KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma

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.

Mechanism of recombinant human S100 calcium binding protein A4 inducing vascular endothelial growth factors in rheumatoid arthritis fibroblast-like synoviocytes / 中华创伤骨科杂志

Objective To investigate the mechanism of inducing production of vascular endothelial growth factors (VEGF) by recombinant human S100 calcium binding protein A4 (rhS100A4) in rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs).Methods Synovial tissue was sampled from the patients with rheumatoid arthritis (RA) undergoing knee arthroplasty for in vitro culture of RAFLSs.CCK-8 assay was conducted to detect the effect of rhS100A4 and the effect of its interaction with Rapamycin (Rap),an inhibitor of mammalian rapamycin target 1 (mTORC1) signaling pathway,on the proliferation of RAFLSs.The effects of rhS100A4 and its interaction with Rap on the expression of VEGF in RAFLSs were detected by immunofluorescence.After rhS100A4 and its cooperation with Rap stimulated the conditioned medium (CM)produced by RAFLSs,the effect of CM on formation of lumen in human unbilical vein endothelial cells (HUVECs) in vitro was observed to detect the angiogenic ability of rhS100A4.Western blot was used to detect the effect of rhS100A4 on the phosphorylation of downstream ribosomal protein S6 (S6) in the mTORC1 signaling pathway in RAFLSs and to analyze the effects of rhS100A4 and Rap on phosphorylation of S6 protein and expression of VEGF protein in RAFLSs.Results rhS100A4 promoted cell proliferation and expression of VEGF protein in RAFLSs,and the CM formed by rhS100A4 promoted HUVECs to form blood vessels in vitro.Rap inhibited the above biological effects of rhS100A4,rhS100A4 activated the downstream protein S6 in the mTORC1 signaling pathway in RAFLSs cells to increase their phosphorylation levels.The effects of rhS100A4 on the phosphorylation of S6 protein and on the expression of VEGF protein in RAFLSs were inhibited by Rap.Conclusion rhS10OA4 promotes production of VEGF in RAFLSs by activating the mTORC 1 signaling pathway.

Role of AKT / mTORC1 pathway in pancreatic β - cell proliferation / Participación de la vía de señalización AKT/mTORC1 en la proliferación de las células β del páncreas

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

Factores de crecimiento y nutrientes son reguladores muy importantes de la masa y función de las células β, pero las vías de señalización que unen estas señales a estos procesos no han sido completamente elucidadas. Estudios recientes han demostrado que la proteína mTOR integra señales provenientes de factores de crecimiento y disponibilidad de nutrientes con procesos celulares como transcripción, traducción, organización del citoesqueleto y metabolismo mitocondrial. mTOR puede hacer parte de dos complejos diferentes, mTORC1 y mTORC2. En el complejo mTORC1, la proteina mTOR la cual es sensible a rapamicina y se encuentra asociada a las proteínas Raptor, G β L, deptor y PRAS40, activa reguladores claves en la síntesis de proteínas, tales como la proteína cinasa ribosomal S6 (S6K) y la proteína de unión al factor eucariótico de iniciación 4E. El presente trabajo recopila información reciente sobre la participación de la vía de señalización AKT/mTORC1 en la regulación de la proliferación y masa de las células β del páncreas. mTORC1 regula la progresión del ciclo celular en células β, mediante la modulación de los niveles de las ciclinas D2 y D3 y la actividad del complejo Cdk4/ ciclina D. Estos estudios que revelan nuevos puntos de control del ciclo celular en células β, pueden ser utilizados en el desarrollo de nuevos enfoques para expandir la masa de células β, sin el riesgo de inducir una transformación oncogénica. Los resultados relacionados en el presente trabajo aportan información muy valiosa para el desarrollo de nuevas estrategias terapéuticas para el tratamiento la diabetes tipo 2.