ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.
Subject(s)
Adult , Aged , Animals , Female , Humans , Male , Mice , Middle Aged , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/metabolism , Kinesins/metabolism , Liver Neoplasms/pathology , Mice, Inbred BALB C , Neoplasm Staging , Prognosis , Protein Binding , RNA, Small Interfering/metabolism , Survival Analysis , Tumor Burden , Wnt Signaling Pathway , Xenograft Model Antitumor Assays , beta Catenin/metabolismABSTRACT
OBJECTIVE@#To evaluate the influence of temperature and humidity on the drug stability by initial average rate experiment, and to obtained the kinetic parameters.@*METHODS@#The effect of concentration error, drug degradation extent, humidity and temperature numbers, humidity and temperature range, and average humidity and temperature on the accuracy and precision of kinetic parameters in the initial average rate experiment was explored. The stability of vitamin C, as a solid state model, was investigated by an initial average rate experiment.@*RESULTS@#Under the same experimental conditions, the kinetic parameters obtained from this proposed method were comparable to those from classical isothermal experiment at constant humidity. The estimates were more accurate and precise by controlling the extent of drug degradation, changing humidity and temperature range, or by setting the average temperature closer to room temperature.@*CONCLUSION@#Compared with isothermal experiments at constant humidity, our proposed method saves time, labor, and materials.