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SST; somatostatin (3q28)

Gene Summary

Gene:SST; somatostatin
Aliases: SMST
Location:3q28
Summary:The hormone somatostatin has active 14 aa and 28 aa forms that are produced by alternate cleavage of the single preproprotein encoded by this gene. Somatostatin is expressed throughout the body and inhibits the release of numerous secondary hormones by binding to high-affinity G-protein-coupled somatostatin receptors. This hormone is an important regulator of the endocrine system through its interactions with pituitary growth hormone, thyroid stimulating hormone, and most hormones of the gastrointestinal tract. Somatostatin also affects rates of neurotransmission in the central nervous system and proliferation of both normal and tumorigenic cells. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:somatostatin
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (18)

Pathways:

What pathways are this gene/protein implicaed in?
- Ghrelin BIOCARTA
- Neuroactive ligand-receptor interaction KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Carcinoma, Medullary
  • Pancreatic Cancer
  • RTPCR
  • Receptors, Somatostatin
  • Messenger RNA
  • Somatostatin
  • Chromosome 3
  • Transcription
  • Octreotide
  • Tumor Markers
  • Nucleic Acid Hybridization
  • Cancer Gene Expression Regulation
  • Cell Line
  • DNA Methylation
  • DNA
  • Stomach Cancer
  • Neuroendocrine Tumors
  • Teratocarcinoma
  • Gastrointestinal Cancers
  • Cell Proliferation
  • Pituitary Tumors
  • Adenoma
  • Molecular Sequence Data
  • Base Sequence
  • Virus Replication
  • Kinetics
  • Adenocarcinoma
  • Prostate Cancer
  • Amino Acid Sequence
  • Brain Tumours
  • Promoter Regions
  • In Situ Hybridization
  • Substance P
  • Oligonucleotide Array Sequence Analysis
  • Antineoplastic Agents, Hormonal
  • Protein Precursors
  • Immunohistochemistry
  • Gene Expression
  • Thymidine
  • Brain Tumours
  • Somatostatinoma
  • Glucagon
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (6)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
-Therapeutic use of Somatostatin and Somatostatin Analogues View Publications310
Brain Tumours, ChildhoodSST and Brain Tumours View Publications8
Gastrointestinal CancersSST and Gastrointestinal Cancers View Publications5
Stomach CancerSST and Stomach Cancer View Publications4
Pancreatic CancerSST and Pancreatic Cancer View Publications2
Prostate CancerSST and Prostate Cancer View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: SST (cancer-related)

Tulassay Z
[Editor's commentary: Clinical use of somatostatin].
Orv Hetil. 2013; 154(39):1526 [PubMed] Related Publications


Lécolle K, Bégard S, Caillierez R, et al.
Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors.
Gene Ther. 2013; 20(3):283-97 [PubMed] Related Publications
Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (ii) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors.


Lyons J, Anthony CT, Woltering EA
The role of angiogenesis in neuroendocrine tumors.
Endocrinol Metab Clin North Am. 2010; 39(4):839-52 [PubMed] Related Publications
The first studies to assess in vitro angiogenesis in neuroendocrine tumors used animal-based assays to study the antiangiogenic properties of somatostatin analogs. Current technologies enable investigators to directly appraise the in vitro angiogenic response of an individual's neuroendocrine tumor with and without potential antiangiogenic reagents. This article describes the evolution of methods to assess in vitro angiogenesis in neuroendocrine tumors and describes some of the clinical data.

Related: Angiogenesis Inhibitors Angiogenesis and Cancer


Jackson K, Soutto M, Peng D, et al.
Epigenetic silencing of somatostatin in gastric cancer.
Dig Dis Sci. 2011; 56(1):125-30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, has potent antitumor and anti-secretory activity in several human cancers.
AIMS: This study was performed to investigate the SST gene expression levels and possible epigenetic mechanisms that regulate expression of SST in gastric adenocarcinomas.
METHODS: Quantitative real-time (RT)-PCR and quantitative bisulfite pyrosequencing were used to study primary gastric cancer tissue samples and cell lines.
RESULTS: Quantitative RT-PCR analysis revealed down-regulation of the SST transcript in 93% of gastric carcinoma samples (30/32), compared with 21 normal samples (P<0.001). Because of the presence of a large CpG island in the SST promoter, we next examined its promoter DNA methylation levels by use of quantitative bisulfite pyrosequencing. The results revealed a significant increase in SST promoter DNA methylation in tumor samples compared with normal samples (P<0.05). Promoter DNA hypermethylation and silencing of SST was also detected in seven gastric cancer cell lines that we tested. To confirm the role of promoter DNA methylation as an epigenetic mechanism regulating SST expression, AGS gastric cancer cells were treated with 5-Aza-dc. This treatment led to reduction of promoter DNA methylation levels of SST accompanied by restoration of its mRNA expression.
CONCLUSIONS: Our results indicate that promoter DNA methylation levels play a critical role in regulating SST expression in gastric cancer. This finding provides a foundation for further studies on the role of SST in gastric carcinogenesis and its potential as a biomarker for gastric cancers.

