Does Subtelomeric Position of COMMD5 Influence Cancer Progression?

The COMMD proteins are a family of ten pleiotropic factors which are widely conserved throughout evolution and are involved in the regulation of many cellular and physiological processes. COMMD proteins are mainly expressed in adult tissue and their downregulation has been correlated with tumor progression and poor prognosis in cancer. Among this family, COMMD5 emerged as a versatile modulator of tumor progression. Its expression can range from being downregulated to highly up regulated in a variety of cancer types. Accordingly, two opposing functions could be proposed for COMMD5 in cancer. Our studies supported a role for COMMD5 in the establishment and maintenance of the epithelial cell phenotype, suggesting a tumor suppressor function. However, genetic alterations leading to amplification of COMMD5 proteins have also been observed in various types of cancer, suggesting an oncogenic function. Interestingly, COMMD5 is the only member of this family that is located at the extreme end of chromosome 8, near its telomere. Here, we review some data concerning expression and role of COMMD5 and propose a novel rationale for the potential link between the subtelomeric position of COMMD5 on chromosome 8 and its contrasting functions in cancer.

COMMD5/HCaRG Hooks Endosomes on Cytoskeleton and Coordinates EGFR Trafficking.

COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity.

HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma.

Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is highly expressed in renal proximal tubules, where it contributes to the control of cell proliferation and differentiation. HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney injury. Sustained hyper-proliferation and de-differentiation are important hallmarks of tumor progression. Here, we demonstrate that cancer cells overexpressing HCaRG maintain a more differentiated phenotype, while several of them undergo autophagic cell death. Its overexpression in mouse renal cell carcinomas led to smaller tumor size with less tumor vascularization in a homograft tumor model. Mechanistically, HCaRG promotes de-phosphorylation of the proto-oncogene erythroblastosis oncogene B (ErbB)2/HER2 and epigenetic gene silencing of epidermal growth factor receptor and ErbB3 via promoter methylation. Extracellular signal-regulated kinase, AKT and mammalian target of rapamycin which mediate ErbB-dowstream signaling pathways are inactivated by HCaRG expression. In addition, HCaRG is underexpressed in human renal cell carcinomas and more expressed in normal tissue adjacent to renal cell carcinomas of patients with favorable prognosis. Taken together, our data suggest a role for HCaRG in the inhibition of tumor progression as a natural inhibitor of the ErbB signals in cancer and as a potential prognostic marker for renal cell carcinomas.

Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy.

PURPOSE OF REVIEW: Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. OBJECTIVE: In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. METHODS: We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. KEY FINDINGS: In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. LIMITATIONS: Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. IMPLICATIONS: Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.

La néphropathie diabétique (ND) est une affection évolutive causée par des modifications dans la physionomie et la fonction des reins. Elle constitue l'une des principales causes d'insuffisance rénale terminale (IRT). L'objectif de cette revue est de faire état des plus récentes connaissances au sujet des biomarqueurs de la ND, en mettant l'accent sur les nouvelles stratégies qui augmentent la sensibilité des biomarqueurs à dépister les patients susceptibles de développer la ND ou qui courent le risque de voir leur état évoluer vers l'insuffisance rénale terminale. OBJECTIF DE LA REVUE: Dans cette revue, nous fournissons d'abord une description de la physiopathologie de la ND. Nous proposons ensuite un panel de nouveaux biomarqueurs putatifs associés à la physiopathologie de la ND, et qui ont de plus en plus été étudiés dans le but d'établir le diagnostic de la maladie, de prédire son évolution ou de fournir un traitement individuel efficace. MÉTHODOLOGIE: Nous avons procédé à une revue de la littérature sur PubMed et Google Scholar afin de recueillir des données de base au sujet de la physiopathologie de la ND ainsi que sur les biomarqueurs qui y sont associés. Nous avons concentré nos recherches sur les biomarqueurs nouvellement identifiés ou émergents. PRINCIPALES CONCLUSIONS: La revue fait un résumé des voies de signalisation essentielles et des processus biologiques impliqués dans l'évolution de la ND, en plus de mettre en évidence les médiateurs pathogènes de la maladie. Nous faisons également état des avancées majeures réalisées dans l'identification de nouveaux biomarqueurs plus sensibles et plus fiables que ceux qui sont utilisés à l'heure actuelle. Enfin, cette revue collige des renseignements au sujet des biomarqueurs émergents tels que les ARN non codants fonctionnels, les microARN, les longs ARN non codants, les exosomes et les microparticules. LIMITES DE LA REVUE: À ce jour, malgré des stratégies de plus en plus pointues et le fait que la recherche soit en constante progression, aucun traitement unique n'a réussi à inverser ou même à freiner l'évolution de la néphropathie diabétique, ni à réduire la morbidité et la mortalité associées à cette maladie. L'hétérogénéité des maladies rénales observée dans la population des personnes atteintes contribue probablement aux difficultés rencontrées. CONCLUSIONS: La généralisation du dépistage par la protéomique, notamment par la mesure du stress oxydatif et des marqueurs inflammatoires, ainsi que l'approche métabolomique pourraient contribuer à améliorer la valeur pronostique et aider à cibler les patients atteints de diabète qui courent un risque élevé de développer de l'insuffisance rénale.

The CCAAT/enhancer-binding protein beta-2 isoform (CEBPß-2) upregulates galectin-7 expression in human breast cancer cells.

