Mammalian Target of Rapamycin (mTOR) Regulates Transforming Growth Factor-ß1 (TGF-ß1)-Induced Epithelial-Mesenchymal Transition via Decreased Pyruvate Kinase M2 (PKM2) Expression in Cervical Cancer Cells.

BACKGROUND Epithelial-mesenchymal transition (EMT) plays an important role in cancer tumorigenesis. Transforming growth factor ß1 (TGF-ß1) can induced EMT, which could increase tumor migration and invasion. Moreover, recent studies have been proven that mammalian target of rapamycin (mTOR) is a critical regulator of EMT. We investigated the mechanisms of mTOR in transforming growth factor ß1 (TGF-ß1)-induced EMT in cervical cancer cells. MATERIAL AND METHODS HeLa and SiHa cells were treated with 10 ng/ml TGF-ß1 to induce EMT. Then, they were treated with or without rapamycin. CCK8 assay was performed to determine cell proliferation. Cell migration was detected by wound-healing assay; apoptosis was analyzed by flow cytometry; mTOR inhibitors inhibited mTOR pathway to assess the expression of E-cadherin, Vimentin STAT3, Snail2, p-p70s6k, and PKM2 expression. RESULTS TGF-ß1 promoted proliferation and migration, and attenuated apoptosis in cervical carcinoma cells. Rapamycin abolished TGF-ß1-induced EMT cell proliferation and migration and reversed TGF-ß1-induced EMT. E-cadherin were suppressed, whereas Vimentin and PKM2 were increased in HeLa and SiHa cells after stimulation with TGF-ß1. Moreover, mTOR was activated in the process of TGF-ß1-induced EMT. Rapamycin inhibited the phosphorylation of p70s6k. Furthermore, inhibition of the mTOR pathway decreased PKM2 expression. CONCLUSIONS Inhibition of the mTOR pathway abolished TGF-ß1-induced EMT and reduced mTOR/p70s6k signaling, which downregulated PKM2 expression. Our results provide novel mechanistic insight into the anti-tumor effects of inhibition of mTOR.

Survivin Overexpression Is Associated with Aggressive Clinicopathological Features in Cervical Carcinoma: A Meta-Analysis.

OBJECTIVE: Overexpression of survivin has been reported in many human tumors. However, the clinicopathological features associated with survivin overexpression in cervical carcinoma remain controversial. Thus, the current meta-analysis was performed to assess the clinicopathological significance of survivin in cervical carcinoma. METHODS: PubMed, EMBASE, and Web of Science databases were searched for relevant studies published through November 1, 2015. A meta-analysis was performed to evaluate the association between survivin expression and clinicopathological outcome in cervical carcinoma. RESULTS: Eleven eligible studies with a total of 865 patients were included. Survivin overexpression was closely related to lymph node metastasis (odds ratio [OR] = 0.679, 95% confidence interval [CI]: 0.509-0.905, P = 0.008) but was not significantly associated with tumor FIGO stage (I+II vs. III+IV) (OR = 0.843, 95% CI: 0.626-1.137, P = 0.264), tumor grade (G1+G2 vs. G3) (OR = 0.913, 95% CI: 0.689-1.210, P = 0.527), tumor size (>4 vs. ≤4 cm) (OR = 0.825, 95% CI: 0.434-1.570, P = 0.559), or stromal involvement (OR = 0.820, 95% CI: 0.545-1.233, P = 0.340). The correlation between survivin expression and overall survival was evaluated among a total of 238 patients from three eligible studies. The pooled HR was 1.129 (95% CI: 0.597-1.661; P = 0.000), indicating that survivin expression was significantly associated with poor survival in cervical carcinoma. CONCLUSIONS: Based on the current meta-analysis, survivin is strongly associated with lymph node metastasis and poor prognosis. Additionally, survivin is a novel clinicopathological marker of cervical carcinoma and thus may be a therapeutic target for cervical carcinoma.

c-myc Gene Copy Number Variation in Cervical Exfoliated Cells Detected on Fluorescence in situ Hybridization for Cervical Cancer Screening.

PURPOSE: This study assessed the clinical significance of c-myc gene copy number gain detected by fluorescence in situ hybridization (FISH) in the prediction of cervical intraepithelial neoplasia (CIN) progression. METHODS: We retrospectively investigated 140 Thinprep cytologic test (TCT) specimens that were histopathologically diagnosed with various stages of cervical neoplasia or malignancy. The specimens were subjected to TCT, human papillomavirus (HPV) testing, and FISH analysis with a c-myc-specific probe. The diagnostic reliability of these methods in determining progression was assessed according to sensitivity, specificity, and κ coefficients. RESULTS: The gene copy number gain of c-myc was significantly higher in the cervical lesion of advanced histologic grade (p < 0.001). For CIN2+ lesions, the sensitivities of TCT, HPV DNA testing, and FISH analysis were 72.3, 92.1, and 64.5%, respectively; the specificities were 81.3, 57.8, and 93.8%, respectively (p < 0.001). The κ coefficients between the c-myc gene test and either the TCT or the HPV DNA test were 0.538 and 0.399, respectively (p < 0.001). CONCLUSIONS: FISH analysis of the c-myc oncogene could be a useful adjunct screening method for the early diagnosis of high-grade cervical lesions. Moreover, c-myc may be a new molecular biomarker for the early diagnosis of cervical lesion progression.