RESUMO
Yes-associated protein (YAP) is a vital transcriptional co-activator that activates cell proliferation and evasion of apoptosis for the promotion of tumorigenesis. The von Hippel-Lindau tumor suppressor protein (pVHL), as a critical component of E3 ubiquitin ligase, targets various substrates to regulate tumor progression. However, the precise molecular mechanisms of pVHL during tumorigenesis remain largely unclear. Herein, we found that there was a significant negative correlation between pVHL and YAP at protein level in the TCGA-LUAD dataset and our cohort. Over-expression of pVHL decreased YAP protein expression and reduced its transcriptional activity. Further study indicated that pVHL did not affect YAP mRNA level but decreased YAP protein stability in a lysosome-dependent manner. In addition, the pVHL-mediated degradation of YAP inhibited cellular proliferation, migration, and enhanced chemosensitivity to cisplatin in lung adenocarcinoma cells. Interestingly, the pVHL-mediated YAP degradation was blocked by elevated O-GlcNAcylation. Collectively, our findings demonstrate that pVHL modulates the lysosomal degradation of YAP, and may provide more clues to better understanding the tumor suppressive effects of pVHL.
Assuntos
Adenocarcinoma de Pulmão/metabolismo , Carcinogênese/metabolismo , Neoplasias Pulmonares/metabolismo , Lisossomos/metabolismo , Proteólise , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteínas de Sinalização YAP/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinogênese/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Lisossomos/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteínas de Sinalização YAP/genéticaRESUMO
Liver fibrosis is a continuous wound healing response caused by chronic liver injury, and the activation of hepatic stellate cells (HSCs) is considered as the main event for it. Core fucosylation catalyzed by FUT8 refers to adding the fucosyl moiety to the innermost GlcNAc residue of N-linked oligosaccharides and is involved in many biological processes such as cell differentiation, migration, and signaling transduction. Aberrant core fucosylation is associated with a variety of diseases including cardiovascular disease, tumors and neuroinflammation, but much less is understood in liver fibrosis. Herein, we reported FUT8 mRNA level was increased in patients with liver fibrosis from GEO database and positively correlated with fibrosis progression. FUT8 expression and the core fucosylation were also elevated in TAA-induced mouse liver fibrosis model, and were mainly distributed in the fibrous septum of mouse liver. TGF-ß1, as the most pro-fibrogenic cytokine, could promote the expression of FUT8 and total core fucosylation levels in HSCs in vitro. However, up-regulation of FUT8 in turn inhibited TGF-ß1-induced trans-differentiation, migration and pro-fibrogenic signaling pathways in HSCs. In conclusion, our results suggest that the up-regulation of FUT8 inhibits TGF-ß1-induced HSC activation in a negative feedback loop, and provide potential new therapeutic strategy for liver fibrosis by targeting FUT8.
Assuntos
Fucosiltransferases/genética , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/patologia , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fucosiltransferases/metabolismo , Expressão Gênica , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Masculino , Camundongos Endogâmicos C57BL , Ratos , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/toxicidade , Fator de Crescimento Transformador beta1/farmacologia , Regulação para CimaRESUMO
Cervical cancer remains the first leading cause of cancer-related mortality among female reproductive system malignancies worldwide, and invasion and lymph node metastasis of cervical cancer represent the major reason for its poor prognosis. In this study, we found that RACK1 facilitated tumor cell invasion and lymphatic tube formation in vitro, as well as promoted lymphangiogenesis and lymph node metastasis in vivo in a galectin-1-dependent manner. Mechanism studies revealed that RACK1 promoted the expression and secretion of galectin-1 by reducing miR-1275 levels. Additionally, RACK1 also augmented galectin-1-induced downstream MEK/ERK, FAK, and AKT signaling via integrin-ß1 in cervical cancer cells. Tissue microarray confirmed that RACK1 was upregulated in squamous intraepithelial lesion and cancer, and RACK1 was positively correlated with invasion/metastasis phenotype, galectin-1 expression, and unfavorable prognosis in cervical cancer cases. Human papillomavirus E6 oncogene contributes to increased expression of RACK1 via the enhancement of its O-GlcNAcylation and protein stability. Together, our results demonstrate that RACK1 stimulates tumor invasion and lymph node metastasis of cervical cancer via galectin-1 and imply that targeting RACK1/galectin-1 axis provides promising means for cervical cancer treatment.