Abstract
The present study was performed to explore the effects of Notch pathway inhibition on the proliferation and apoptosis of renal carcinoma cells. The expression levels of Notch1 and Jagged1 were examined by western blot analysis and immunohistochemistry in pathologically identified clear cell renal cell carcinoma (RCC) and normal kidney tissues. Next, γ-secretase inhibitor was used to suppress the Notch pathway in renal carcinoma cell lines. The proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry analysis was performed to determine the apoptosis, as well as cell cycle alteration. The expression of Notch1 and Jagged1 proteins was detected to be higher in tumor tissues than in non-neoplastic tissues by western blot analysis. The positive staining rates of Notch1 and Jagged1 in clear cell RCC were higher than in normal kidney tissues [95.3 vs. 36.4% (P<0. 05); 93.0 vs. 42.4% (P<0.05), respectively]. The expression levels of Notch1 and Jagged1 were found to statistically correlate with tumor size, grade, TNM stage and disease relapse. The suppression of the Notch pathway was associated with cell proliferation inhibition, as well as induced G2/M phase cell cycle arrest and cell apoptosis. The Notch pathway may be important in oncogenesis of clear cell RCC and the γ-secretase inhibitor may be a potential agent for target therapy of RCC.
Highlights
Renal cell carcinoma (RCC) accounts for 2‐3% of all adult malignant neoplasms
The aberrant regulation of Notch signaling has been implicated in tumorigenesis; conflicting theories concerning the role of the Notch pathway in RCC exist [12,14,15]
The expression of Notch1 and Jagged1 was detected and an elevated level was shown in neoplastic tissue as compared with that in normal kidney tissue, which was confirmed by western blot analysis
Summary
Renal cell carcinoma (RCC) accounts for 2‐3% of all adult malignant neoplasms. Annually, RCC affects ~150,000 individuals and causes ~78,000 mortalities worldwide [1]. 25‐30% of patients present with metastatic RCC at diagnosis [2]. Notch signaling is initiated through the interactions between the plasma‐embedded Notch receptors (Notch1‐4) and cell surface ligands (Jagged and Jagged and δ‐like 1, 2 and 4) present on adjacent cells [6]. This results in a conformational change in Notch to reveal the cleavage site 2 for metalloproteases (ADAM10 and ADAM17), which leaves a 12 amino acid stub of the Notch extracellular domain, required for subsequent recognition and cleavage by the γ‐secretase complex. This results in a conformational change in Notch to reveal the cleavage site 2 for metalloproteases (ADAM10 and ADAM17), which leaves a 12 amino acid stub of the Notch extracellular domain, required for subsequent recognition and cleavage by the γ‐secretase complex. γ‐secretase cleavage of Notch liberates the intracellular domain, which translocates to the nucleus, enabling gene transcription of Notch downstream targets [7]
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