Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms

Donna E. Hansel, Ayman Rahman, Michael House, Raheela Ashfaq, Karin Berg, Charles J. Yeo, Anirban Maitra

Research output: Contribution to journalArticle

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Abstract

Pancreatic endocrine neoplasms are neoplastic proliferations of islet cells or islet cell precursors and are capable of secreting a variety of synthetic products, including insulin, glucagon, gastrin, and vasoactive intestinal peptide. The biological behavior of pancreatic endocrine neoplasms is often unpredictable, and there are few reliable histopathologic criteria reliably correlating with metastatic ability. We have used the Affymetrix U133 GeneChip set (HG_U133 A and B; Affymetrix; Santa Clara, CA) representing ∼33,000 characterized transcripts to examine global gene expression profiles from well-differentiated nonmetastatic (n = 5) and metastatic (n = 7) pancreatic endocrine neoplasms to determine molecular markers that predict disease progression. Microarray hybridization data were normalized using the GeneLogic GeneExpress Software System to identify differentially up- and down-regulated genes in metastatic versus nonmetastatic pancreatic endocrine neoplasms. Using a 3-fold change in gene expression as a threshold, we have identified 65 overexpressed and 57 underexpressed genes in metastatic pancreatic endocrine neoplasms as compared with nonmetastatic pancreatic endocrine neoplasms. Several classes of genes, including growth factors and growth factor-related molecules (IGFBP1, IGFBP3, and MET), developmental factors (TBX3 and MEIS2), cytoskeletal factors (β 1 tubulin and ACTN2), cholesterol homeostasis mediators (LRP5, SLC27A2, and RXRG), intracellular signaling pathway mediators (DYRK1A, PK1B, and AK2), methyltransferases (MGMT and GAMT), and DNA repair and regulatory molecules (CHEK1 and ZNF198), were identified as differentially over- or underexpressed via this method. Immunohistochemical validation of microarray data were performed for two overexpressed genes, namely, the met protooncogene (MET) and insulin-like growth factor binding protein 3 (IGFBP3) with tissue microarrays of nonmetastatic (R = 24) and metastatic (R = 15) pancreatic endocrine neoplasms. Increased expression of IGFBP3 was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (12 of 15, 80% versus 10 of 24, 42%), as well as in lymph node (6 of 7, 86%) and liver (9 of 9, 100%) metastases. Similarly, overexpression of MET was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (5 of 15, 33% versus 4 of 24, 17%), as well as in lymph node metastases (4 of 7, 57%) and liver metastases (5 of 9, 56%). The majority of genes that demonstrated altered expression has not been previously identified as differentially expressed in metastatic pancreatic endocrine neoplasm lesions and may therefore represent newly identified molecules in the progression of these lesions.

Original languageEnglish (US)
Pages (from-to)6152-6158
Number of pages7
JournalClinical Cancer Research
Volume10
Issue number18 I
DOIs
StatePublished - Sep 15 2004
Externally publishedYes

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Insulin-Like Growth Factor Binding Protein 3
Proto-Oncogenes
Pancreatic Neoplasms
Genes
Neoplasm Metastasis
Islets of Langerhans
Intercellular Signaling Peptides and Proteins
Lymph Nodes
Liver
Vasoactive Intestinal Peptide
Gastrins
Methyltransferases
Tubulin
Glucagon
Transcriptome
DNA Repair
Disease Progression
Homeostasis
Software
Cholesterol

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. / Hansel, Donna E.; Rahman, Ayman; House, Michael; Ashfaq, Raheela; Berg, Karin; Yeo, Charles J.; Maitra, Anirban.

In: Clinical Cancer Research, Vol. 10, No. 18 I, 15.09.2004, p. 6152-6158.

Research output: Contribution to journalArticle

Hansel, Donna E. ; Rahman, Ayman ; House, Michael ; Ashfaq, Raheela ; Berg, Karin ; Yeo, Charles J. ; Maitra, Anirban. / Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 18 I. pp. 6152-6158.
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