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Accumulation of nonphosphorylated β-catenin and c-myc in primary and uremic secondary hyperparathyroid tumors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi, Endocrine Surgery)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi, Endocrine Surgery)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. (Endokrinkirurgi, Endocrine Surgery)
2007 (Engelska)Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, nr 1, s. 338-344Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

CONTEXT: Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology, affecting about 1% of the adult population, with an even higher prevalence for elderly individuals. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. OBJECTIVE: Aberrant Wnt/beta-catenin signaling with accumulation of beta-catenin in the cytoplasm/nucleus is involved in the development of a variety of neoplasms. The aim of this study was to evaluate whether the Wnt/beta-catenin signaling pathway is activated in parathyroid adenomas of pHPT and in hyperplastic glands from uremic patients with sHPT. DESIGN: Immunohistochemistry, Western blotting, real-time quantitative RT-PCR, and DNA sequencing were performed. RESULTS: beta-Catenin was accumulated in all analyzed parathyroid tumors (n = 47) from patients with pHPT and from patients with HPT secondary to uremia. The accumulation included nonphosphorylated, stabilized (transcriptionally active) beta-catenin. The overexpression was not related to increased beta-catenin mRNA levels. A protein-stabilizing mutation in exon 3 of beta-catenin (S37A) was detected in three of 20 pHPT tumors (15%). No mutation was detected in secondary hyperplastic glands (n = 20), and no evidence for truncated adenomatosis polyposis coli proteins was found in adenomas and secondary hyperplastic glands. Mutations in other Wnt signaling components leading to beta-catenin accumulation, other than in beta-catenin itself, are therefore anticipated. The beta-catenin target gene c-myc was overexpressed in a substantial fraction of the parathyroid tumors. CONCLUSION: Our results strongly suggest that modifications in the Wnt/beta-catenin signaling pathway may be involved in the development of hyperparathyroidism.

Ort, förlag, år, upplaga, sidor
2007. Vol. 92, nr 1, s. 338-344
Nyckelord [en]
Kidney disease, Urinary system disease, Endocrinology, Secondary, Primary, Tumor, Protooncogene, myc Gene, Renal failure, C-Onc gene, Accumulation, β Catenin
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-96470DOI: 10.1210/jc.2006-1197ISI: 000243317500058PubMedID: 17047023OAI: oai:DiVA.org:uu-96470DiVA, id: diva2:171051
Tillgänglig från: 2007-11-16 Skapad: 2007-11-16 Senast uppdaterad: 2017-12-14
Ingår i avhandling
1. Wnt/β-Catenin Signalling in Parathyroid Tumours
Öppna denna publikation i ny flik eller fönster >>Wnt/β-Catenin Signalling in Parathyroid Tumours
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2007. s. 63
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 293
Nyckelord
Surgery, Hyperparathyroidism, β-catenin, Mutation, Human parathyroid cell line, LRP5, Alternative splicing, Kirurgi
Identifikatorer
urn:nbn:se:uu:diva-8317 (URN)978-91-554-7029-6 (ISBN)
Disputation
2007-12-08, Enghoffsalen, Entre 50, Akademiska sjukhuset, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2007-11-16 Skapad: 2007-11-16Bibliografiskt granskad

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