RESUMEN
Glioblastoma is the prevailing and highly malignant form of primary brain neoplasm with poor prognosis. Exosomes derived from glioblastoma cells act a vital role in malignant progression via regulating tumor microenvironment (TME), exosomal tetraspanin protein family members (TSPANs) are important actors of cell communication in TME. Among all the TSPANs, TSPAN6 exhibited predominantly higher expression levels in comparison to normal tissues. Meanwhile, glioblastoma patients with high level of TSPAN6 had shorter overall survival compared with low level of TSPAN6. Furthermore, TSPAN6 promoted the malignant progression of glioblastoma via promoting the proliferation and metastatic potential of glioblastoma cells. More interestingly, TSPAN6 overexpression in glioblastoma cells promoted the migration of vascular endothelial cell, and exosome secretion inhibitor reversed the migrative ability of vascular endothelial cells enhanced by TSPAN6 overexpressing glioblastoma cells, indicating that TSPAN6 might reinforce angiogenesis via exosomes in TME. Mechanistically, TSPAN6 enhanced the malignant progression of glioblastoma by interacting with CDK5RAP3 and regulating STAT3 signaling pathway. In addition, TSPAN6 overexpression in glioblastoma cells enhanced angiogenesis via regulating TME and STAT3 signaling pathway. Collectively, TSPAN6 has the potential to serve as both a therapeutic target and a prognostic biomarker for the treatment of glioblastoma.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Factor de Transcripción STAT3 , Transducción de Señal , Tetraspaninas , Animales , Humanos , Ratones , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Exosomas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Factor de Transcripción STAT3/metabolismo , Tetraspaninas/metabolismo , Tetraspaninas/genéticaRESUMEN
Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)1α in liver cancer cells. However, to date, no selective HIF1α inhibitor has been clinically approved. The aim of this study is to investigate a drugtargetable molecule that can regulate HIF1α under hypoxia. The present study demonstrated that hyperactivation of dualspecificity tyrosinephosphorylationregulated kinase 1A (DYRK1A)/HIF1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpressionvector transfection in liver cancer cell lines notably induced HIF1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF1α and positively regulate HIF1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the antiliver cancer effects of regorafenib and sorafenib under hypoxia. Cotreatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.