RESUMO
Background: Epithelial-mesenchymal transition (EMT) is a critical process in tumor invasion and metastasis. EMT has been shown to significantly influence the invasion, metastasis, and poor prognosis in lung adenocarcinoma (LUAD). This study aimed to develop a novel EMT-related prognostic model capable of predicting overall survival (OS) in patients with LUAD. Methods: A total of 283 LUAD patients from TCGA RNA-seq dataset were assigned to a training cohort for model building, and 310 LUAD patients from GEO RNA-seq dataset were assigned to a validation cohort. EMT genes were acquired from MsigDB database and then prognosis-related EMT genes were identified by univariate Cox regression. Lasso regression was then performed to determine the genes and the corresponding variables to construct a prognosis risk model from the training cohort. Furthermore, characteristics of the tumor microenvironment (TME), mutation status and chemotherapy responses were analyzed to assess the differences between the two risk groups based on the prognostic model. In addition, RT-qPCR was employed to validate the expression patterns of the 6 genes derived from the risk model. Results: A six-gene EMT signature (PMEPA1, LOXL2, PLOD2, MMP14, SPOCK1 and DCN) was successfully constructed and validated. The signature assigned the LUAD patients into high-risk and low-risk groups. In comparison with the low-risk group, patients in the high-risk group had a significantly lower survival rate. ROC curves and calibration curves for the risk model demonstrated reliable stratification and predictive ability. The risk model was robustly correlated with multiple TME characteristics. Besides, the data showed that patients in the low-risk group had more immune activities, higher stemness scores and cytolytic activity scores and higher TMB. In addition, RT-qPCR results revealed that PMEPA1, LOXL2, PLOD2, MMP14, and SPOCK1 were notably upregulated in LUAD tissues, while DCN was downregulated. Conclusion: Our study successfully developed a novel EMT-related signature to predict prognosis of LUAD patients and guide treatment strategies. The six genes derived from the prediction signature might play a potential role in antitumor immunity and serve as promising therapeutic targets in LUAD.
RESUMO
Focal adhesion kinase (FAK) is known to promote the proliferation, migration and survival of synovial cells and plays an important role in the occurrence, development and pathological process of rheumatoid arthritis (RA). The aim of the present study was to observe FAK changes in synovial cells of rats with collagen-induced arthritis (CIA) and after intervention with disease modifying anti-rheumatic drugs (DMARDs) alone or in combination in a CIA female SD rat model induced by collagen type II. The rats were randomized to 8 groups: normal control group, CIA model control group, methotrexate (MTX, 0.9 mg/kg/w) group, cyclophosphamide (CTX, 24 mg/kg/3 w) group, leflunomide (LEF, 1.2 mg/kg/d) group, MTX + CTX group, LEF + CTX group, and MTX + LEF group. They were intervened with DMARDs alone or in combination for six weeks. The experiment lasted a total of 9 weeks in vivo. Articular inflammation was measured during the process of drug intervention in terms of the degree of swelling degree in the right hind foot using a venire caliper. All animals were sacrificed by breaking the neck after 9 weeks. Then, the ankle was fixed, decalcified, embedded, and HE stained, and prepared into slices to observe pathological changes in the synovial tissue. FAK expression in synovial cells was assayed by immunohistochemistry and the mean optical density (OD) value was measured using the HPIAS-2000 image analysis system. It was found that FAK expression was negative in normal control group, positive in CIA model control group, and decreased in the three DMARD combination treatment groups significantly as compared with that in the three single-drug groups (P < 0.05). FAK expression in LEF + CTX group or MTX + CTX group decreased more significantly than that in MTX + LEF group (P < 0.05), and there was no statistically significant difference between LEF + CTX and MTX + CTX groups. The arthritis index and pathological change in the synovial tissue in LEF + CTX group or MTX + CTX group were improved more significantly than those in MTX + LEF group or single-drug groups. Our results showed that FAK expression was positive in CIA rats, indicating that it played an important role in the pathogenesis of RA, and that intervention with DMARDs could reduce the FAK expression in synovial cells of CIA rats. We hope these findings would contribute to the treatment of RA and other rheumatic diseases by reducing adhesion, proliferation and migration of synovial cells and inhibiting the over-expression of FAK.