Related: Azacitidine Stomach Cancer Gastric Cancer


Strosberg J, Kvols L
Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors.
World J Gastroenterol. 2010; 16(24):2963-70 [PubMed] Free Access to Full Article Related Publications
Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.

Related: Gastrointestinal System Cancers Cancer of the Pancreas Pancreatic Cancer Signal Transduction


Zhang X, Yang JJ, Kim YS, et al.
An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer.
Int J Oncol. 2010; 36(2):405-14 [PubMed] Related Publications
We have identified an 8-gene signature with significant expression differences between gastric cancer and normal gastric tissues. This 8-gene set can predict the normal and cancer status of gastric tissues with more than 96% accuracy in a totally independent microarray dataset. The 8 genes are composed of down-regulated KLF4, GPX3, SST and LIPF, together with up-regulated SERPINH1, THY1 and INHBA in gastric cancer. To corroborate the differential gene expression pattern, we chose GPX3 and examined its expression pattern in detail. A comparison of GPX3 expression pattern shows a broader down-regulated pattern in multiple types of cancers, including cervical, thyroid, head and neck, lung cancers and melanoma than in healthy controls. An immuno-histostaining analysis in tissue microarrays confirms GPX3 down-regulation in gastric cancer. Mechanism-wise GPX3 down-regulation in gastric cancer is due to promoter hypermethylation. Collectively, these results show a correct identification of 8 genes as gastric cancer biomarkers.

Related: Stomach Cancer Gastric Cancer


Kang JU, Koo SH, Kwon KC, et al.
Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.
BMC Cancer. 2009; 9:237 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The underlying genetic alterations for squamous cell carcinoma (SCC) and adenocarcinoma (AC) carcinogenesis are largely unknown.
METHODS: High-resolution array- CGH was performed to identify the differences in the patterns of genomic imbalances between SCC and AC of non-small cell lung cancer (NSCLC).
RESULTS: On a genome-wide profile, SCCs showed higher frequency of gains than ACs (p = 0.067). More specifically, statistically significant differences were observed across the histologic subtypes for gains at 2q14.2, 3q26.2-q29, 12p13.2-p13.33, and 19p13.3, as well as losses at 3p26.2-p26.3, 16p13.11, and 17p11.2 in SCC, and gains at 7q22.1 and losses at 15q22.2-q25.2 occurred in AC (P < 0.05). The most striking difference between SCC and AC was gains at the 3q26.2-q29, occurring in 86% (19/22) of SCCs, but in only 21% (3/14) of ACs. Many significant genes at the 3q26.2-q29 regions previously linked to a specific histology, such as EVI1,MDS1, PIK3CA and TP73L, were observed in SCC (P < 0.05). In addition, we identified the following possible target genes (> 30% of patients) at 3q26.2-q29: LOC389174 (3q26.2),KCNMB3 (3q26.32),EPHB3 (3q27.1), MASP1 and SST (3q27.3), LPP and FGF12 (3q28), and OPA1,KIAA022,LOC220729, LOC440996,LOC440997, and LOC440998 (3q29), all of which were significantly targeted in SCC (P < 0.05). Among these same genes, high-level amplifications were detected for the gene, EPHB3, at 3q27.1, and MASP1 and SST, at 3q27.3 (18, 18, and 14%, respectively). Quantitative real time PCR demonstrated array CGH detected potential candidate genes that were over expressed in SCCs.
CONCLUSION: Using whole-genome array CGH, we have successfully identified significant differences and unique information of chromosomal signatures prevalent between the SCC and AC subtypes of NSCLC. The newly identified candidate target genes may prove to be highly attractive candidate molecular markers for the classification of NSCLC histologic subtypes, and could potentially contribute to the pathogenesis of the squamous cell carcinoma of the lung.

Related: Non-Small Cell Lung Cancer Chromosome 3 Lung Cancer EPHB3


Johansson M, McKay JD, Wiklund F, et al.
Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk.
Cancer Epidemiol Biomarkers Prev. 2009; 18(5):1644-50 [PubMed] Related Publications
BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels.
MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC).
RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels.
CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk.

Related: IGF1 Prostate Cancer


Pasquali D, Rossi V, Conzo G, et al.
Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells.
J Mol Endocrinol. 2008; 40(6):263-71 [PubMed] Related Publications
Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor(1-5) mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10(-6) M and SOM230 10(-7) M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.

Related: Apoptosis CASP3


Jin Z, Mori Y, Hamilton JP, et al.
Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis.
Cancer. 2008; 112(1):43-9 [PubMed] Related Publications
BACKGROUND: The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis.
METHODS: SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC).
RESULTS: SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05).
CONCLUSIONS: SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus.

