Chromogranin A and Its Fragments as Regulators of Small Intestinal Neuroendocrine Neoplasm Proliferation

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Introduction

Chromogranin A is a neuroendocrine secretory product and its loss is a feature of malignant NEN de-differentiation. We hypothesized that chromogranin A fragments were differentially expressed during NEN metastasis and played a role in the regulation of NEN proliferation.

Methods

Chromogranin A mRNA (PCR) and protein (ELISA/western blot) were studied in 10 normal human mucosa, 5 enterochromaffin cell preparations, 26 small intestinal NEN primaries and 9 liver metastases. Cell viability (WST-1 assay), proliferation (bromodeoxyuridine ELISA) and expression of AKT/AKT-P (CASE ELISA/western blot) in response to chromogranin A silencing, inhibition of prohormone convertase and mTOR inhibition (RAD001/AKT antisense) as well as different chromogranin A fragments were examined in 4 SI-NEN cell lines.

Results

Chromogranin A mRNA and protein levels were increased (37-340 fold, p<0.0001) in small intestinal NENs compared to normal enterochromaffin cells. Western blot identified chromogranin A-associated processing bands including vasostatin in small intestinal NENs as well as up-regulated expression of prohormone convertase in metastases. Proliferation in small intestinal NEN cell lines was decreased by silencing chromogranin A as well as by inhibition of prohormone convertase ( p<0.05). This inhibition also decreased secretion of chromogranin A ( p<0.05) and 5-HT ( p<0.05) as well as expression of vasostatin. Metastatic small intestinal NEN cell lines were stimulated (50-80%, p<0.05) and AKT phosphorylated (Ser473: p<0.05) by vasostatin I, which was completely reversed by RAD001 ( p<0.01) and AKT antisense ( p<0.05) while chromostatin inhibited proliferation (~50%, p<0.05).

Conclusion

Chromogranin A was differentially regulated in primary and metastatic small intestinal NENs and cell lines. Chromogranin A fragments regulated metastatic small intestinal NEN proliferation via the AKT pathway indicating that CgA plays a far more complex role in the biology of these tumors than previously considered.

Related collections

Most cited references 41

Record: found
Abstract: not found
Article: not found

The chromogranin-secretogranin family.

Laurent Taupenot, Kimberly Harper, Daniel T. O'Connor (2003)

0 comments Cited 135 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease.

Marianne Pavel, S Moss, Irvin Modlin … (2010)

Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement. Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases. CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (approximately 25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in approximately 90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation. CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.

0 comments Cited 105 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides.

Nabil Seidah, M Chretien (1999)

Proproteins and prohormones are the fundamental units from which bioactive proteins and peptides as well as neuropeptides are derived by limited proteolysis within the secretory pathway. Precursors are usually cleaved at the general motif (K/R)--(X)n--(K/R)down arrow, where n=0, 2, 4 or 6 and X is any amino acid and usually is not a Cys. Seven mammalian precursor convertases (PCs) have been identified: PC1, PC2, furin, PC4, PC5, PACE4 and PC7. Each of these enzymes, either alone or in combination with others, is responsible for the tissue-specific processing of multiple polypeptide precursors both in the brain and in periphery. This combinatorial mechanism generates a large diversity of bioactive molecules in an exquisitively regulated manner. The production of null mice allowed the assessment of the critical role of convertases in vivo. Thus, male PC4 (-/-) mice are infertile, furin (-/-) and PC1(-/-) mice are embryonic lethal, and PC2 (-/-) mice are mildly diabetic and runted. Interestingly, animals deficient in 7B2, a PC2-specific binding protein, exhibit a Cushing-like syndrome and die soon after birth. Recently, the first member of a new class of subtilisin--kexin-like convertases, called SKI-1, was identified. Its structure is closer to pyrolysin than to mammalian PCs and it exhibits a specificity for cleavage at the motif (R/K)--X--X--(L,T) down arrow as deduced from its ability to process sterol regulatory element binding proteins and pro-brain derived neurotrophic factor. Thus, while PCs are responsible for the processing of neuropeptides, adhesion molecules, receptors, growth factors, cell surface glycoprotein and enzymes, SKI-1 cleaves proproteins that are critical for the control of cholesterol and fatty acid metabolism and for neuronal protection and growth.

0 comments Cited 88 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Salvatore Papa: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 19 November 2013

Volume: 8

Issue: 11

Electronic Location Identifier: e81111

Affiliations

[1 ]Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America

[2 ]Laboratory of Translational Surgery-LURM, University of Verona, Verona, Italy

[3 ]University Hospital of General, Visceral- and Transplantation-Surgery of Heidelberg, Heidelberg, Germany

[4 ]Department of Pathophysiology and Immunology, University of Graz, Graz, Austria

Institute of Hepatology - Birkbeck, University of London, United Kingdom

Author notes

* E-mail: mark.kidd@ 123456yale.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: MK BS FG SS IM RP. Performed the experiments: MK BS DA SS FG. Analyzed the data: MK BS SS FG. Contributed reagents/materials/analysis tools: MK SS RP IM. Wrote the manuscript: MK BS SS FG.

Article

Publisher ID: PONE-D-13-11842

DOI: 10.1371/journal.pone.0081111

PMC ID: 3834250

PubMed ID: 24260544

SO-VID: 87ee7b1b-cdd8-4780-8a11-a53948bb89c0

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Chromogranin A and Its Fragments as Regulators of Small Intestinal Neuroendocrine Neoplasm Proliferation

Read this article at

Abstract

Introduction

Methods

Results

Conclusion

Related collections

PLOS Climate

Most cited references 41

The chromogranin-secretogranin family.

Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease.

Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Funding

Categories

Comments

Comment on this article

Similar content 160

Cited by 6

Most referenced authors 352