No Significant Association between PIK3CA Mutation and Survival of Esophageal Squamous Cell Carcinoma: A Meta-analysis / 华中科技大学学报（医学）（英德文版）

The prognostic value of phosphatidylinositol-4,5-bisphosphate 3-kinase,catalytic subunit alpha (PIK3CA) in patients with esophageal squamous cell carcinoma (ESCC) is controversial.We aimed to investigate the prognostic significance of PIK3CA mutation in patients with ESCC.EMBASE,PubMed,and Web of Science databases were systematically searched from inception through Oct.3,2016.The hazard ratios (HRs) and 95％ confidence intervals (CI) were calculated using a random effects model for overall survival (OS) and disease-free survival (DFS).Seven studies enrolling 1505 patients were eligible for inclusion of the current meta-analysis.Results revealed that PIK3CA mutation was not significantly associated with OS (HR:0.90,95％ CI:0.63-1.30,P=0.591),with a significant heterogeneity (I2=65.7％,P=0.012).Additionally,subgroup analyses were further conducted according to various variables,such as types of specimen,the sample size,technique and statistical methodology.All results suggested that no significant relationship was found between PIK3CA mutation and OS in patients with ESCC.For DFS,there was no significant association between PIK3CA mutation and DFS in patients with ESCC (HR:1.00,95％ CI=0.47-2.11,P=0.993,I2=73.7％).Publication bias was not present and the results of sensitivity analysis were very stable in the current meta-analysis.Our findings suggest that PIK3CA mutation has no significant effects on OS and DFS in ESCC patients.More well-designed prospective studies with better methodology for PIK3CA assessment are required to clarify the prognostic significance of PIK3CA mutation in ESCC patients.

Phosphatidylinositol 4-phosphate 5-kinase alpha negatively regulates nerve growth factor-induced neurite outgrowth in PC12 cells

Neurite outgrowth, a cell differentiation process involving membrane morphological changes, is critical for neuronal network and development. The membrane lipid, phosphatidylinositol (PI) 4,5-bisphosphate (PIP2), is a key regulator of many important cell surface events of membrane signaling, trafficking and dynamics. This lipid is produced mainly by the type I PI 4-phosphate 5-kinase (PIP5K) family members. In this study, we addressed whether PIP5Kalpha, an isoform of PIP5K, could have a role in neurite outgrowth induced by nerve growth factor (NGF). For this purpose, we knocked down PIP5Kalpha in PC12 rat pheochromocytoma cells by stable expression of PIP5Kalpha microRNA that significantly reduced PIP5Kalpha expression and PIP2 level. Interestingly, NGF-induced neurite outgrowth was more prominent in PIP5Kalpha-knockdown (KD) cells than in control cells. Conversely, add-back of PIP5Kalpha into PIP5Kalpha KD cells abrogated the effect of NGF on neurite outgrowth. NGF treatment activated PI 3-kinase (PI3K)/Akt pathway, which seemed to be associated with reactive oxygen species generation. Similar to the changes in neurite outgrowth, the PI3K/Akt activation by NGF was potentiated by PIP5Kalpha KD, but was attenuated by the reintroduction of PIP5Kalpha. Moreover, exogenously applied PIP2 to PIP5Kalpha KD cells also suppressed Akt activation by NGF. Together, our results suggest that PIP5Kalpha acts as a negative regulator of NGF-induced neurite outgrowth by inhibiting PI3K/Akt signaling pathway in PC12 cells.

A double point mutation in PCL-gamma1 (Y509A/F510A) enhances Y783 phosphorylation and inositol phospholipid-hydrolyzing activity upon EGF stimulation

Growth factor stimulation induces Y783 phosphorylation of phosphoinositide-specific PLC-gamma1, and the subsequent activation of this enzyme in a cellular signaling cascade. Previously, we showed that a double point mutation, Y509A/F510A, of PLC-gamma1, abolished interactions with translational elongation factor 1-alpha. Here, we report that the Y509A/F510A mutant PLC-gamma1 displayed extremely high levels of Y783 phosphorylation and enhanced catalytic activity, compared to wild-type PLC-gamma1, upon treatment of COS7 cells with EGF. In quiescent COS7 cells, the Y509A/F510A mutant PLC-gamma1 exhibited a constitutive hydrolytic activity, whereas the wild-type counterpart displayed a basal level of activity. Upon treatment of COS7 cells with EGF, the Y783F mutation in Y509A/F510A PLC-gamma1 (Y509A/F510A/Y783F triple mutant) cells also led to an enhanced catalytic activity, whereas Y783F mutation alone displayed a basal level of activity. Our results collectively suggest that the Y509A/F510A mutant is more susceptible to receptor tyrosine kinase-induced Y783 phosphorylation than is wild-type PLC-gamma1, but no longer requires Y783 phosphorylation step for the Y509A/F510A mutant PLC-gamma1 activation in vivo.