mTORC1 and mTORC2 Expressions in the Oral Squmous Cell Carcinoma: an Immunohistochemical and Clinicopathological Study

Goro Kawasaki DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Tomofumi Naruse DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Toshihiro Kawano DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Satoshi Rokutanda DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Hidenori Takahashi DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Yuki Matsushita DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
Tohru Ikeda DDS, PhD, Oral Pathology and Bone Metabolism, Nagasaki University, Nagasaki, Japan
Masahiro Umeda DDS, PhD, Clinical Oral Oncology, Nagasaki University, Nagasaki, Japan
The mammalian target of rapamycin (mTOR) is a 289-KDa serine/threonine kinase belonging to the phosphoinositide 3-kinase (PI3K)-related kinase family that regulates cell growth, proliferation, and progression of the cell cycle. mTOR is activated by the phosphorylation of Ser2448 through the PI3K/AKT signaling pathway, and completes these functions by activating p70 ribosomal S6 kinase and phosphorylating the eukaryotic initiation factor 4E binding protein 1. mTOR consists of two separate multi-protein complexes, mTORC1and mTORC2, that are both activated by growth factor stimulation. Rapalogs are first generation mTOR inhibitors and they allosterically inhibit the mTORC1 but not mTORC2. Activated mTOR has been associated with poor prognosis in various cancers including oral squamouse cell carcinoma (OSCC). However, the anti-tumor effect of the mTOR inhibitor in OSCC remains unclear. For the effect of the mTOR inhibitor to OSCC, it is important to investigate the expressions of mTORC1 and mTORC2 in OSCC. In the present study, we investigated the immunohistochemical expressions of mTORC1 and mTORC2 in OSCC.

Materials and methods: Paraffin-embedded sections were obtained from the biopsy specimens of 70 patients with OSCC who underwent radical surgery in our Department between January 2000 and December 2007. The tumor stage was classified according to the TNM classification of the International Union Against Cancer. The histological differentiation of tumors was defined according to the WHO classification.  Immunohistochemical staining was performed using the Envision system (ENVISION+; DAKO, Glostrup, Denmark). The primary antibodies used were against mTORC1, mTORC2 proliferating cell nuclear antigen (PCNA), VEGF-A , VEGF-C and HIF1. Results were evaluated by calculating the total immunostaining score as the product of the proportional score and intensity score. The proportional scores described the estimated fraction of positively-stained tumor cells (0, none; 1, <10%; 2, 10-50%; 3, 50- 80%; 4, >80%). The intensity score represented the estimated staining intensity (0, no staining; 1, weak; 2, moderate; 3, strong). Total scores ranged from 0-12. Immunohistochemical overexpression was defined as a total score greater than 4 because immunohistochemical expression in samples showed a bimodal distribution with the discriminating nadir at a total score value of 3 to 4. The relationships between the sample expression of target molecules and clinicopathological features were assessed by Fischer’s exact test. Survival analysis was calculated using the Kaplan-Meier method and compared using the log-rank test. A multiple regression study was performed using Cox’s proportional hazard analysis.

Results: mTORC1and mTORC2 were overexpressed in 37 tumors and 50 tumors, respectively. mTORC1 and mTORC2 protein expressions were absent or minimal in the cytoplasm of epithelial cells in normal oral tissue. mTORC1 was correlated with the T classification, N classification, and survival rate (P<0.05). mTORC2 was correlated with the T classification (P<0.05). Both mTORC1 and mTORC2 had a correlation with cancer cell invasivion and expression of PCNA (P<0.05). The numbers of  mTORC1(-)mTORC2(+) and mTORC1(+)mTORC2(-) were 16 and 17 of 72, respectively. Expressions of VEGFs and HIF1 in mTORC1(+)mTORC2(-) group was significantly lower than those of other groups.

Conclusions: mTORC1 and mTORC2 were overexpressed in OSCC, and they were significantly correlated with clinicopathological factors. We suggest tthat mTORC1 and mTORC2 could be a promising target for the anti-tumor effect for OSCC.

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