Cell signalling pathways play a critical role in tumorigenesis that is frequently investigated in the recent years. Deregulation of the signaling pathways drives the cancer cell growth, survival, differantiation, invasion, and metastasis of all malignant tumors. These pathways include the Wnt/β-catenin, Notch, JAK/STAT, Hedgehog, PI3K/AKT/mTOR, Peroxisome-proliferator-activated receptor (PPAR), TGF β/SMAD, and the nuclear factor kappa beta (NF-kB) signaling pathway [16]. Among these signaling pathways, the mTOR pathway accepted increased focus because strong evidence has proven that targeting the mTOR pathway could be a promising anticancer therapeutic option. More importantly, many mTOR inhibitors have been and are being investigated in clinical trials several types of human cancers. Accumulated evidence has also demonstrated that DEPTOR plays pivotal roles in tumorigenesis [4].
Previous studies reported that DEPTOR displays dual roles in tumorigenesis. It is well known that DEPTOR is negatively regulated by mTORC1 and mTORC2, which are frequently activated in human malignancies. Most studies suggest that DEPTOR plays a tumor-suppressive role by mTORC1 and mTORC2 inactivation and low DEPTOR expression is related to the promotion of cancer cell survival and tumor formation. In pancreatic cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and lung adenocarcinoma, the expression of DEPTOR is downregulated which predicts a poor prognosis [17–21]. However, some studies have shown that DEPTOR was overexpressed in some malignancies, possibly because DEPTOR not only inhibited the activity of mTORC1, but also reducing the feedback inhibition from S6K1 to PI3K, leading to AKT activation. Thus, DEPTOR acts as an oncogen. However, the role and the prognostic value of DEPTOR in MF remains unclear.
The importance of the PI3K/AKT/mTOR signaling network in CTCL pathogenesis has been noted recently. mTOR phosphorylation regulates downstream p70S6K and 4E-BP1 which controls DNA and protein synthesis and can act as protooncogenes. The activated form of these proteins has been detected by immunohistochemistry in a study with 50 MF patients and expression of p-AKT, p-4E-BP1, and p-p70S6K has been reported to be associated with advanced stage. With these findings, it can be proposed that phosphorylated p-AKT, p-mTOR, p-p70S6K, and p-4E-BP1 serve as a potential prognostic marker in advanced-stage MF [6]. In another study Witzig et al. revealed that CTCL cells had activated mTOR pathway and the mTORC1 inhibitor everolimus had substantial antitumor activity in vitro [7]. In this study, we reported it for the first time that DEPTOR levels were significantly lower in patients with MF than in healthy controls. However, as we only collected 40 MF samples in our study, we did not observe significant correlation between DEPTOR levels according to disease stage. This may be due to the lower number of patients in some subgroups. So, the correlation analysis is needed to be reevaluated in a large patient population. When the patients with MF grouped by early and advanced stages, the mean serum DEPTOR concentration in patients with advanced stage was lower than that in early stages, but the difference was not statistically significant. This may be explained by only 4 patients (10%) in our study who had advanced stage disease and lack of stage 2B and stage 4 patients, making it statistically difficult to investigate the association among the parameters of the study.
Several publications have shown regulation of DEPTOR by cancer treatment drugs. Obara et al. determined that treatment of liver cancer cells with metformin resulted in an increase in DEPTOR protein levels by inhibition of proteasome activities, thus suppressing cell proliferation through inhibiting mTOR signaling [22]. A recent study reported gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification in lung adenocarcinoma cell lines [23]. In another study by Ma et al. gastric cancer tissues with decreased DEPTOR expression was shown that restored DEPTOR markedly suppressed the proliferation in gastric cancer cells via disturbing mTORC1 function [24]. It is interesting to further explore in regulating the DEPTOR/mTOR signaling axis since signaling pathway members present as promising agents to treat the pathologic condition with low DEPTOR activation including MF.
There are several weak points in this study. Firstly, only the serum DEPTOR level was evaluated, immunohistochemistry was not done. Secondly, the sample size was decided according to the size of the DEPTOR ELISA kit and for this reason the small sample size limits the study. Thirdly, there were few patients with advanced MF (only stage 3), therefore we didn’t have enough data to understand the prognostic value of DEPTOR.