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1.
Cancers (Basel) ; 14(3)2022 Feb 04.
Article in English | MEDLINE | ID: mdl-35159062

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

2.
Tumour Biol ; 39(7): 1010428317707372, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28714373

ABSTRACT

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Cation Transport Proteins/biosynthesis , MicroRNAs/genetics , Organic Cation Transport Proteins/biosynthesis , Organic Cation Transporter 1/biosynthesis , Antagomirs/genetics , Apoptosis/drug effects , Benzimidazoles/administration & dosage , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Copper Transporter 1 , Drug Resistance, Neoplasm/genetics , Fluorouracil/administration & dosage , Gene Expression Regulation, Neoplastic/drug effects , Humans , Organic Cation Transporter 2 , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Paclitaxel/administration & dosage , Quinolones/administration & dosage , Signal Transduction
3.
Biochim Biophys Acta Mol Basis Dis ; 1863(6): 1336-1349, 2017 06.
Article in English | MEDLINE | ID: mdl-28366875

ABSTRACT

Acute kidney injury (AKI) is characterized by acute tubular necrosis (ATN) which involves mainly proximal tubules. Past AKI is associated with higher risk of chronic kidney disease (CKD). The MUC1 mucin is a large glycoprotein responsible for epithelial protection and locates to convoluted distal tubules and collecting ducts. Since MUC1 activates the epithelial-mesenchymal transition (EMT) in carcinoma cells, we hypothesized that MUC1 could be involved in epithelial tubular cell plasticity, a process that not only accompanies epithelial repair, but also participates into kidney fibrosis, histological substratum of CKD. In cultured human proximal cells and in human kidney allograft biopsies, we observed MUC1 induction in proximal tubules displaying ATN. Transient MUC1 induction localized with mesenchymal and stem-cell markers and was associated in vitro with reduced anoikis. In a mouse ischemia-reperfusion (IR) model, Muc1 expression mitigates severe tubular injury, as WT displayed less ATN than Muc1 KO mice. But, WT mice displayed more severe kidney fibrosis than Muc1 KO 28days after ischemia. Besides, sustained Muc1 expression in WT was associated with less kidney M2 macrophages. Human kidney biopsies performed within the first week (W1) of transplantation in the context of IR showed MUC1 W1 induction associated with EMT markers. Protocol biopsies performed 3months after demonstrated sustained abnormal MUC1 induction in atrophic tubules within kidney fibrosis. Altogether these data showed that sustained abnormal MUC1 induction accompanies failing epithelial repair, chronic inflammation and kidney fibrosis. In conclusion, MUC1 exerts opposite effects during kidney response to IR: first protective and then harmful.


Subject(s)
Kidney Diseases/metabolism , Kidney Tubules/metabolism , Mucin-1/metabolism , Reperfusion Injury/metabolism , Animals , Fibrosis , HEK293 Cells , Humans , Kidney Diseases/genetics , Kidney Diseases/pathology , Kidney Tubules/pathology , Mice , Mice, Knockout , Mucin-1/genetics , Reperfusion Injury/genetics , Reperfusion Injury/pathology
4.
Oncotarget ; 5(3): 754-63, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24504508

ABSTRACT

MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties. Using shRNA strategy and/or different MUC1 constructs, we found that MUC1-extracellular domain and MUC1-CT are involved in increase of migration, cell viability, resistance to anoikis and in decrease of cell aggregation in cancer cells. Invasiveness depends only on MUC1-CT. Then, by using siRNA strategy and/or pharmacological inhibitors or peptides, we showed that sheddases ADAM10, ADAM17 and gamma-secretase are necessary for MUC1 C-terminal subunit (MUC1-C) nuclear location and in increase of invasion property. Finally, MUC1 overexpression increases ADAM10/17 protein expression suggesting a positive regulatory loop. In conclusion, we report that MUC1 acts in renal cancer progression and MUC1-C nuclear localization drives invasiveness of cancer cells through a sheddase/gamma secretase dependent pathway. MUC1 appears as a therapeutic target by blocking MUC1 cleavage or nuclear translocation by using pharmacological approach and peptide strategies.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Kidney Neoplasms/metabolism , Mucin-1/metabolism , Animals , Cell Line, Tumor , Cell Nucleus/metabolism , Disease Progression , Heterografts , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Mice , Mice, SCID , Mucin-1/genetics , Protein Subunits , Signal Transduction , Transfection
5.
Cancer Lett ; 346(2): 225-36, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24384091

ABSTRACT

MUC1 is overexpressed in human carcinomas. The transcription factor SNAIL can activate epithelial-mesenchymal transition (EMT) in cancer cells. In this study, in renal carcinoma, we demonstrate that (i) MUC1 and SNAIL were overexpressed in human sarcomatoid carcinomas, (ii) SNAIL increased indirectly MUC1 expression, (iii) MUC1 overexpression induced EMT, (iv) MUC1 C-terminal domain (MUC1-C) and ß-catenin increased SNAIL transcriptional activity by interaction with its promoter and (v) blocking MUC1-C nuclear localization decreased Wnt/ß-catenin signaling pathway activation and SNAIL expression. Altogether, our findings demonstrate that MUC1 is an actor in EMT and appears as a new therapeutic target.


Subject(s)
Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Mucin-1/biosynthesis , Transcription Factors/biosynthesis , Wnt Proteins/metabolism , beta Catenin/metabolism , Carcinoma, Renal Cell/genetics , Cell Line, Tumor , Cell Nucleus/metabolism , Epithelial-Mesenchymal Transition , HEK293 Cells , Humans , Kidney Neoplasms/genetics , Mucin-1/genetics , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Snail Family Transcription Factors , Transcription Factors/genetics , Transcriptional Activation , Up-Regulation , Wnt Signaling Pathway
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