A PLCB1-PI3K-AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression.

As a member of the phospholipase family, phospholipase C beta 1 (PLCB1) is involved in phospholipid hydrolysis and is frequently upregulated in human cancer. However, little is known about the role of PLCB1 in cholangiocarcinoma (CCA). In this study, we uncover a role for PLCB1 in CCA progression and identify the underlying mechanisms. Both human CCA tissues and CCA cell lines expressed high levels of PLCB1. PLCB1 promoted tumor development and growth in various CCA mouse models, including transposon-based tumorigenesis models. PLCB1 activated PI3K/AKT signaling to induce CCA cells to undergo epithelial-to-mesenchymal transition (EMT). Mechanistically, PABPC1 interacted with PLCB1 and PI3K to amplify PLCB1-mediated EMT via PI3K/AKT/GSK3ß/Snail signaling. Ectopic PLCB1 induced resistance to treatment with gemcitabine combined with cisplatin, which could be reversed by the AKT inhibitor MK2206. PLCB1 expression was regulated by miR-26b-5p through direct interaction with PLCB1 3'UTR. Collectively, these data identify a PLCB1-PI3K-AKT signaling axis vital for CCA development and EMT, suggesting that AKT can be used as a therapeutic target to overcome chemotherapy resistance in CCA patients with high PLCB1 expression. SIGNIFICANCE: PLCB1 functions as an oncogenic driver in cholangiocarcinoma development that confers an actionable therapeutic vulnerability to AKT inhibition.

NCAPG2 overexpression promotes hepatocellular carcinoma proliferation and metastasis through activating the STAT3 and NF-κB/miR-188-3p pathways.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly fatal malignant cancer worldwide. Elucidating the underlying molecular mechanism of HCC progression is critical for the identification of new therapeutic targets for HCC. This study aimed to determine the role of Non-SMC condensin II complex subunit G2 (NCAPG2) in HCC proliferation and metastasis. METHODS: We detected NCAPG2 expression in tissues using immunohistochemistry, western blotting and real-time PCR. The effects of NCAPG2 on cell proliferation and metastasis were evaluated both in vitro and in vivo. Immunocytochemistry, enzyme linked immunosorbent assay, co-immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanisms. FINDINGS: We found that NCAPG2 is frequently upregulated in HCC tumour tissues and predicts a poor prognosis. NCAPG2 overexpression promotes HCC proliferation, migration, and invasion through activating STAT3 and NF-κB signalling pathways. Moreover, NCAPG2 is a direct target of miR-188-3p. We demonstrated the existence of a positive feedback loop between NCAPG2 and p-STAT3 and a negative feedback loop between NCAPG2 and miR-188-3p. INTERPRETATION: Our study indicates that NCAPG2 overexpression could drive HCC proliferation and metastasis through activation of the STAT3 and NF-κB/miR-188-3p pathways. These findings may contribute to the identification of novel biomarkers and therapeutic targets for HCC. FUND: National Key Program for Science and Technology Research and Development (Grant No. 2016YFC0905902); the National Natural Scientific Foundation of China (Nos. 81772588, 81602058, 81773194); University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (Grant No. UNPYSCT-2016200); the Innovative Research Program for Graduate of Harbin Medical University (Grant Nos. YJSCX2017-38HYD, YJSCX2016-18HYD).

Can variations in visual behavior measures be good predictors of driver sleepiness? A real driving test study.

OBJECTIVE: The primary purpose of this study was to examine the association between variations in visual behavior measures and subjective sleepiness levels across age groups over time to determine a quantitative method of measuring drivers' sleepiness levels. METHOD: A total of 128 volunteer drivers in 4 age groups were asked to finish 2-, 3-, and 4-h continuous driving tasks on expressways, during which the driver's fixation, saccade, and blink measures were recorded by an eye-tracking system and the subjective sleepiness level was measured through the Stanford Sleepiness Scale. Two-way repeated measures analysis of variance was then used to examine the change in visual behavior measures across age groups over time and compare the interactive effects of these 2 factors on the dependent visual measures. RESULTS: Drivers' visual behavior measures and subjective sleepiness levels vary significantly over time but not across age groups. A statistically significant interaction between age group and driving duration was found in drivers' pupil diameter, deviation of search angle, saccade amplitude, blink frequency, blink duration, and closure duration. Additionally, change in a driver's subjective sleepiness level is positively or negatively associated with variation in visual behavior measures, and such relationships can be expressed in regression models for different period of driving duration. CONCLUSIONS: Driving duration affects drivers' sleepiness significantly, so the amount of continuous driving time should be strictly controlled. Moreover, driving sleepiness can be quantified through the change rate of drivers' visual behavior measures to alert drivers of sleepiness risk and to encourage rest periods. These results provide insight into potential strategies for reducing and preventing traffic accidents and injuries.