Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

Bettuzzi, Saverio; Davalli, Pierpaola; Davoli, Serena; Chayka, Olesya; Rizzi, Federica; Belloni, Lucia; Pellacani, Davide; Fregni, Giulia; Astancolle, Serenella; Fassan, Matteo; Corti, Angelo; Baffa, Raffaele; Sala, Arturo

doi:10.1038/onc.2009.286

Cited by 43 publications

(48 citation statements)

References 37 publications

(43 reference statements)

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“…The highly significant inverse correlation found between CLU and Nf-kB expression is consistent with what is already known about the inhibitory activity of CLU on Nf-kB activity and expression [15]. However, although Nf-kB is known to be involved in initiation and cancer progression, there are no studies showing a correlation between Nf-kB and cancer OS and DFS.…”

Section: Discussionsupporting

confidence: 75%

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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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Section: Discussionsupporting

confidence: 75%

“…Several in vitro studies demonstrated that Nf-kB activation is inhibited by CLU [13,14] and that the deletion of CLU induces activation of Nf-kB [15] suggesting an interrelationship between these 2 proteins.…”

Section: Introductionmentioning

confidence: 99%

Prognostic role of clusterin in resected adenocarcinomas of the lung

et al. 2013

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“…It has been found that CLU expression levels correlated positively with most inflammatory diseases and virus infections [16]. More recently, CLU gene expression was found to be induced during progression of primary osteoarthritis [67]. Interestingly, CLU seems to also directly intervene in NF-κB regulation, although its role remains debated; depending on the experimental model, CLU had either a negative [39] or a positive effect [40] on NF-κB activity.…”

Section: Functional Implication Of Clu In Ageing and Age-related Disementioning

confidence: 99%

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Trougakos

2013

Gerontology

116

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Background: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. Objective: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. Conclusion: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

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“…As a tumor modifier, clusterin may interfere with several signaling pathways mediated by NF-κB, PI3 kinase, or MAP kinase [5,15,18]. A few studies have focused on nuclear clusterin, a cell death protein that plays a pro-apoptotic role [11,12,13].…”

Section: Discussionmentioning

confidence: 99%

“…This downregulation may promote tumorigenesis and metastasis. Several recent studies have shown that genetic inactivation of clusterin can promote tumorigenesis and metastasis [14,15]. In addition, clusterin represents a positive biomarker of better overall survival [16,17,18].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Clusterin Expression in Human Testicular Seminoma

Liu

Han

Zhang

et al. 2013

Cell Physiol Biochem

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Background: Clusterin, a heterodimeric glycoprotein of approximately 80 kDa, exists extensively in human body fluids. The abnormal expression of clusterin is closely related to the occurrence, progression, and prognosis of tumors. Up to now, few studies have focused on clusterin in human testicular cancer. This study describes an extensive exploration of the presence and expression of clusterin in testicular seminoma. Methods: Tumor tissues and normal testis tissues were collected from 13 patients with testicular seminoma and 16 patients undergoing surgical castration for prostate cancer. Real-time polymerase chain reaction (PCR) was performed to detect the expression difference of clusterin mRNA between testicular seminoma and normal testis. Western blot and immunohistochemical analysis were performed to detect the presence and expression difference of clusterin protein between two groups. Results: Real-time PCR showed the expression of clusterin mRNA in testicular seminoma to be significantly lower than in normal testis (only 13% relative quantification). Western blot analysis indicated marked reductions in the expression of clusterin protein in testicular seminoma. Similar results were observed upon immunohistochemical analysis. Conclusion: In testicular seminoma and normal testis, clusterin exists in its heterodimeric secretory isoform. Clusterin expression is significantly lower in testicular seminoma than in normal testis. This is the first comprehensive study of the presence and expression of clusterin in human testicular cancer.

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Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

Cited by 43 publications

References 37 publications

Prognostic role of clusterin in resected adenocarcinomas of the lung

Prognostic role of clusterin in resected adenocarcinomas of the lung

The Molecular Chaperone Apolipoprotein J/Clusterin as a Sensor of Oxidative Stress: Implications in Therapeutic Approaches - A Mini-Review

Downregulation of Clusterin Expression in Human Testicular Seminoma

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