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Activated β-catenin in the novel human parathyroid tumor cell line sHPT-1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Endokrinkirurgi, Endocrine Surgery)
2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 2, 532-536 p.Article in journal (Refereed) Published
Abstract [en]

Misregulation of the Wnt/beta-catenin signalling pathway is involved in the development and progression of many cancers. Recently, we presented evidence for aberrant accumulation of non-phosphorylated (stabilized) beta-catenin in benign parathyroid tumors from patients with primary hyperparathyroidism (pHPT) or HPT secondary to uremia (sHPT). Here we have used a human parathyroid hormone (PTH)-producing cell line (sHPT-1), established from a hyperplastic parathyroid gland removed at operation of a patient with sHPT, to further investigate the potential importance of beta-catenin in parathyroid tumorigenesis. Our studies demonstrate that efficient and specific knockdown of beta-catenin by small interfering RNA (siRNA) markedly decreased endogenous beta-catenin transcriptional activity as well as expression of the Wnt/beta-catenin target genes cyclin D1 and c-myc, known to be overexpressed in a substantial fraction of parathyroid tumors. Furthermore, siRNA to beta-catenin inhibited cellular growth and induced cell death. Growth and survival of the parathyroid tumor cells are thus dependent on maintained expression level of beta-catenin. The Wnt/beta-catenin signalling pathway, and beta-catenin in particular, presents a potential therapeutic target for HPT.

Place, publisher, year, edition, pages
2007. Vol. 352, no 2, 532-536 p.
Keyword [en]
β-Catenin, c-myc, Cyclin D1, Hyperparathyroidism, Parathyroid cell line, Wnt signalling
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96472DOI: 10.1016/j.bbrc.2006.11.056ISI: 000243196300040PubMedID: 17126301OAI: oai:DiVA.org:uu-96472DiVA: diva2:171053
Available from: 2007-11-16 Created: 2007-11-16 Last updated: 2016-04-28
In thesis
1. Wnt/β-Catenin Signalling in Parathyroid Tumours
Open this publication in new window or tab >>Wnt/β-Catenin Signalling in Parathyroid Tumours
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary hyperparathyroidism (pHPT) due to parathyroid tumours with hypersecretion of parathyroid hormone and hypercalcaemia is a common disease with incompletely understood etiology affecting more than 1 % of the population, primarily postmenopausal women. In secondary hyperparathyroidism (sHPT), parathyroid tumours develop in response to calcium and vitamin D deficiency generally in patients with uraemia. HPT is usually treated by surgical removal of enlarged parathyroid glands.

The aim of this thesis was to examine the Wnt/β-catenin signalling pathway in parathyroid tumours.

Aberrantly accumulated β-catenin was found in all analysed pHPT and sHPT tumours, with a stabilising homozygous mutation (Ser37Ala) in 7.3% of the pHPT tumours. Truncation of the APC protein was not found. MYC, a β-catenin target gene was overexpressed in a substantial fraction of pHPT and sHPT parathyroid tumours.

A parathyroid tumour cell line (sHPT-1) was established from a hyperplastic gland removed at operation of a patient with sHPT. The cells produced parathyroid hormone and grew with a doubling time of approximately 72 hours. Stabilised nonphosphorylated transcriptionally active β-catenin was expressed. Efficient transfection of siRNA against β-catenin decreased expression of cyclin D1 and MYC, and inhibited cell growth with ensuring cell death.

The Wnt coreceptor LRP5 was found expressed with an internal deletion of 142 amino acids (LRP5Δ) in 86% and 100% of pHPT and sHPT tumours, respectively. Stabilising mutation of β-catenin and expression of LRP5Δ was mutually exclusive. Expression of LRP5Δ was required to maintain the nonphosphorylated transcriptionally active ß-catenin level, MYC expression, parathyroid cell growth in vitro, and tumour growth in transplanted SCID mice. Wnt3 ligand and LRP5Δ strongly activated transcription, and LRP5Δ was insensitive to inhibition by DKK1.

Aberrant accumulation of β-catenin by stabilising mutation or expression of LRP5Δ appears as a common pathogenic pathway for hyperparathyroid disease. LRP5Δ in particular presents a potential target for therapeutic intervention.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 293
Keyword
Surgery, Hyperparathyroidism, β-catenin, Mutation, Human parathyroid cell line, LRP5, Alternative splicing, Kirurgi
Identifiers
urn:nbn:se:uu:diva-8317 (URN)978-91-554-7029-6 (ISBN)
Public defence
2007-12-08, Enghoffsalen, Entre 50, Akademiska sjukhuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-11-16 Created: 2007-11-16Bibliographically approved

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Björklund, PeymanÅkerström, GöranWestin, Gunnar

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