Related: Azacitidine Cancer of the Esophagus Esophageal Cancer


Resmini E, Dadati P, Ravetti JL, et al.
Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient.
J Clin Endocrinol Metab. 2007; 92(5):1592-9 [PubMed] Related Publications
CONTEXT: Criteria to define the response to somatostatin (SS) analogs (SSA) in acromegaly are based on biochemical control of the disease. However, the mechanisms of action of SSAs in inhibiting tumor growth and hormonal secretion are only partially understood, and the two effects may occur independently.
OBJECTIVE: The objective of the study was to investigate the dissociation between antiproliferative and antisecretive effects of SSA in an octreotide-resistant patient displaying dramatic tumor shrinkage during primary therapy with octreotide LAR.
DESIGN AND SETTING: We characterized somatostatin and dopamine D(2) receptor expression by immunohistochemistry and real-time RT-PCR. The effects of different receptor-selective, bispecific analogs, and chimeric somatostatin/dopamine compounds on GH secretion and cell proliferation in primary cell cultures of the tumor were assessed.
RESULTS: The expression of SS receptor subtypes (sst)(5) and D(2) receptor was higher, compared with the other receptor subtypes. GH inhibition by SS-14 and the two chimeric somatostatin/dopamine compounds was scant but greater than subtype-selective and sst(2)/sst(5) bispecific agonists. Conversely, cell growth was potently inhibited by all test substances. However, SS-14, sst(2)/sst(5) bispecific agonist, and chimeric molecules were more potent than the other compounds.
CONCLUSIONS: The significant antiproliferative effect of octreotide seems to be related to the higher expression of sst(5) and the negligible antihormonal effect to the lower expression of sst(2). However, activation of multiple receptors by new analogs may produce better control of tumor cell activities. The dissociation between antisecretive and antiproliferative effects observed in vivo and in vitro confirms that SSAs may induce tumor shrinkage despite the lack of effect on GH secretion.

Related: IGF1 Pituitary Tumors


Judd LM, Bredin K, Kalantzis A, et al.
STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis.
Gastroenterology. 2006; 131(4):1073-85 [PubMed] Related Publications
BACKGROUND & AIMS: The gp130(757F/F) mouse is a well-characterized and robust model of distal gastric tumorigenesis displaying many of the characteristics of human intestinal type gastric cancer. Key to the development of tumors in this model, and in many examples of human tumor development, is hyperactivation of the transcription factor STAT3. This study addressed the requirement for STAT3 activation in tumor initiation and characterized some of the genes downstream of STAT3 required for tumor development. Furthermore, the interaction among STAT3, the microbial environment, and tumorigenesis was evaluated.
METHODS: The role of STAT3 in gastric tumor development was assessed in detail in gp130(757F/Y757F):STAT3(+/-) mice displaying reduced STAT3 activity. Tumor size was quantified morphologically, and the effects on endocrine cell populations, neovascularization, and inflammatory cell infiltration as well as the outcome of STAT3 activation on transcription of a number of genes relevant in growth and inflammation were quantified.
RESULTS: Loss of one STAT3 allele in gp130(757F/F) mice reduced the frequency and rate of tumor development because of inhibition of proliferation-induced glandular hyperplasia. There was also a concomitant reduction in the degree of inflammatory infiltration and cytokine and chemokine expression, angiogenesis, and expression of metalloproteinases and growth factors. Antimicrobial treatment of gp130(757F/F) mice slowed tumor growth coincident with reduced macrophage and neutrophil infiltration.
CONCLUSIONS: Activation of STAT3 and the microbial environment are pivotal for gastric tumor initiation and development in the gp130(757F/F) mouse, thus supporting the notion that STAT3 activation may play a role in human gastric cancer development.

Related: Angiogenesis and Cancer Stomach Cancer Gastric Cancer


Mori Y, Cai K, Cheng Y, et al.
A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer.
Gastroenterology. 2006; 131(3):797-808 [PubMed] Related Publications
BACKGROUND & AIMS: Gene silencing via promoter hypermethylation is a central event in the pathogenesis of cancers. To identify novel methylation targets in colon cancer, we conducted a genome-wide, microarray-based, in silico, and epigenetic search.
METHODS: Complementary DNA microarray experiments were first performed to identify genes down-regulated in primary colon cancers and up-regulated in colon cancer cell lines after global DNA demethylation by 5-aza-2'-deoxycitidine. Candidate methylation targets were then identified by combining these microarray data with in silico genetic and functional searches. Candidate genes recognized by these searches were further investigated for promoter hypermethylation in colon cancer using methylation-specific polymerase chain reaction.
RESULTS: We identified 51 novel and 3 known candidate methylation targets. Subsequent epigenetic analysis revealed that primary colon cancers demonstrated frequent methylation of somatostatin (SST, 30 of 34 cases, 88%) and the substance P precursor gene tachykinin-1 (TAC1; 16 of 34 cases, 47%). TAC1 methylation intensity was significantly higher in Dukes A/B than in Dukes C/D cancers (P = .01). SST methylation intensity was significantly higher in low-level microsatellite instability (MSI-L) than in non-MSI-L cancers (P = .02). Methylation was associated with messenger RNA down-regulation for both SST and TAC1. Furthermore, we isolated 5 additional novel promoter methylation targets: NELL1, AKAP12, caveolin-1, endoglin, and MAL.
CONCLUSIONS: These data strongly suggest that SST and TAC1 are involved in colon carcinogenesis. Further studies are now indicated to elucidate mechanisms underlying their involvement in colon cancer and their values as clinical biomarkers. NELL1, AKAP12, caveolin-1, endoglin, and MAL are also promising tumor suppressor gene candidates deserving of further study.