Galectin-7 is considered a gene under the control of p53. However, elevated expression of galectin-7 has been reported in several forms of cancer harboring an inactive p53 pathway. This is especially true for breast cancer where galectin-7 expression is readily expressed in a high proportion in basal-like breast cancer tissues, conferring cancer cells with increased resistance to cell death and metastatic properties. These observations suggest that other transcription factors are capable of inducing galectin-7 expression. In the present work, we have examined the role of CCAAT/enhancer-binding protein beta (C/EBPß) in inducing expression of galectin-7. C/EBP proteins have been shown to contribute to breast cancer by upregulating pro-metastatic genes. We paid particular attention to C/EBPß-2 (also known as LAP2), the most transcriptionally active of the C/EBPß isoforms. Our results showed that ectopic expression of C/EBPß-2 in human breast cancer cells was sufficient to induce expression of galectin-7 at both the mRNA and protein levels. In silico analysis further revealed the presence of an established CEBP element in the galectin-7 promoter. Mutation of this binding site abolished the transcriptional activity of the galectin-7 promoter. Chromatin immunoprecipitation analysis confirmed that C/EBPß-2 binds to the endogenous galectin-7 promoter. Analysis of galectin-7 protein expression in normal epithelia and in breast carcinoma by immunohistochemistry further showed the expression pattern of C/EBPß closely micmicked that of galectin-7, most notably in mammary myoepithelial cells and basal-like breast cancer where galectin-7 is preferentially expressed. Taken together, our findings suggest that C/EBPß is an important mediator of galectin-7 gene activation in breast cancer cells and highlight the different transcriptional mechanisms controlling galectin-7 in cancer cells.

Expression of galectin-7 is induced in breast cancer cells by mutant p53.

Galectin-7 was initially described as a marker of epithelial differentiation expressed in the stratified epithelium of various tissues. Like other members of the galectin family, its expression level is often significantly altered in cancer cells. In breast cancer, its expression is significantly augmented in aggressive molecular subtypes, most notably in estrogen receptor-negative tumors and in cell lines with a basal-like phenotype. Studies using experimental mouse models have further shown high expression of galectin-7 was sufficient to increase the metastatic behavior of poorly metastatic breast cancer cells, rendering them more resistant to apoptosis. This expression pattern in breast cancer cells is unexpected because galectin-7 was originally identified as a p53-induced gene. To address this paradox, we have examined the molecular mechanisms regulating galectin-7 in breast cancer cells. Our results showed that transfection of breast cancer cells with expression vectors encoding mutant p53 was sufficient to induce galectin-7 at both mRNA and protein levels. Doxorubicin treatment of breast cancer cells harboring a mutant p53 also induced galectin-7. This induction was specific since knockdown of endogenous mutant p53 inhibited doxorubicin-induced galectin-7 expression. The p53-induced galectin-7 expression in breast cancer cells correlated with increased NF-κB activity and was inhibited by NF-κB inhibitors, indicating that the ability of mutant p53 to induce galectin-7 was dependent on NF-κB activity. The implication of NF-κB was further supported by data showing that NF-κB bound to the endogenous galectin-7 promoter and that TNFα-induced galectin-7 expression was abolished by NF-κB inhibitors. Taken together, our data provide an explanation to the observed high galectin-7 expression levels in cancer cells and suggest that galectin-7 could be part of a common pathway used by mutant p53 to promote cancer progression.

A distinctive role for galectin-7 in cancer ?

The galectins are a family of evolutionay-conserved carbohydrate-binding proteins. They are distributed widely in all living organisms and have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis. Several members of the galectin family have also been shown to be involved in cancer progression and metastasis. In the case of galectin-7, several studies have reported alterations in its expression pattern during cancer progression. In a variety of tumors, its expression can range from being completely down-regulated to highly up-regulated. Accordingly, its precise role in this field is still debated. The evidence shows that galectin-7 may promote or inhibit cancer development. In this article, we review the data concerning expression and roles of galectin-7 in cancer and propose a comprehensive view of its contribution during cancer progression.

Transcription factors Sp1 and C/EBP regulate NRAMP1 gene expression.

The natural resistance-associated macrophage protein 1 (Nramp1), which belongs to a conserved family of membrane metal transporters, contributes to phagocyte-autonomous antimicrobial defense mechanisms. Genetic polymorphisms in the human NRAMP1 gene predispose to susceptibility to infectious or inflammatory diseases. To characterize the transcriptional mechanisms controlling NRAMP1 expression, we previously showed that a 263 bp region upstream of the ATG drives basal promoter activity, and that a 325 bp region further upstream confers myeloid specificity and activation during differentiation of HL-60 cells induced by vitamin D. Herein, the major transcription start site was mapped in the basal region by S1 protection assay, and two cis-acting elements essential for myeloid transactivation were characterized by in vitro DNase footprinting, electrophoretic mobility shift experiments, in vivo transfection assays using linker-mutated constructs, and chromatin immunoprecipitation assays in differentiated monocytic cells. One distal cis element binds Sp1 and is required for NRAMP1 myeloid regulation. Another site in the proximal region binds CCAAT enhancer binding proteins alpha or beta and is crucial for transcription. This study implicates Sp1 and C/EBP factors in regulating the expression of the NRAMP1 gene in myeloid cells.