hes1-protein--human and Carcinoma--Ovarian-Epithelial

To explore the expression of Stomatin-like protein 2 (SLP-2) and its clinical significance in epithelial ovarian cancer (EOC).. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the differential expression of SLP-2 in EOC tissues and cell lines. The relationship between SLP-2 expression and clinical pathological data of EOC patients was analyzed.. QRT-PCR results suggested that the SLP-2 was up-regulated in both EOC tissues and EOC cells by comparing with normal control. SLP-2 expression was a correlation with tumor pathological grade, distant metastasis, and TNM stage in EOC patients. Down-regulation of SLP-2 could significantly inhibit proliferation and promote apoptosis of EOC cells by activating the Notch signaling pathway. Knockdown of SLP-2 markedly downregulated Notch1 and Hes1.. SLP-2 was a novel factor involved in EOC progression, and could be utilized as a potential biomarker and therapeutic target for the EOC patients.

Topics: Apoptosis; Biomarkers, Tumor; Blood Proteins; Carcinoma, Ovarian Epithelial; Cell Line; Cell Proliferation; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Middle Aged; Ovarian Neoplasms; Receptor, Notch1; Signal Transduction; Transcription Factor HES-1; Up-Regulation

Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notch1 induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notch1 increases TGFβ/Smad signaling by upregulating the expression of TGFβ and TGFβ type 1 receptor. Time course experiments demonstrate that inhibition of Notch by DAPT (a γ-secretase inhibitor) decreases TGFβ-induced phosphorylation of receptor Smads at late, but not at early, timepoints. These results suggest that Notch activation plays a role in sustaining TGFβ/Smad signaling in EOC cells. Furthermore, inhibition of Notch by DAPT decreases TGFβ induction of Slug and repression of E-cadherin and knockdown of Notch1 decreases TGFβ-induced repression of E-cadherin, indicating that Notch is required, at least in part, for TGFβ-induced EMT in EOC cells. On the other hand, TGFβ treatment increases the expression of Notch ligand Jagged1 and Notch target gene HES1 in EOC cells. Functionally, the combination of Notch1 activation and TGFβ treatment is more potent in promoting motility and migration of EOC cells than either stimulation alone. Taken together, our results indicate that Notch and TGFβ form a reciprocal positive regulatory loop and cooperatively regulate EMT and promote EOC cell motility and migration.

Topics: Antigens, CD; Cadherins; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Humans; Jagged-1 Protein; Ligands; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Notch; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transcription Factor HES-1; Transforming Growth Factor beta; Up-Regulation