Prognostic significance of PI3K/AKT/ mTOR signaling pathway members in clear cell renal cell carcinoma

Abstract

Background Renal cell carcinoma (RCC) is a fatal disease, in which the PI3K/AKT/mTOR signaling pathway serves an important role in the tumorigenesis. Previous studies have reported the prognostic significance of PI3K/AKT/mTOR signaling pathway members in RCC; however, there is insufficient evidence to date to confirm this. Thus, the present study aimed to systematically investigate the prognostic roles of multiple PI3K/AKT/mTOR signaling proteins in clear cell RCC (ccRCC) using online large-scale databases. Methods The mRNA expression profiles of PI3K/AKT/mTOR signaling pathway proteins PTEN, PIK3CA, PIK3CB, PIK3CD, PIK3CG, AKT1, AKT2, AKT3 and mTOR were investigated using the Gene Expression Profiling Interactive Analysis (GEPIA) and Oncomine databases, and the protein expression levels of PI3K, AKT and mTOR were detected using western blotting (WB) analysis. In addition, the correlation between mRNA or protein expression levels and the prognostic significance was analyzed using the Kaplan-Meier (K-M) plotter (n = 530), the Human Protein Atlas (HPA; n = 528) and The Cancer Protein Atlas (TCPA; n = 445) databases. Results The GEPIA revealed that the mRNA expression of major PI3K/AKT/mTOR pathway members, including PTEN, PIK3CA, PIK3CB, AKT1, AKT2 and AKT3, were negatively correlated with ccRCC stages (P < 0.05), though most of their mRNA and protein expression levels were notsignificantly different between ccRCC and normal tissues using GEPIA, Oncomine and WB analyses (P < 0.05). Meanwhile, using the K-M plotter and HPA prognostic analysis, it was found that the mRNA expression levels of the majority of the PI3K/AKT/mTOR signaling pathway members, including PTEN, PIK3CA, PIK3CB, PIK3CG, AKT3 and mTOR were positively correlated with overall survival (OS), whereas PIK3CD mRNA expression was negatively correlated with OS (P < 0.05). Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway [PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05). In conclusion, the present study suggested that several members of the PI3K/AKT/mTOR signaling pathway, especially PTEN, may be favorable prognostic factors in ccRCC, which indicated that the PI3K/AKT/mTOR signaling pathway may be implicated in ccRCC initiation and progression.

Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma

“…WB demonstrated that the expression level of mTOR showed a decreasing trend in ccRCC compared with adjacent specimens (P = 0.077, Fig. 1), which was consistent with its mRNA expression (Fan et al, 2020). While p-mTOR expression was stable in both malignant and adjacent non-tumor tissues (P = 0.894).…”

“…Using integrative proteogenomic analysis, Zhang found that p-mTOR expression level was significantly correlated with improved outcomes in 32 major types of cancer including RCC, which was contradictory to the experimental results (Zhang et al, 2017). Similarly, we reported the prognosis of PI3K/AKT/mTOR pathway members in ccRCC using public databases analysis, which demonstrated that mTOR mRNA were positively correlated with OS of over 500 ccRCC patients, and p-mTOR (S2448) was also positively correlated with OS in patients with ccRCC (n = 445) (Fan et al, 2020). But no experimental evidence has validated the positive prognosis of mTOR in ccRCC patients yet.…”

“…These literatures revealed the negative role of p-mTOR in the patient's survival. Through large-scale proteogenomic analysis, several researches demonstrated mTOR alteration or activation in RCC, but most of them were not involved in its prognosis (Cancer Genome Atlas Research Network, 2013;Chen et al, 2016;Fan et al, 2020;Han et al, 2017;Zhang et al, 2017). Using integrative proteogenomic analysis, Zhang found that p-mTOR expression level was significantly correlated with improved outcomes in 32 major types of cancer including RCC, which was contradictory to the experimental results (Zhang et al, 2017).…”

“…Increasing literature has elaborated mTOR activation in RCC, while its clinical value during RCC pathogenesis has not been fully elucidated yet (Cancer Genome Atlas Research Network, 2013;Chen et al, 2016;Darwish et al, 2013;Han et al, 2017;Zhang et al, 2017). Our previous study revealed that expression of mTOR pathway members might play distinguished roles in different stages or grades of RCC, implying the complexity of mTOR signaling pathway in the development of RCC (Fan et al, 2020). Thus, it is necessary to present a better looking of the relationship between mTOR signaling pathway and RCC.…”

“…Previous studies demonstrated that phosphorylated mTOR (p-mTOR) was increased in RCC, and enhanced p-mTOR was associated with impaired overall survival (OS), which indicated that the PI3K/AKT/mTOR signaling pathway could promote the initiation and progression of RCC (Darwish et al, 2013;Kruck et al, 2010;Liontos et al, 2017;Rausch et al, 2019). Recent large-scale proteogenomic analyses found that mTOR and/or p-mTOR expression levels were significantly correlated with improved outcomes in RCC (Fan et al, 2020;Zhang et al, 2017), which was contradictory to the most widely accepted research and data. Collectively, the above studies failed to reach a consistent conclusion, and the prognostic role of mTOR in RCC remains controversial.…”