Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma

Abstract

Abstract. DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently identified mTOR-interacting protein, is a novel candidate oncogene. Previous studies reveal that high DEPTOR expression is required to maintain PI3K and Akt activation and to inhibit apoptosis. However, its significance in differentiated thyroid carcinoma (DTC) is not yet known. The present study verifies the mRNA and protein expression of DEPTOR in five cell lines, DTC tissues and normal adjacent tissues. Tissue microarrays of 114 DTC patients were used to detect DEPTOR protein expression. The assessment of DEPTOR levels demonstrated that DEPTOR in DTC cells and tissues was significantly increased compared with normal cells and adjacent normal tissues. DEPTOR protein expression was significantly associated with lymph node status, extrathyroid extension and distant metastasis. Patients exhibiting high DEPTOR expression were statistically susceptible to earlier recurrence and poorer survival than those with low expression. Univariate and multivariate analyses showed that DEPTOR expression was an independent prognostic factor for DTC recurrence. In conclusion, our data indicate DEPTOR as a novel prognostic marker for DTC. IntroductionDifferentiated thyroid carcinoma (DTC) is the most common histological type of thyroid malignancy and its incidence is increasing (1). Although the majority of DTCs have a relative low mortality, with 10-year survival rates of 83-95%, approximately 30% of patients with DTC still undergo recurrence during the decades following initial therapy during several decades (2,3). Establishing relevant biomarkers with prognostic significance may prove crucial in reducing the recurrence rate and modifying therapeutic strategies for individual DTC patients (4). To date, few molecular prognostic indicators have been used to evaluate the efficiency of DTC patient diagnosis and prognosis (5,6).DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently identified 48 kDa mTOR-interacting protein, is a novel candidate oncogene (7). DEPTOR is capable of inhibiting mTORC1 signaling and activation of mTORC2 signaling (8-10). As the downstream signal of DEPTOR, mTORC2 protein complex displays PDK-2 activity leading to serine 473 phosphorylation and overactivation of the PI3K/Akt pathway (11,12). Many key functions of PI3K/Akt signaling, such as genetic mutations of kinases and regulatory proteins, epigenetic alterations and post-translational modifications, have already been confirmed by in vitro studies and clinical data in thyroid cancer and a wide variety of other tumors (13-15). The significant role of DEPTOR in regulating tumor growth and progression indicates that it may closely correlate with aggressive clinical behaviors of DTC.However, the expression level of DEPTOR in DTC is largely unknown and the role of DEPTOR in clinical progression remains to be established. Therefore, we evaluated DEPTOR expression on the mRNA and protein level in thyroid ca...

Deptor: not only a mTOR inhibitor

“…Similar findings have been reported in differentiated thyroid carcinoma (DTC) cell lines and tissues, where Deptor levels have been found associated with lymph node status, extra thyroid extension and distant metastasis, confirming its important role in tumor progression [45]. However, Deptor mRNA did not correlate to protein levels in these cells, suggesting the presence of post-transcriptional events controlling Deptor degradation [45].…”

“…However, Deptor mRNA did not correlate to protein levels in these cells, suggesting the presence of post-transcriptional events controlling Deptor degradation [45]. In agreement, a strong correlation between Deptor overexpression and reduced overall survival has been observed in DTC patients [45]. …”

Downregulation of DEPTOR inhibits the proliferation, migration, and survival of osteosarcoma through PI3K/Akt/mTOR pathway

“…These results are consistent with DEPTOR expression in some subtypes of breast cancer, prostate cancer, chronic myeloid leukemia, and MM. 5 , 12 , 19 , 38 , 39 In one case, DEPTOR expression showed minor difference between the corresponding adjacent benign tissue and cancer tissue. In addition, DEPTOR mRNA and protein expression in one OS cell line, U2OS, was not as high as that observed in MG63 and MNNG/HOS cells.…”

DEPTOR has growth suppression activity against pancreatic cancer cells

“…Several prior studies have reported conflicting correlations between DEPTOR expression and patient prognosis or disease status in human malignancies. One study showed that DEPTOR overexpression correlates with poor prognosis in differentiated thyroid carcinoma [ 23 ], whereas another study revealed that DEPTOR expression negatively correlates with tumor progression in colorectal cancer [ 24 ]. Here we show that DEPTOR expression is gradually lost during pancreatic tumorigenesis, and completely lost in PDAC tissues.…”