5294

PIK3CG

phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma;PIK3CG;phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma

1-phosphatidylinositol 3-kinase|PI3-kinase subunit gamma|phosphatidylinositol 3 kinase gamma, p110 gamma|phosphatidylinositol 3-kinase catalytic 110-kD gamma|phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform|phosphatidylinosit

7q22.3

protein-coding

The phosphoinositide-3 kinase (PI3K)-AKT- mammalian target of rapamycin (mTOR) pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion and drug response. We hypothesized that genetic variations in the PI3K-AKT-mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single-nucleotide polymorphisms (SNPs) of 20 genes in the PI3K-AKT-mTOR pathway as predicators of survival. In multivariate Cox regression, AKT2 rs3730050, PIK3R1 rs10515074 and RAPTOR rs9906827 were significantly associated with survival. In combined analysis, we found a cumulative effect of these three SNPs on survival. With the increasing number of unfavorable genotypes, there was a significant trend of higher risk of death in multivariate Cox regression (P for trend <0.001) and shorter median survival time in Kaplan-Meier estimates (P log rank <0.001). This is the first study to evaluate the role of germ line genetic variations in the PI3K-AKT-mTOR pathway genes as predictors of MiM-BC clinical outcomes. These findings warrant further replication in independent populations and may provide information on disease management and development of target therapies.

HRG-beta1 stimulation of breast cancer cell line SKBR3 resulted in not only increased cell migration and invasion, upregulation of some mesenchymal markers, and downregulation of epithelial marker, but also upregulation of transcription factor Snail and its nuclear translocation. Similar results were acquired for cells transfected with Snail cDNA. Furthermore, downregulation of Snail by siRNA attenuated HRG-beta1 induced EMT-like phenotype. Inhibition of Akt kinase activation by a PI3K inhibitor LY294002, or exogenous expression of a kinase-dead mutant of Akt abrogated the increase of Snail expression induced by HRG-beta1. Conversely, expression of a constitutively active Akt resulted in increase of Snail expression. These results indicated that Snail upregulation by HRG-beta1 is mediated via the PI3K/Akt signaling pathway and that Snail plays a key role in HRG-beta1 induced breast cancer cell metastasis through induction of EMT.

BACKGROUND & OBJECTIVE: Phosphatidylinositol 3-kinase /protein kinase B (PI3K/Akt) signaling pathway is involved in a variety of important cellular functions, including genesis and progression of neoplasms. However, its role in cervical cancer is unclear. This study was to detect the expression of PI3K and Akt proteins in different cervical lesions, and to investigate the correlation of PI3K/Akt signal transduction pathway to biological behaviors of cervical carcinoma. METHODS: The expression of PI3K and Akt in 76 specimens of cervical carcinoma,21 specimens of cervical intraepithelial neoplasia and 10 specimens of normal cervical epithelium were detected by SP immunohistochemistry. Their correlations to clinicopathologic features of cervical carcinoma were analyzed. RESULTS: The positive rates of PI3K and Akt were significantly lower in normal cervical epithelium and cervical intraepithelial neoplasia than in cervical carcinoma (0.0% and 42.9% vs. 69.7%, P<0.01;10.0% and 52.4% vs. 75.0%,P<0.01). The expression of PI3K and Akt proteins were correlated to clinical stage, pathologic grade and lymph node metastasis(P<0.01), but not to age, the size of primary focus, and histological type(P>0.05).The expression of PI3K protein was positively correlated to the expression of Akt protein(r=0.425,P<0.01). CONCLUSION: High expression of PI3K and Akt are involved in proliferation, malignant transformation, invasion and metastasis of cervical carcinoma, both of which may play important roles in the occurrence and development of human cervical carcinoma.

BACKGROUND: Ewing's sarcoma family of tumours (ESFT) is a malignant small round-cell tumour of the bone and soft tissues. It is characterised by a strong tendency to invade and form metastases. The microenvironment of the bone marrow is a large repository for many growth factors, including the basic fibroblast growth factor (bFGF). However, the role of bFGF in the invasive and metastatic phenotype of ESFT has not been investigated. METHODS: The motility and invasion of ESFT cells were assessed by a wound-healing assay, chemotaxis assay, and invasion assay. The expression and activation of FGF receptors (FGFRs) in ESFT cell lines and clinical samples were detected by RT-PCR, western blotting, and immunohistochemistry. The morphology of ESFT cells was investigated by phase-contrast microscopy and fluorescence staining for actin. Activation of Rac1 was analysed by a pull-down assay. RESULTS: bFGF strongly induced the motility and invasion of ESFT cells. Furthermore, FGFR1 was found to be expressed and activated in clinical samples of ESFT. Basic FGF-induced cell motility was mediated through the FGFR1-phosphatidylinositol 3-kinase (PI3K)-Rac1 pathway. Conditioned medium from bone marrow stromal cells induced the motility of ESFT cells by activating bFGF/FGFR1 signalling. CONCLUSION: The bFGF-FGFR1-PI3K-Rac1 pathway in the bone microenvironment may have a significant role in the invasion and metastasis of ESFT.