Engel JB, Schally AV, Halmos G, et al.
Targeted therapy with a cytotoxic somatostatin analog, AN-238, inhibits growth of human experimental endometrial carcinomas expressing multidrug resistance protein MDR-1.
Cancer. 2005; 104(6):1312-21 [PubMed] Related Publications
BACKGROUND: Chemoresistance mediated by membrane transporters such as multidrug resistance (MDR-1) glycoprotein remains a challenge in the chemotherapy treatment of advanced or recurrent endometrial carcinoma. Targeted chemotherapy might overcome this resistance. The cytotoxic somatostatin (SST) analog, AN-238, consists of a superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to the SST analog carrier, RC-121. This conjugate binds strongly to SST receptor subtypes (sst) 2a (sst2(a)) and 5 (sst(5)) and can be targeted to tumors that express these receptors.
METHODS: The presence of sst2(a) and sst(5) was determined in 3 human endometrial carcinoma cell lines (HEC-1A, RL-95-2, and AN3CA). Nude mice bearing xenografts of these cancers were treated with AN-238 and its radical, AN-201. The antitumor effects and toxicity were compared. The authors studied the effects of AN-238 and AN-201 on the expression levels of MDR-1, multidrug resistance related protein (MRP-1), and breast carcinoma resistance protein (BCRP) by real-time polymerase chain reaction.
RESULTS: The authors demonstrated the presence of mRNA and receptor protein for sst(2a) and sst(5) on HEC-1A, RL-95-2, and AN3CA tumors. AN-238 significantly (P < 0.05) inhibited the growth of these tumors, whereas AN-201 had no effect. Blockade of SST receptors nullified the effects of AN-238. In all 3 endometrial carcinoma lines, AN-238 caused a weaker induction of MDR-1 than AN-201. No major induction of MRP-1 and BCRP occurred after treatment with AN-238 or AN-201.
CONCLUSIONS: Targeted chemotherapy with the cytotoxic SST analog, AN-238, inhibited powerfully the growth of endometrial carcinoma, which express SST receptors, regardless of their expression level of MDR-1.

Related: Doxorubicin Endometrial (Uterus) Cancer Endometrial Cancer ABCG2


Lasfer M, Vadrot N, Schally AV, et al.
Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238.
J Hepatol. 2005; 42(2):230-7 [PubMed] Related Publications
BACKGROUND/AIMS: The efficacy of a targeted cytotoxic hybrid somatostatin analogue AN-238 and of its superactive radical 2-pyrrolinodoxorubicin (AN-201) to induce apoptosis of HepG2 and Hep3B human hepatoma cell lines were studied. AN-238 was designed to selectively target tumor cells expressing somatostatin receptor subtypes (sst(s)). Its effects on HepG2 or Hep3B cells displaying or lacking tumor suppressor p53, respectively, were compared. Normal rat isolated hepatocytes were also tested.
METHODS: sst(s) were characterized by binding assays and RT-PCR. Cytotoxicity was quantified by flow cytometry. DNA fragmentation was studied by gel electrophoresis, PARP cleavage by Western blot and ROS formation using fluorescent probes.
RESULTS: Specific binding of iodinated RC-160 to HepG2 and Hep3B cells, and its displacement by AN-238 was characterized. mRNA for hsst(2A) was found in both cell lines. Flow cytometry showed a stronger effect of AN-238 than AN-201 to induce sub-G1 phase. DNA fragmentation, nuclear bodies, and PARP cleavage were observed. In addition, AN-238 increased formation of ROS more potently than AN-201. However, no inductions of DNA fragmentation by AN-201 or AN-238 were observed on rat hepatocytes.
CONCLUSIONS: Our results indicate that, in liver cancer, the cytotoxic somatostatin analogue AN-238 is a powerful agent that can induce apoptosis, through sst(s) and independently of p53.

