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Knockdown of NF-?B1 by shRNA Inhibits the Growth of Renal Cell Carcinoma In Vitro and In Vivo.

ABSTRACT: Renal cell carcinoma (RCC) accounts for approximately 2%-3% of human malignancies and is the most aggressive among urologic tumors. Biological heterogeneity, drug resistance, and chemotherapy side effects are the biggest obstacles to the effective treatment of RCC. The NF-?B transcription factor is one of several molecules identified to be responsible for the aggressive phenotype of this tumor. In the past decade, several studies have demonstrated the activation of NF-?B in RCC, and many have implicated NF-?B1 (p50) as an important molecule in tumor progression and metastasis. In the present study, a lentivirus was used to deliver shRNA targeting NF-?B1 into mouse RCC (Renca) cells. It was determined that the knockdown of the NF-?B1 gene led to a reduction in cell proliferation and late apoptosis/necrosis in vitro. Flow cytometry analysis demonstrated G2/M arrest in the cells. In addition, immunoblotting analysis revealed a significant increase in cyclin B1 and Bax. In vivo experiments showed that Renca-shRNA-NF-?B1 cells have significantly diminished tumorigenicity. Moreover, immunohistochemical analysis revealed an increase in necrotic areas of Renca-shRNA-NF-?B1 tumors. Thus, this study indicates that downregulation of NF-?B1 can suppress RCC tumorigenesis by inducing late apoptosis/necrosis. Therefore, NF-?B1 may be a potential therapeutic target for RCC.

SUBMITTER: Ikegami A

PROVIDER: S-EPMC7844753 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Knockdown of NF-κB1 by shRNA Inhibits the Growth of Renal Cell Carcinoma In Vitro and In Vivo.

Ikegami Amanda A Teixeira Luiz Felipe S LFS Braga Marina S MS Dias Matheus Henrique Dos S MHDS Lopes Eduardo C EC Bellini Maria Helena MH

Oncology research 20171201 5

Renal cell carcinoma (RCC) accounts for approximately 2%-3% of human malignancies and is the most aggressive among urologic tumors. Biological heterogeneity, drug resistance, and chemotherapy side effects are the biggest obstacles to the effective treatment of RCC. The NF-κB transcription factor is one of several molecules identified to be responsible for the aggressive phenotype of this tumor. In the past decade, several studies have demonstrated the activation of NF-κB in RCC, and many have im ...[more]

PMID: 29212573

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Project description:The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPAR? is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPAR? gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPAR? is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPAR? in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPAR? reduced the tumourigenicity of GSC in vivo. PPAR?-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPAR? KD GSC xenografts failed to establish viable intracranial tumours. PPAR? KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPAR? KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPAR?-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPAR? in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPAR? expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

Knockdown of NF-?B1 by shRNA Inhibits the Growth of Renal Cell Carcinoma In Vitro and In Vivo.

Publications

Knockdown of NF-κB1 by shRNA Inhibits the Growth of Renal Cell Carcinoma In Vitro and In Vivo.

Similar Datasets

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