Caveolin-1 in renal cell carcinoma promotes tumour cell invasion, and in co-operation with pERK predicts metastases in patients with clinically confined disease

Journal of Translational Medicine

Mark Gumbleton²  David FR Griffiths¹  Mathew W Smith²  Simon Gumbleton²  Rosie Griffiths¹  Nigel Gumbleton²  Robert Gutteridge²  Ghaith Al-Jayyoussi²  Lee Campbell² 

[1] Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK

关键词: Biomarkers;    Invasion;    Renal Cell Carcinoma;    ERK-1/2;    Caveolin-1;   

Others  :  825242
DOI  :  10.1186/1479-5876-11-255

 received in 2013-05-30, accepted in 2013-09-30,  发布年份 2013

【 摘 要 】

Background

Up to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways.

Methods

Using immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival. Using a panel of RCC cell lines we explored the functional effects of Cav-1 knockdown upon cell growth, cell invasion and VEGF-A secretion, as well Cav-1 regulation by cognate cell signalling pathways.

Results

We found a significant correlation (P = 0.03) between Cav-1 and pERK in a cohort of patients with clinically confined disease which represented a prognostic biomarker combination (HR = 4.2) that effectively stratified patients into low, intermediate and high risk groups with respect to relapse, even if the patients’ tumours displayed low grade and/or low stage disease. In RCC cell lines Cav-1 knockdown unequivocally reduced cell invasive capacity while also displaying both pro-and anti-proliferative effects; targeted knockdown of Cav-1 also partially suppressed VEGF-A secretion in VHL-negative RCC cells. The actions of Cav-1 in the RCC cell lines appeared independent of both ERK and AKT/mTOR signalling pathways.

Conclusion

The combined expression of Cav-1 and pERK serves as an independent biomarker signature with potential merit in RCC surveillance strategies able to predict those patients with clinically confined disease who will eventually relapse. In a panel of in-vitro RCC cells Cav-1 promotes cell invasion with variable effects on cell growth and VEGF-A secretion. Cav-1 has potential as a therapeutic target for the prevention and treatment of mRCC.

【 授权许可】

   
2013 Campbell et al.; licensee BioMed Central Ltd.

【 图 表 】

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