Clusterin, a Haploinsufficient Tumor Suppressor Gene in Neuroblastomas

Chayka, Olesya; Corvetta, Daisy; Dews, Michael; Caccamo, Alessandro E.; Piotrowska, Izabela; Santilli, Giorgia; Gibson, Sian; Sebire, Neil J.; Himoudi, Nourredine; Hogarty, Michael D.; Anderson, John; Bettuzzi, Saverio; Thomas-Tikhonenko, Andrei; Sala, Arturo

doi:10.1093/jnci/djp063

Cited by 82 publications

(100 citation statements)

References 56 publications

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“…Among those upregulated genes, CLU is a recently reported NB tumor-and metastasissuppressor gene, 15 while NGFR also suppresses NB tumorigenicity. 16 To validate the microarray data, we performed real-time PCR focus on those genes that involved in tumor growth and developmental processes.…”

Section: Resultsmentioning

confidence: 99%

“…Although HDAC inhibitors result in activation of hundreds of genes, treatment with TSA induces only CASZ1 and 3 other genes in the 30 genes that localize to the Chr1p36 SRO between the markers D1S508 and D1S244. 15 This indicates that only a subset of Chr1p36 genes may be silenced by histone deacetylation. Taken together, the above information suggests that epigenetic silencing either directly or indirectly contributes to the low expression of CASZ1 in NB cells.…”

Section: Resultsmentioning

confidence: 99%

“…15,[28][29][30][31] Among the targets that CASZ1 suppresses are the metastasis enhancers HGF and KITLG. 32,33 Preliminary studies have not identified a single critical target gene that mediates CASZ1 functions and current studies are aimed at delineating the targets and signaling pathways by which CASZ1 suppresses tumor growth and metastasis.…”

Section: Resultsmentioning

confidence: 99%

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CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

et al. 2011

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Neuroblastoma (NB) is a common childhood malignant tumor of the neural crest-derived sympathetic nervous system. In NB the frequent loss of heterozygosity (LOH) on chromosome 1p raises the possibility that this region contains tumor-suppressor genes whose inactivation contributes to tumorigenesis. The human homolog of the Drosophila neural fate determination gene CASZ1, a zinc-finger transcription factor, maps to chromosome 1p36.22, a region implicated in NB tumorigenesis. Quantitative real-time PCR analysis showed that low-CASZ1 expression is significantly correlated with increased age (Z18 months), Children's Oncology Group high-risk classification, 1p LOH and MYCN amplification (all Po0.0002) and decreased survival probability (P ¼ 0.0009). CASZ1 was more highly expressed in NB with a differentiated histopathology (Po0.0001). Retinoids and epigenetic modification agents associated with regulation of differentiation induced CASZ1 expression. Expression profiling analysis revealed that CASZ1 regulates the expression of genes involved in regulation of cell growth and developmental processes. Specific restoration of CASZ1 in NB cells induced cell differentiation, enhanced cell adhesion, inhibited migration and suppressed tumorigenicity. These data are consistent with CASZ1 being a critical modulator of neural cell development, and that somatically acquired disruption of normal CASZ1 expression contributes to the malignant phenotype of human NB.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

et al. 2011

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“…The progressive decrease of CLU expression is clearly one of the molecular changes implicated in the progression from pure BAC to invasive adenocarcinoma, and confirm the possible role of CLU as a tumor suppressor factor against infiltration or invasiveness. In fact, CLU has been already found as an important regulator of cell fate, negatively controlling further progression and invasiveness [12,32].…”

Section: Discussionmentioning

confidence: 99%

“…Nf-kB is a transcription factor associated with the initiation and progression of several human tumors, including lung cancer [11] and is considered a potentially oncogenic transcription factor important for proliferation and survival of neoplastic cells [12].…”

Section: Introductionmentioning

confidence: 99%

Prognostic role of clusterin in resected adenocarcinomas of the lung

et al. 2013

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a b s t r a c tRationale: Clusterin expression may change in various human malignancies, including lung cancer. Patients with resectable non-small cell lung cancer (NSCLC), including adenocarcinoma, have a poor prognosis, with a relapse rate of 30-50% within 5 years. Nuclear factor kB (Nf-kB) is an intracellular protein involved in the initiation and progression of several human cancers, including the lung. Objectives: We investigate the role of clusterin and Nf-kB expression in predicting the prognosis of patients with early-stage surgically resected adenocarcinoma of the lung. Findings: The level of clusterin gradually decreased from well-differentiated to poorly differentiated adenocarcinomas. Clusterin expression was significantly higher in patients with low-grade adenocarcinoma, in early-stage disease and in women. Clusterin expression was inversely related to relapse and survival in both univariate and multivariate analyses. Finally, we observed an inverse correlation between Nf-kB and clusterin. Conclusions: Clusterin expression represents an independent prognostic factor in surgically resected lung adenocarcinoma and was proven to be a useful biomarker for fewer relapses and longer survival in patients in the early stage of disease. The inverse correlation between Nf-kB and clusterin expression confirm the previously reported role of clusterin as potent down regulator of Nf-kB.

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Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes

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Mutti

Faustini

et al. 2020

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The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α‐synuclein. Clearance of extracellular α‐synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α‐synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α‐synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α‐synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human‐induced pluripotent stem cell (iPSC)‐derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α‐synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α‐synuclein preformed fibrils (pffs) through dynamin‐dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α‐synuclein pffs exposure. Specifically, we found that clusterin interacts with α‐synuclein pffs in the extracellular compartment and the clusterin/α‐synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock‐out primary astrocytes and clusterin knock‐down hiPSC‐derived astrocytes we observed that clusterin limits the uptake of α‐synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno‐associated virus‐ and the α‐synuclein pffs‐ injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α‐synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.

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Clusterin, a Haploinsufficient Tumor Suppressor Gene in Neuroblastomas

Abstract: We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.

Cited by 82 publications

References 56 publications

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

Prognostic role of clusterin in resected adenocarcinomas of the lung

Extracellular clusterin limits the uptake of α‐synuclein fibrils by murine and human astrocytes

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