Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation

• Verfasst von: Giovinazzo, Francesco [VerfasserIn]
• Verfasst von: Schimmack, Simon [VerfasserIn]
• Verfasst von: Svejda, Bernhard [VerfasserIn]
• Verfasst von: Alaimo, Daniele [VerfasserIn]
• Verfasst von: Pfragner, Roswitha [VerfasserIn]
• Verfasst von: Modlin, Irvin [VerfasserIn]
• Verfasst von: Kidd, Mark [VerfasserIn]
• Titel: Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation
• Verf.angabe: Francesco Giovinazzo, Simon Schimmack, Bernhard Svejda, Daniele Alaimo, Roswitha Pfragner, Irvin Modlin, Mark Kidd
• E-Jahr: 2013
• Jahr: November 19, 2013
• Umfang: 12 S.
• Fussnoten: Gesehen am 10.02.2020
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2013
• Band/Heft Quelle: 8(2013,11) Artikelnummer e81111, 12 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0081111
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Enzyme-linked immunoassays
• Sach-SW: Gastrointestinal tract
• Sach-SW: Gene expression
• Sach-SW: Messenger RNA
• Sach-SW: Metastasis
• Sach-SW: Metastatic tumors
• Sach-SW: Prohormones
• Sach-SW: Secretion
• K10plus-PPN: 1748007777

Abstract

IntroductionChromogranin 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. MethodsChromogranin 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. ResultsChromogranin 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). ConclusionChromogranin 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.