Related: Apoptosis Doxorubicin Liver Cancer


Modlin IM, Kidd M, Hinoue T, et al.
Molecular strategies and 111in-labelled somatostatin analogues in defining the management of neuroendocrine tumour disease: a new paradigm for surgical management.
Surgeon. 2003; 1(3):137-43 [PubMed] Related Publications
This manuscript provides a gene-chip examination of gastric ECL cell proliferation in an animal model of neuroendocrine tumour disease. Data that were used to identify molecular targets were then utilised to develop novel therapeutic strategies as appropriate adjuncts to surgery in human disease. Alterations in growth-mediated cell signaling (the AP-1 pathway) and in the cell cycle were identified in ECL cell tumours in the animal model and confirmed in human tumour tissue. The growth-inhibitory somatostatin receptor subtype 2 was identified as a potential clinical target. An investigation of patients with neuroendocrine tumours treated using SSTR2 targeted radiotherapy [111In]pentetreotide producing encouraging preliminary results. Fifty-six per cent of patients with evaluable hormone markers demonstrated stable levels or a significant decrease in one or more measured markers. This data demonstrate that gene pathways recognised to be altered in an animal model of a human disease can be used to identify therapeutic agents. This approach was successfully used to discover novel strategies that can be both effective and appropriate adjuncts to surgery for patients with neuroendocrine tumour disease.


Davies JS, Holter JL, Knight D, et al.
Manipulating sorting signals to generate co-expression of somatostatin and eGFP in the regulated secretory pathway from a monocistronic construct.
J Mol Endocrinol. 2004; 33(2):523-32 [PubMed] Related Publications
Targeted overexpression of biologically active peptides represents a powerful approach to the functional dissection of neuroendocrine systems. However, the requirement to generate separate, biologically active and reporter molecules necessitates the use of internal ribosome entry site (IRES) technology, which often results in preferential translation of the second cistron. We report here a novel approach in which the proteolytic processing machinery of the regulated secretory pathway (RSP) has been exploited to generate multiple mature proteins from a monocistronic construct that encodes a single precursor. This was achieved by duplication of the pre-pro cleavage sites in pre-prosomatostatin cDNA. The duplicated site included 10 flanking amino acids on either side of the Gly-Ala cleavage position. This enabled the incorporation of a foreign protein-coding sequence (in this case, enhanced green fluorescent protein (eGFP)) between these sites. The pre-eGFP-prosomatostatin (PEPS) construct generated co-localized expression of fully processed eGFP and somatostatin to the RSP of transiently transfected AtT20 cells. This approach represents an advance upon bicistronic and other extant approaches to the targeting of multiple, biologically active proteins to neuroendocrine systems, and, importantly, permits the co-expression of fluorescent markers with biologically active neuropeptides. In this study, our demonstration of the fusion of the first 10 amino acids of the prosomatostatin sequence to the N-terminus of eGFP shows that this putative sorting sequence is sufficient to direct expression to the RSP.

Related: Pituitary Tumors


Sinisi AA, Rossi V, Prezioso D, et al.
The role of somatostatin analogs in the management of prostate cancer.
J Endocrinol Invest. 2003; 26(8 Suppl):120-4 [PubMed] Related Publications


Related: Prostate Cancer


O'Driscoll L, Gammell P, Clynes M
Expression in murine teratocarcinoma F9 cells of transcription factors involved in pancreas development.
Transplant Proc. 2004; 36(4):1151-8 [PubMed] Related Publications
BACKGROUND: Although it has been established that formation and functional differentiation of the pancreas from embryonic endoderm is associated with activation/inactivation of many genes controlled by specific sets of transcription factors, the role and activation sequence of individual transcription factors has not yet been fully elucidated. This study sought to differentiate a murine teratocarcinoma cell line, F9, to endodermal-like cells and, subsequently; to investigate the effects of regulated expression of transcription factors in pancreas development.
METHODS: Following differentiation using retinoic acid and db cAMP (RAC), resulting F9 cells (F9-RAC) were transfected with cDNAs for PDX-1, ngn3, beta 2/NeuroD (beta 2), and Nkx2.2, singly or in combination. Expression of these transcription factors was investigated using RT-PCR and immunofluorescence techniques. RT-PCR analysis was used to assess the subsequent effects of expression of these factors on endogenous genes related to pancreas development.
RESULTS: Regulated differentiation of F9 cells generated endodermal-like cell types. Following transfection, PDX-1, ngn3, beta 2, and Nkx2.2 were expressed in F9-RAC cells, with their proteins localized mainly in cellular nuclei. Expression of these factors apparently did not affect the endogenous expression of preproinsulin, PDX-1, beta 2, Isl1, Pax4, Pax6, Sonic hedgehog, and Indian hedgehog.
CONCLUSION: This study describes the successful transient expression of transcription factors related to pancreas development, following directed differentiation of F9 cells to endoderm-like cells, and shows that treatment of F9 cells with a combination of RAC causes up-regulation of genes relevant to pancreatic development. The lack of further effect of regulated transcription factor expression on these genes may suggest that parietal endoderm- like cells derived from F9 cells is not the optimal lineage from which to develop beta cells. It may be useful to include F9-derived visceral endoderm in future studies.

