Tumor-derived secretory clusterin induces epithelial–mesenchymal transition and facilitates hepatocellular carcinoma metastasis

Wang, Cun; Jiang, Kai; Kang, Xiaonan; Gao, Dongmei; Sun, Changgang; Li, Yan; Sun, Lu; Zhang, Shu; Liu, Xiaohui; Wu, Wei‐Zhong; Yang, Pengyuan; Guo, Kun; Liu, Yinkun

doi:10.1016/j.biocel.2012.09.012

Cited by 69 publications

(63 citation statements)

References 33 publications

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“…CLU is a secreted molecular chaperone protein implicated in cancer [15,17,31,42,54,55] that we previously detected in the CSF proteome of DIPG patients [43]. TLN1 is a cytoskeletal protein that controls integrin activation to facilitate cell migration by promoting cell motility and adhesion in glioma [7,40,41,46,56].…”

Section: Discussionmentioning

confidence: 99%

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

et al. 2013

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Diffuse Intrinsic Pontine Glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh frozen DIPG specimens (n=14), normal brain tissue (n=10), and other pediatric brain tumors (n=17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77% of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.

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Section: Discussionmentioning

confidence: 99%

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

et al. 2013

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“…Furthermore, univariate and multivariate analyses indicated that sCLU might be an independent prognostic indicator, in line with the factor of lymph node metastasis. In fact, associations between CLU overexpression and metastasis have been revealed by considerable evidence [31][32][33], and recent studies suggest that abnormal sCLU expression could contribute to metastasis in human HCC [34].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

et al. 2015

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The upregulation of secretory clusterin (sCLU) is associated with tumor progression by contributing to angiogenesis, chemo-resistance, cell survival, and metastasis. However, its diagnostic or prognostic values for hepatocellular carcinoma (HCC) still remain to be clarified. The average serum sCLU level analyzed by an enzyme-linked immunosorbent assay was significantly higher (P < 0.001) in HCC patients than that in any of cases with cirrhosis, chronic hepatitis, or healthy control. The area under receiver operating characteristic curve and diagnostic sensitivity were 0.75 and 74.7 % in sCLU, and 0.74 and 58.7 % in α-fetoprotein (AFP), respectively. The combining detections of sCLU and AFP rose up to 90.7 % for HCC diagnosis. In liver, sCLU by immunohistochemistry was significantly higher (P < 0.001) in the HCC (77.3 %) group than that in their para-cancerous group (33.3 %). Abnormal serum or tissue sCLU expression was closely associated with tumor-node-metastasis (TNM) classification of malignant tumors and lymph node metastasis, as an independent prognosis factor (hazard ratio, 2.287; 95 % confidence interval, 1.044-5.007; P = 0.039), and higher sCLU expression significantly correlated (χ (2) = 4.252, P = 0.039) with poor survival of HCC patients analyzed by multivariate Cox regression or Kaplan-Meier method, suggesting that abnormal sCLU expression associated with tumor progression could be a potential diagnostic and prognostic biomarker for HCC.

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“…Moreover, in prostate cancer cells, CLU mediated TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 [72], while transcriptome profiling in a TGF-β-induced epithelial-mesenchymal transition model revealed extracellular CLU as a target for therapeutic antibodies [73]. Finally, tumor-derived secretory CLU induced epithelial-mesenchymal transition and facilitated hepatocellular carcinoma metastasis [74], while the loss of expression of the tumor suppressor gene NKX3.1 in the early phases of prostate tumorigenesis correlated with CLU induction [75]. In this latter study, the authors also showed that in human prostate tissue samples, loss of NKX3.1 expression and corresponding CLU overexpression are colocalized at sites of prostatic inflammatory atrophy, a possible very early stage of human prostate tumorigenesis [75].…”

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

114

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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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Tumor-derived secretory clusterin induces epithelial–mesenchymal transition and facilitates hepatocellular carcinoma metastasis

Cited by 69 publications

References 33 publications

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

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

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