ArticleBMC cancer2017
A novel FOXO1-mediated dedifferentiation blocking role for DKK3 in adrenocortical carcinogenesis.
Article in BMC cancer, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 13 citations in OpenAlex.
- MET-receptor targeted fluorescent imaging and spectroscopy to detect multifocal papillary thyroid cancer.European journal of nuclear medicine and molecular imaging · 2024Article
- Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma.Frontiers in endocrinology · 2023Review
- Intraoperative MET-receptor targeted fluorescent imaging and spectroscopy for lymph node detection in papillary thyroid cancer: novel diagnostic tools for more selective central lymph node compartment dissection.European journal of nuclear medicine and molecular imaging · 2022Article
- SLC12A7 alters adrenocortical carcinoma cell adhesion properties to promote an aggressive invasive behavior.Cell communication and signaling : CCS · 2018Article
- Characterization of Cell Membrane Extensions and Studying Their Roles in Cancer Cell Adhesion Dynamics.Journal of visualized experiments : JoVE · 2018Article
- The clinicopathological and prognostic significances of Dkk3 expression in cancers: A bioinformatics analysis.Cancer biomarkers : section A of Disease markers · 2018Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundDysregulated WNT signaling dominates adrenocortical malignancies. This study investigates whether silencing of the WNT negative regulator DKK3 (Dickkopf-related protein 3), an implicated adrenocortical differentiation marker and an established tumor suppressor in multiple cancers, allows dedifferentiation of the adrenal cortex.
methodsWe analyzed the expression and regulation of DKK3 in human adrenocortical carcinoma (ACC) by qRT-PCR, immunofluorescence, promoter methylation assay, and copy number analysis. We also conducted functional studies on ACC cell lines, NCI-H295R and SW-13, using siRNAs and enforced DKK3 expression to test DKK3's role in blocking dedifferentiation of adrenal cortex.
resultsWhile robust expression was observed in normal adrenal cortex, DKK3 was down-regulated in the majority (>75%) of adrenocortical carcinomas (ACC) tested. Both genetic (gene copy loss) and epigenetic (promoter methylation) events were found to play significant roles in DKK3 down-regulation in ACCs. While NCI-H295R cells harboring β-catenin activating mutations failed to respond to DKK3 silencing, SW-13 cells showed increased motility and reduced clonal growth. Conversely, exogenously added DKK3 also increased motility of SW-13 cells without influencing their growth. Enforced over-expression of DKK3 in SW-13 cells resulted in slower cell growth by an extension of G1 phase, promoted survival of microcolonies, and resulted in significant impairment of migratory and invasive behaviors, largely attributable to modified cell adhesions and adhesion kinetics. DKK3-over-expressing cells also showed increased expression of Forkhead Box Protein O1 (FOXO1) transcription factor, RNAi silencing of which partially restored the migratory proficiency of cells without interfering with their viability.
conclusionsDKK3 suppression observed in ACCs and the effects of manipulation of DKK3 expression in ACC cell lines suggest a FOXO1-mediated differentiation-promoting role for DKK3 in the adrenal cortex, silencing of which may allow adrenocortical dedifferentiation and malignancy.
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