Related: Cancer of the Pancreas Pancreatic Cancer


Pilling A, Jones S, Turton J
Expression of somatostatin mRNA and peptides in C-cell tumours of the thyroid gland in Han Wistar rats.
Int J Exp Pathol. 2004; 85(1):13-23 [PubMed] Free Access to Full Article Related Publications
C-cell tumours of the thyroid gland are among the most common spontaneous neoplasms of the laboratory rat. With the exception of calcitonin, little attention has been paid to the secretory peptides of C cells during the development of neoplasia. Of these peptides, somatostatin (SS) is of particular interest because it has been shown to have a direct anti-secretory effect on both thyroid follicular and C cells in vitro. In the present study, in situ hybridization and immunohistochemistry were used to investigate the expression of SS mRNA and SS peptides, in normal C cells and a range of spontaneous proliferative C-cell lesions in the Han Wistar rat. It was confirmed that a small minority of C cells in the normal rat thyroid gland produce and store SS peptides; however, approximately half of all C-cell adenomas and C-cell carcinomas stained positively for SS mRNA and peptides. SS expression was also observed in all metastatic deposits of carcinomas in drainage lymph nodes. From these observations, it appears that C-cell tumours are more likely to develop from SS-expressing stem cells, rather than from non-SS-expressing stem cells. In addition, a lack of differentiation of neoplastic C cells, or reversion to more primitive cell types, could account for increased number of cells expressing SS in C-cell tumours relative to the normal C-cell population. Finally, the mean percentage of cells that stained positively for SS mRNA and peptides appeared to be significantly higher in small C-cell tumours, suggesting that SS may have exerted a growth-controlling influence on these lesions.

Related: Thyroid Cancer


Notas G, Kolios G, Mastrodimou N, et al.
Cortistatin production by HepG2 human hepatocellular carcinoma cell line and distribution of somatostatin receptors.
J Hepatol. 2004; 40(5):792-8 [PubMed] Related Publications
BACKGROUND/AIMS: Recently, trials of octreotide have shown a significant survival benefit in the treatment of advanced hepatocellular carcinoma but new data are controversial. We, therefore, examined the production of somatostatin and cortistatin, the expression and distribution of somatostatin receptors (sst) in HepG2 human hepatocellular carcinoma cells, and the possible antiproliferative effect of octreotide on these cells.
METHODS: Radioimmunoassay and RT-PCR studies were performed for the detection of somatostatin and cortistatin. RT-PCR, radioligand binding and immunocytochemistry assays were employed for the detection of the ssts. Growth and viability of cells were measured by the tetrazolium salt assay.
RESULTS: HepG2 cells were found to express sst(2), sst(3) and sst(5) receptors. Immunocytochemistry revealed a mainly intracellular distribution of all ssts with unique patterns for each of them. Membrane binding sites for somatostatin were mainly of the sst(3) (39+/-8%) and sst(5) (59+/-5%) types, while only minor sst(2) binding could be detected (5+/-12%). Octreotide was found to inhibit the proliferation of HepG2 cells (IC(50) 1.25 x 10(-9)M) via protein tyrosine phosphatases. HepG2 cells produced cortistatin while somatostatin expression was not detected.
CONCLUSIONS: In conclusion, HepG2 cells express cortistatin, which regulates somatostatin receptors. Cell proliferation was reduced by octreotide via a protein tyrosine phosphatase dependent mechanism.

Related: Liver Cancer


Hofsli E
[The somatostatin receptor family--a window against new diagnosis and therapy of cancer].
Tidsskr Nor Laegeforen. 2002; 122(5):487-91 [PubMed] Related Publications
BACKGROUND: The peptide hormone somatostatin (SST) inhibits secretion from a wide variety of both endocrine and exocrine cells. It functions as a neurotransmitter and plays an important role in regulation of cell proliferation and differentiation. SST exerts its effects through binding to specific surface membrane receptors.
MATERIAL AND METHODS: The article presents a literature-based review of the somatostatin receptor (SSTR) family, and diagnostic and therapeutic strategies based upon SSTR expression in neuroendocrine (NE) gastroenteropancreatic (GEP) tumours.
RESULTS: Five different human SSTR subtypes have been characterised (SSTR1-5), and their genes cloned. The receptors are G-protein coupled, and binding activates several different signal mechanisms. SSTRs have a characteristic expression pattern both in the central nervous system and in peripheral organs. Many tumour cell lines as well as the majority of human tumours express SSTR mRNAs, usually more than one subtype. The frequency of expression is especially high in NE GEP tumours. SSTR scintigraphy has become an important diagnostic tool for staging of NE GEP tumours and it may also predict sensitivity to treatment with somatostatin analogues. These are regarded as the main choice for symptomatic treatment of hormone related syndromes related to NE GEP tumours. In contrast, the antitumour effects of somatostatin analogues in patients have been rather disappointing. More encouragingly, radiotherapy with radiolabeled somatostatin analogues has more recently been carried out with survival benefit. Gene therapy has shown promising results in animal studies.
INTERPRETATION: Increased molecular understanding of the SSTR family and especially how the receptors are being regulated will probably lead to the development of new diagnostic and therapeutic strategies against cancer.

