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The inhibin/activin signalling pathway in human gonadal and adrenal cancers.

Abstract
The biological function of the inhibin-α subunit (INHA) in gonadal tumorigenesis is different in humans compared with mouse. The INHA subunit is up-regulated in most human ovarian and testicular cancers but knock-out studies in mice showed the INHA subunit is a tumour suppressor with gonadal and adrenal specificity. The INHA subunit is a component of the inhibin/activin signalling pathway, which includes activin receptors ActRIIA/IIB and intracellular Smads-2/3. To resolve the incongruity in function in humans versus mouse, we re-evaluated the inhibin/activin pathway in human gonadal and adrenal cancers using contemporary protein and mRNA expression data for multiple pathway components rather than INHA alone. We used an INHA antibody raised against the N-terminal domain to compare immunoreactivity with the more commonly used antibody raised against the C-terminal domain. This study also described, for the first time, a comprehensive protein expression profile of activin-βC in reproductive and adrenal cancers, and its effect on a human granulosa cell line, providing evidence for a role in ovarian, testis and adrenal tumour biology. Our data show reduced INHA expression at both protein and mRNA levels, and increased activin signalling in human testicular, ovarian and malignant versus benign forms of adrenal cancer. We also found that activin-C acts as an activin-A antagonist by binding to activin receptor subunits IIA and IIB and modulating the canonical Smad pathway. In conclusion, analysis of the inhibin/activin signalling pathway helps to explain discrepancies arising from studies of only one hormone or subunit and suggests that altered expression of the inhibin and activin subunits is associated with reproductive and adrenal cancer biology.
AuthorsFrancesco Elia Marino, Gail Risbridger, Elspeth Gold
JournalMolecular human reproduction (Mol Hum Reprod) Vol. 20 Issue 12 Pg. 1223-37 (Dec 2014) ISSN: 1460-2407 [Electronic] England
PMID25180271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected].
Chemical References
  • INHBC protein, human
  • RNA, Messenger
  • Smad Proteins, Receptor-Regulated
  • activin A
  • activin B
  • inhibin-alpha subunit
  • Activins
  • Inhibins
  • Inhibin-beta Subunits
  • Activin Receptors, Type II
  • activin receptor type II-A
  • activin receptor type II-B
Topics
  • Activin Receptors, Type II (metabolism)
  • Activins (genetics, metabolism)
  • Adrenal Gland Neoplasms (genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Databases, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibin-beta Subunits (metabolism)
  • Inhibins (genetics, metabolism)
  • Male
  • Ovarian Neoplasms (genetics, metabolism, pathology)
  • Protein Structure, Tertiary
  • RNA, Messenger (metabolism)
  • Signal Transduction
  • Smad Proteins, Receptor-Regulated (metabolism)
  • Testicular Neoplasms (genetics, metabolism, pathology)

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