Notch 1 is a valuable therapeutic target against cell survival and proliferation in clear cell renal cell carcinoma

Abstract

Notch 1 is a key component of the Notch pathway, which performs a crucial role in clear cell renal cell carcinoma (CCRCC) development. The present study aimed to investigate whether Notch 1 could serve as a potential target for CCRCC treatment. Firstly, an association analysis was performed using 52 CCRCC cases and 30 normal controls. The results indicated that Notch 1 protein expression in renal tissues was closely associated with the incidence of CCRCC. In addition, higher Notch 1 expression in CCRCC tissues was positively associated with higher tumor-node-metastasis stage and Fuhrman grade, in addition to larger tumor size. Subsequently, an in vitro study was conducted to examine the biological functions of Notch 1 in CCRCC 786-O cells through inhibiting the Notch 1 expression with Notch 1-specific small interfering RNA (siRNA). As a result, the inhibition of Notch 1 expression by increasing concentrations of Notch 1-specific siRNA dose-dependently decreased cell proliferation and increased cell apoptosis in 786-O cells. Furthermore, B-cell lymphoma-2 and procaspase-3 expression exhibited a dose-dependent decrease accompanied with a dose-dependent inactivation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway in Notch 1 siRNA-treated 786-O cells. These findings demonstrated that Notch 1 was associated with CCRCC carcinogenesis and progression, the underlying mechanism of which was that Notch 1 acted as an activator for cell proliferation and a suppressor for cell apoptosis through the Akt/mTOR signaling-dependent pathway in CCRCC. In conclusion, the present study confirmed that Notch 1 is a valuable target against cell survival and proliferation in CCRCC treatment.

Notch Signaling Pathway in Cancer—Review with Bioinformatic Analysis

“…In terms of the individual genes, NOTCH1 expression was positively correlated with clear cell renal cell carcinoma (CCRCC) carcinogenesis and progression. Indeed, Zhuang Z. and colleagues reported that NOTCH1 protein expression was exhibited in patients with higher TNM stage or Fuhrman grade or larger tumor size [ 64 ]. Moreover, NOTCH1 and JAG1 expression were significantly elevated in localized and metastatic CCRCC tumors [ 65 , 66 ], and they were also linked to reduced overall and disease-free survival [ 67 ].…”

Prognostic Signatures and Therapeutic Value Based on the Notch Pathway in Renal Clear Cell Carcinoma

“…Specific inhibition of Notch1 in renal carcinoma cells reduced the level of B-cell lymphoma/leukemia-2 (BC1-2) proteib and increased apoptosis. Meanwhile, the phosphorylation of phosphatidylinositol-3kinase (P13K)/protein kinase B (Akt), which is involved in promoting cell growth and proliferation, decreased [ 49 ], suggesting that Notch1 simultaneously regulates the proliferation and apoptosis of tumor cells and inhibits Notch1 signaling, which may be a new therapeutic target. Von Hippe1 is known to cause protein inactivation.…”

Neo-Fs Index: A Novel Immunohistochemical Biomarker Panel Predicts Survival and Response to Anti-Angiogenetic Agents in Clear Cell Renal Cell Carcinoma

“…NOTCH1 expression is associated with poor survival as well as advanced grade or TNM stage in hepatocellular carcinoma (HCC) and colorectal cancer [ 10 ]. In clear cell RCC, NOTCH1 expression is associated with advanced TNM stage and higher Fuhrman grade [ 11 ]. ARID1A loss—correlated with microsatellite instability and increased mutation burden across cancer types [ 12 ]—has shown favorable prognostic impact—is known to be associated with peritumoral lymphoid aggregates/tumor-infiltrating lymphocytes—in esophageal adenocarcinoma, suggesting the impact of neoantigen-induced immunogenicity on survival [ 13 ].…”