Related: Gastrointestinal System Cancers Cancer of the Pancreas Pancreatic Cancer Signal Transduction


Brouland JP, Manivet P, Brocheriou-Spelle I, et al.
Histological, immunohistochemical, ultrastructural and biochemical study of human gastric composite tumor: expression of the serotonin-2B receptor by the neuroendocrine component.
Endocr Pathol. 2001; 12(1):77-86 [PubMed] Related Publications
We report a case of a human gastric composite tumor occurring seven years after a partial gastrectomy for a low grade B cell MALT lymphoma. Histological examination of the tumor revealed two intimately intermingled components: 1. A moderately to poorly differentiated tubulo-acinar adenocarcinoma with signet-ring cells; and 2. Isolated or clustered small neuroendocrine cells without atypia expressing chromogranin A, somatostatin and/or glucagon, serotonin (5-HT) and, the 5-HT2B receptors. In addition to immunohistochemical detection, the presence of 5-HT2B receptors was shown pharmacologically through [125I]-DOI binding. Since 5-HT2B receptors have been demonstrated to have autocrine functions and, mitogenic and transforming properties, these results suggest a role of 5-HT in neuroendocrine malignant transformation. On the other hand, the expression of somatostatin and the detection by reverse transcriptase polymerase chain reaction (RT-PCR) of somatostatin receptor subtypes 2, 3, and 5, which have been shown to be involved in tumor regression, might account for the long evolution of this case (> 5 yr). This case illustrates the importance of local humoral modulation in tumor growth. Moreover, ultrastructural results favor a unique origin of the tumor cells from one amphicrine cell type.

Related: Stomach Cancer Gastric Cancer


Ferone D, van Hagen MP, Kwekkeboom DJ, et al.
Somatostatin receptor subtypes in human thymoma and inhibition of cell proliferation by octreotide in vitro.
J Clin Endocrinol Metab. 2000; 85(4):1719-26 [PubMed] Related Publications
Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1-5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of [111In-DTPA-D-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11] SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 +/- 2.5 pmol/L) with low maximum binding capacity (23.5 +/- 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine incorporation by 40.6% and 43.2%, respectively. The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS receptor scintigraphy.

Related: Thymoma and Thymic Carcinoma


Lung RW, Lee KA
The cellular oncogene EWS/activating transcription factor 1 is unable to activate adenovirus-borne promoters: implications for cytotoxic prodrug therapy of malignant melanoma of soft parts.
Cancer Gene Ther. 2000; 7(3):396-406 [PubMed] Related Publications
The cellular oncoprotein Ewing's sarcoma oncogene (EWS)/activating transcription factor 1 (ATF1) is a highly specific marker for malignant melanoma of soft parts (MMSP) and is a potent activator of several cAMP-inducible promoters, including the somatostatin promoter. Here we explored the potential for using the somatostatin promoter to direct toxic gene expression in MMSP cells. When introduced into MMSP cells, a somatostatin-herpes simplex virus thymidine kinase fusion gene confers strong and cell-specific sensitivity to the cytotoxic prodrug ganciclovir. Ganciclovir sensitivity requires the ATF-binding site present in the somatostatin promoter, indicating that toxic gene expression is caused by EWS/ATF1. We also tested the efficacy of recombinant adenoviruses adenoviruses for gene delivery and expression in two MMSP cell lines (DTC1 and Su-ccs-1). Surprisingly, several promoters (including somatostatin) that are strongly activated by EWS/ATF1 in transient assays are not activated in DTC1 and Su-ccs-1 cells when present in an adenovirus vector. In summary, our findings demonstrate the potential for using the somatostatin promoter for cytotoxic prodrug therapy for MMSP. However, first-generation adenovirus vectors cannot be used as promoter delivery vehicles for toxic gene expression in MMSP cells.


Cui G, Qvigstad G, Falkmer S, et al.
Spontaneous ECLomas in cotton rats (Sigmodon hispidus): tumours occurring in hypoacidic/hypergastrinaemic animals with normal parietal cells.
Carcinogenesis. 2000; 21(1):23-7 [PubMed] Related Publications
We have identified cotton rats with a high female-predominant occurrence of spontaneous gastric carcinomas localized to the oxyntic mucosa, classified as malignant enterochromaffin-like (ECL) omas. The present study was made to further characterize these ECLomas and surrounding oxyntic mucosa, both morphologically using histochemical and immunohistochemical methods, and for gene expression by northern blot analysis. Among eight female cotton rats, three had an irregularly thickened oxyntic mucosa, increased stomach weight and a high serum gastrin level. Histopathological examination showed adenomatous hyperplasia of the thickened oxyntic mucosa with areas of an invasive neoplastic tumour. Immunohistochemistry, using the general neuroendocrine cell marker chromogranin A (CgA) and the specific ECL cell marker histidine decarboxylase (HDC), showed a considerably increased ECL cell density. These ECL cells displayed active proliferation, with hyperplasia, dysplasia and neoplasia. Parietal cells were not found in the tumour tissue. Parietal cell density was only slightly reduced in the surrounding oxyntic mucosa. The antral mucosa was histopathologically normal with a normal number of gastrin-immunoreactive cells. Likewise, somatostatin-immunoreactive cells did not show any differences in the antral and oxyntic mucosa between rats with pathological and normal oxyntic mucosa. Northern blot analysis revealed increased expression of CgA and HDC mRNA in the thickened oxyntic mucosa, whereas H(+)/K(+) ATPase mRNA was similar in the oxyntic mucosa of those with thickened and normal oxyntic mucosa. Gastrin mRNA in the antral mucosa was high in animals with thickened oxyntic mucosa. Somatostatin mRNA expression was similar in the antral mucosa of control animals and animals with a thickened oxyntic mucosa. We conclude that the spontaneous gastric carcinoma occurring in female cotton rats is an ECLoma developing secondary to hypergastrinaemia due to reduced intragastric pH. The mechanism for reduced acidity is not known, but is not gastric atrophy.

