RESUMO
Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5'-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.
Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Receptores ErbB/metabolismo , Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima/genética , Regiões 5' não Traduzidas/genética , Processamento Alternativo/genética , Aurora Quinases , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Ativação Enzimática/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Splenic artery embolization (SAE) has been used as an adjunct to the nonsurgical treatment of blunt splenic injuries since 1981. It is imperative to define the role of SAE in the management of splenic trauma and to establish a guideline for its use. METHODS: In this study, 39 consecutive patients with blunt splenic ruptures were evaluated. All the patients were treated according to the authors' protocol, which included SAE as an adjunct. Angiographic study was performed for patients with any of the following presentations: recurrent hypotension despite fluid resuscitation, significant hemoperitoneum or extravasation of contrast media on computed tomography, grade 4 or 5 splenic injury, or progressive need for blood transfusion. Laparotomy was reserved for patients with unstable hemodynamics or failure of SAE. RESULTS: Four patients were excluded from the study, and 6 of the 35 remaining patients (male-to-female ratio, 22:13) received SAE. One of the six SAE patients underwent operation because of persistent hemorrhage after SAE. Nonoperative treatment was successful for 31 patients. Splenic artery embolization increased the success rate for nonsurgical management from 74% (26 of 35 patients) to 89% (31 of 35 patients). CONCLUSIONS: Judicious use of SAE for patients with blunt splenic injury avoids unnecessary surgery and expands the number of patients who can retain their spleen.
