RESUMO
BACKGROUND: Doublecortin-like kinase 2 (DCLK2) is a microtubule-associated protein kinase that participates in neural development and maturation; however, whether it is involved in tumour progression remains unclear. METHODS: DCLK2 overexpression and knockdown clones were established by lentivirus transfection. Western blot, PCR assays and bioinformatics analyses were conducted to observe the expression of DCLK2. CCK8, colony formation, scratch migration and Transwell assays were used to detect cell proliferation, migration and invasion, respectively. Tumour metastasis was evaluated in vivo using a tail vein metastasis model. Bioinformatics analyses were performed to analyse the expression correlation between DCLK2 and TCF4, or EMT markers in breast cancer. RESULTS: Our data indicate that DCLK2 is highly expressed in breast cancer cells and is associated with poor prognosis. Silencing DCLK2 does not affect the proliferation rate of tumour cells, but significantly suppresses migration and invasion as well as lung metastasis processes. Overexpression of DCLK2 can enhance the migratory and invasive abilities of normal breast epithelial cells. Moreover, TCF4/ß-catenin inhibitor LF3 downregulates the expression of DCLK2 and inhibits the migration and invasion of breast cancer cells. Furthermore, we found that the downregulation of DCLK2 blocks the epithelial-mesenchymal transition (EMT) process. CONCLUSION: Our study indicates that DCLK2 plays an important role in EMT, cell invasion and metastasis, suggesting that DCLK2 is a potential target for the treatment of metastatic breast cancer.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Humanos , Feminino , Quinases Semelhantes a Duplacortina , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Neoplasias Pulmonares/genética , Invasividade Neoplásica/genética , Transição Epitelial-Mesenquimal , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Metástase NeoplásicaRESUMO
OBJECTIVES: Acute kidney injury is a common complication of major surgery. However, acute kidney injury occurring within the first 48 hours after surgery (early acute kidney injury) and therefore likely related to the surgery itself is possibly different from acute kidney injury occurring after 48 hours (late acute kidney injury). The aim of this study was to describe the epidemiology and identify differences in risk factors and outcomes between early and late acute kidney injury following major surgery. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center. PATIENTS: Patients admitted to ICU following noncardiac major surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 3,499 patients and defined acute kidney injury according to full Kidney Disease: Improving Global Outcomes criteria and classified as early (48 hr or less) or late (> 48 hr to 7 d) based on time from surgery. Separate multivariable logistic regression models were fit to identify risk factors of early acute kidney injury compared with no acute kidney injury and risk factors of late acute kidney injury compared with no acute kidney injury. Overall 41.7% (1,459/3,499) developed early acute kidney injury versus 14.4% (504/3,499) late acute kidney injury. Most acute kidney injury occurred within 48 hours following surgery and 12 hours was the peak interval. Risk factors for early acute kidney injury included increased age, body mass index, decreased estimated glomerular filtration rate, and anemia, whereas late acute kidney injury cases were closely associated with postoperative factors, like sepsis, mechanical ventilation, positive fluid balance, blood transfusions and exposure to diuretics, vasopressors, and nonsteroidal anti-inflammatory drugs. After adjusting for age, body mass index, estimated glomerular filtration rate, comorbidities, surgery type, both early acute kidney injury (odds ratio [95% CI], 1.84 [1.50-2.27]) and late acute kidney injury (odds ratio [95% CI], 1.42 [1.09-1.85]) were associated with higher 1-year mortality compared with patients without acute kidney injury. We found similar results in a validation cohort of 10,723 patients admitted between 2008 and 2014. CONCLUSIONS: Most surgery-related acute kidney injury occurred within 48 hours of surgery. Acute kidney injury occurring within the first 48 hours was associated with underlying health, whereas acute kidney injury occurring after 48 hours was related to postoperative complications or drugs. Design of clinical and experimental interventions for acute kidney injury in this population should consider these differences.