Related: Stomach Cancer Gastric Cancer


Kasprzak A, Zabel M, Surdyk-Zasada J, Seidel J
Hybridocytochemical detection of mRNA for calcitonin, CGRP, somatostatin and NPY in cultured cells of medullary thyroid carcinoma using immunomax technique.
Folia Histochem Cytobiol. 1999; 37(2):59-60 [PubMed] Related Publications


Related: Thyroid Cancer


Hirota N, Matsumoto K, Iida M, et al.
Expression of somatostatin messenger RNA and receptor in cultured brain tumor cells.
Anticancer Res. 1998 Sep-Oct; 18(5A):3295-7 [PubMed] Related Publications
In order to understand the role of somatostatin in tumor cell growth, the expression of somatostatin in 7 cultured brain tumor cells was investigated. Radioimmunoassay demonstrated the production of somatostatin into the culture supernatant of 6 tumor cells. The expression of somatostatin mRNA and receptor was investigated by reverse transcription polymerase chain reaction (RT-PCR) and a binding assay with 125I-somatostatin-14, respectively. Only two cell lines, GBS-1 and U87MG, expressed somatostatin mRNA, whereas somatostatin receptor was expressed in all cultured cells. These results suggest that somatostatin is an important factor for regulating cell growth.

Related: Childhood Medulloblastoma / PNET


Mato E, Matías-Guiu X, Chico A, et al.
Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma.
J Clin Endocrinol Metab. 1998; 83(7):2417-20 [PubMed] Related Publications
The possible existence of an autocrine/paracrine role for SRIF in normal and neoplastic thyroid parafollicular C cells has supported the use of SRIF analogues in the treatment of patients with medullary thyroid carcinoma (MTC). In this study, we have investigated the expression of SRIF by immunohistochemistry and RT-PCR, and the expression of SRIF receptor (SSTR) subtypes by RT-PCR, in a series of 14 MTCs. SRIF messenger RNA was detected in all cases, although immunoreactive cells were only identified in 8. SSTR messenger RNA was present in 12 out of the 14 tumors. Expression of more than 1 SSTR subtype was detected in 10 tumors. SSTR2, the subtype that preferentially binds to the SRIF analogue octreotide, was the subtype most frequently detected, whereas SSTR4 was not detected in any case. These results confirm the frequent expression of both SRIF and its receptors in MTC. The presence of different combinations of SSTR subtypes in a given patient may explain the variable clinical response to SRIF analogues and may promote the search for more selective drugs with different affinities to the various receptor subtypes.

Related: Thyroid Cancer


Laurance ME, Kwok RP, Huang MS, et al.
Differential activation of viral and cellular promoters by human T-cell lymphotropic virus-1 tax and cAMP-responsive element modulator isoforms.
J Biol Chem. 1997; 272(5):2646-51 [PubMed] Related Publications
We have previously proposed that cAMP-responsive element-binding protein (CREB) activity is stimulated by human T-cell lymphotropic virus-1 (HTLV-1) Tax through two mechanisms that are differentially dependent upon CREB phosphorylation. We have tested this model by examining how Tax affects transcriptional activation mediated by the cAMP-responsive element (CRE) modulator (CREM). The CREM proteins are highly homologous to CREB, particularly in their DNA-binding domains and the kinase-inducible domain (KID), a region that interacts with the coactivator CREB-binding protein (CBP) in a phosphorylation-dependent manner. Despite this similarity, most CREM isoforms are transcriptional repressors. CREMalpha lacks the glutamine-rich domains found in CREB that are essential for transcriptional activation. We show that the normally repressive CREMalpha activates the HTLV-1 and cellular CREs in the presence of Tax; activation of the viral element is phosphorylation-independent, and activation of the cellular CRE is phosphorylation-dependent. CREMDelta(C-G) lacks both the KID and the glutamine-rich regions. This isoform activates the HTLV-1 long terminal repeat in a phosphorylation-independent manner, but does not activate the cellular CRE. This study suggests that Tax, interacting with the basic/zipper region of CREM, recruits CBP to the viral promoter. Tax activation of the cellular CRE depends on the KID and its ability to interact with CBP in a phosphorylation-dependent manner.


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