mmol/ml glucose but not in 2.8 mmol/ml glucose. Although increased glucagon levels may be mainly responsible for hypersecretion of insulin on OGTT, possible local increase of ghrelin secreted from glucagonoma may also contribute to it.

In conclusion, we reported the ghrelin-expressing glucagonoma, which was associated with MEN I. Although the expression of ghrelin in pancreatic endocrine tumors has been reported, the expression levels were as low as can be detected by only RT-PCR (5). In our case, the expression of ghrelin was detected by Northern blot analysis with total RNA of 20 µg. Further search for glucagonoma with increased levels of circulating ghrelin will contribute for the understanding of the pathophysiological significance of ghrelin.

Acknowledgments

Footnotes

Abbreviation: MEN I, Multiple endocrine neoplasm type I.

Received June 5, 2002.

Accepted August 13, 2002.

References

1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660[CrossRef][Medline]
2. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M 2000 Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141:4255–4261[Abstract/Free Full Text]
3. Gualillo O, Caminos JE, Blanco M, Garcia-Caballero T, Kojima M, Kangawa K, Dieguez C, Casanueva FF 2001 Ghrelin, a novel placental-derived hormone. Endocrinology 142:788–794[Abstract/Free Full Text]
4. Mori K, Yoshimoto A, Takaya K, Hosoda K, Ariyasu H, Yahata K, Mukoyama M, Sugawara A, Hosoda H, Kojima M, Kangawa K, Nakao K 2000 Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 486:213–216[CrossRef][Medline]
5. Korbonits M, Bustin SA, Kojima M, Jordan S, Adams EF, Lowe DG, Kangawa K, Grossman AB 2001 The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab 86:881–887[Abstract/Free Full Text]
6. Tena-Sempere M, Barreiro ML, Gonzalez LC, Gaytan F, Zhang FP, Caminos JE, Pinilla L, Casanueva FF, Dieguez C, Aguilar E 2002 Novel expression and functional role of ghrelin in rat testis. Endocrinology 143:717–725[Abstract/Free Full Text]
7. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M 2001 ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345[CrossRef][Medline]
8. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K 2000 Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276:905–908[CrossRef][Medline]
9. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K 2001 Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:227–232[Abstract/Free Full Text]
10. Seoane LM, Tovar S, Baldelli R, Arvat E, Ghigo E, Casanueva FF, Dieguez C 2000 Ghrelin elicits a marked stimulatory effect on GH secretion in freely moving rats. Eur J Endocrinol 143:R7–R9
11. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K 2000 Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 85:4908–4911[Abstract/Free Full Text]
12. Peino R, Baldelli R, Rodriguez-Garcia J, Rodriguez-Segade S, Kojima M, Kangawa K, Arvat E, Ghigo E, Dieguez C, Casanueva FF 2000 Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol 143:R11–R14
13. Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E 2000 Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 23:493–495[Medline]
14. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K, Nakazato M 2000 Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun 275:477–480[CrossRef][Medline]
15. Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S 2001 Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 280:904–907[CrossRef][Medline]
16. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K 2001 Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280:R1483–R1487
17. Tschop M, Smiley DL, Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407:908–913[CrossRef][Medline]
18. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR 2000 The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141:4325–4328[Abstract/Free Full Text]
19. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M 2001 Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345
20. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S 2001 A role for ghrelin in the central regulation of feeding. Nature 409:194–198[CrossRef][Medline]
21. Inui A 2001 Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2:551–560[CrossRef][Medline]
22. Papotti M, Cassoni P, Volante M, Deghenghi R, Muccioli G, Ghigo E 2001 Ghrelin-producing endocrine tumors of the stomach and intestine. J Clin Endocrinol Metab 86:5052–5059[Abstract/Free Full Text]
23. Kanamoto N, Akamizu T, Hosoda H, Hataya Y, Ariyasu H, Takaya K, Hosoda K, Saijo M, Moriyama K, Shimatsu A, Kojima M, Kangawa K, Nakao K 2001 Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. J Clin Endocrinol Metab 86:4984–4990[Abstract/Free Full Text]
24. Korbonits M, Kojima M, Kangawa K, Grossman AB 2001 Presence of ghrelin in normal and adenomatous human pituitary. Endocrine 14:101–104[CrossRef][Medline]
25. Volante M, AllIa E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E, Papotti M 2002 Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 87:1300–1308[Abstract/Free Full Text]
26. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T, Matsukura S 2002 Ghrelin is present in pancreatic -cells of humans and rats and stimulates insulin secretion. Diabetes 51:124–129[Abstract/Free Full Text]
27. Matsuda J, Hosoda K, Itoh H, Son C, Doi K, Hanaoka I, Inoue G, Nishimura H, Yoshimasa Y, Yamori Y, Odaka H, Nakao K 1998 Increased adipose expression of the uncoupling protein-3 gene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes. Diabetes 47:1809–1814[Abstract]
28. Hosoda H, Kojima M, Matsuo H, Kangawa K 2000 Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279:909–913[CrossRef][Medline]
29. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K 2001 Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 86:4753–4758[Abstract/Free Full Text]
30. Kojima M, Hosoda H, Matsuo H, Kangawa K 2001 Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 12:118–122[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iwakura, H. Articles by Nakao, K. Search for Related Content PubMed PubMed Citation Articles by Iwakura, H. Articles by Nakao, K.