MiR-19a-3p Promotes Aerobic Glycolysis in Ovarian Cancer Cells via IGFBP3/PI3K/AKT Pathway.

Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer.

[PI3K isoforms PI3Kß and PI3Kδ play different roles in KIT mutation-mediated cell transformation].

Objective To investigate the role of phosphatidylinositol 3-kinase (PI3K) isoforms in type III receptor tyrosine kinase KIT mutation-mediated signaling and cell proliferation. Methods The wild-type KIT and the common KIT mutations V560D and W557K558del in gastrointestinal stromal tumors (GIST) were stably expressed in BaF3 cells. The cells were treated with PI3K isoforms PI3Kα, PI3Kß and PI3Kδ specific inhibitors or pan PI3K inhibitor. The activation of KIT and its downstream signals was detected by immunoprecipitation and Western blot analysis. GIST-T1 cells were treated with the same drug, and the activation of KIT and its downstream signals was also detected by immunoprecipitation and Western blot analysis, and cell proliferation and apoptosis were detected by MTT assay and flow cytometry, respectively. Results Compared with the controls, in BaF3 cells expressing wild-type KIT and its mutants, the activation of KIT and its downstream signaling molecules AKT and ERK was inhibited the most by PI3Kδ specific inhibitor, followed by the specific inhibitors of PI3Kα and PI3Kß subtype. In GIST-T1 cells, the activation of KIT and its downstream signals was inhibited the most by PI3Kß specific inhibitor, followed by PI3Kδ and PI3Kα specific inhibitors. Conclusion In BaF3 cells, PI3Kδ subtype plays a major role in KIT activation and its downstream signal transduction, while in GIST-T1 cells, PI3Kß subtype plays a major role in KIT activation and its downstream signal transduction. These results indicate that PI3K isoforms play different roles in KIT mutation-mediated cell transformation depending on the host cells.

The NF-κB modulated miR-194-5p/IGF1R/PPFIBP axis is crucial for the tumorigenesis of ovarian cancer.

miRNAs are involved in the tumorigenesis of various malignancies. In the current study, we found that miR-194-5p expression is downregulated in ovarian cancer tissues, and downregulation of miR-194-5p expression promotes proliferation, invasion and migration of human ovarian cancer cells in vitro and ovarian tumor growth in nude mice. We further found that IGF1R and PPFIBP are targets of miR-194-5p, and downregulation of miR-194-5p expression increases IGF1R and PPFIBP expression, resulting in increased proliferation, invasion and migration of ovarian cancer cells. Moreover, we showed that NF-κB can bind to the promoter region of miR-194-5p, and negatively regulate the expression of miR-194-5p in ovarian cancer cells. Taken together, our results suggested a NF-κB modulated miR-194-5p/IGF1R/ PPFIBP axis that is crucial for the tumorigenesis of ovarian cancer, which provides a new insight into the development of ovarian cancer.