Investigate the role of regulator of chromosome condensation 2 () on lung adenocarcinoma (LUAD) metastasis. Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD. RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues ( < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor ( = 0.002), lymph node metastasis ( = 0.004), and advanced clinical stage ( = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis and significantly enhanced LUAD cell migration, invasion, and proliferation Further study found that RCC2 induced epithelial-mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9. RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK-JNK signaling. .
Double minute chromosomes (DMs) are the cytogenetic hallmark of extra-chromosomal genomic amplification. The frequency of DMs in primary cancer and the cytogenetic features of DMs-positive primary cancer cases are largely unknown. To unravel these issues, we retrieved the Mitelman database and analyzed all DMs-positive primary cancerous karyotypes (787 karyotypes). The overall frequency of DMs is 1.4% (787 DMs-positive cases; total 54,398 cases). We found that DMs have the highest frequency in adrenal carcinoma (28.6%, topography) and neuroblastoma (31.7%, morphology). The frequencies of DMs in each tumor were much lower than in previous reports. The frequency of DMs in malignant cancers is significantly higher than in benign cancers, which confirms that DMs are malignant cytogenetic markers. DMs combined cytogenetic abnormalities are identified and sorted into two groups by principal component analysis (PCA), with one group containing −4, −5, −8, −9, −10, −13, −14, −15, −16, −17, −18, −20, −21, and −22, and the other containing −1p, −5q, +7, and +20. The prominent imbalance in DMs-positive cancer cases is chromosome loss. However, DMs-positive cancer cases, deriving from different morphologic cancers, cannot be clearly divided into subgroups. Our large database analysis provides novel knowledge of DMs and their combined cytogenetic abnormalities in primary cancer.
BackgroundIntegrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is widely performed for staging solitary pulmonary nodules (SPNs). However, the diagnostic efficacy of SPNs based on PET/CT is not optimal. Here, we propose a method of detection based on PET/CT that can differentiate malignant and benign SPNs with few false-positives.MethodOur proposed method combines the features of positron-emission tomography (PET) and computed tomography (CT). A dynamic threshold segmentation method was used to identify lung parenchyma in CT images and suspicious areas in PET images. Then, an improved watershed method was used to mark suspicious areas on the CT image. Next, the support vector machine (SVM) method was used to classify SPNs based on textural features of CT images and metabolic features of PET images to validate the proposed method.ResultsOur proposed method was more efficient than traditional methods and methods based on the CT or PET features alone (sensitivity 95.6%; average of 2.9 false positives per scan).
BackgroundSei-1 is an oncogene capable of inducing double minute chromosomes (DMs) formation. DMs are hallmarks of amplification and contribute to oncogenesis. However, the mechanism of Sei-1 inducing DMs formation remains unelucidated.ResultsDMs formation significantly increased during serial passage in vivo and gradually decreased following culture in vitro. micro nuclei (MN) was found to be responsible for the reduction. Of the DMs-carrying genes, Met was found to be markedly amplified, overexpressed and highly correlated with DMs formation. Inhibition of Met signaling decreased the number of DMs and reduced the amplification of the DMs-carrying genes. We identified a 3.57Mb DMs representing the majority population, which consists of the 1.21 Mb AMP1 from locus 6qA2 and the 2.36 Mb AMP2 from locus 6qA2-3.Materials and MethodsWe employed NIH-3T3 cell line with Sei-1 overexpression to monitor and characterize DMs in vivo and in vitro. Array comparative genome hybridization (aCGH) and fluorescence in situ hybridization (FISH) were performed to reveal amplification regions and DMs-carrying genes. Metaphase spread was prepared to count the DMs. Western blot and Met inhibition rescue experiments were performed to examine for involvement of altered Met signaling in Sei-1 induced DMs. Genomic walking and PCR were adopted to reveal DMs structure.ConclusionsMet is an important promotor of DMs formation.
Human non-small cell lung cancer (NSCLC) is one of the most common malignancies in the modern world. Its recurrence is mainly due to its ability to invade and metastasize. However, the precise mechanism for tumor development and metastasis is still not fully understood. To shed light on the development of lung cancer, the human giant cell lung carcinoma cell lines 95D with high metastatic potential and 95C with low metastatic potential were selected in this study. The 2 cell lines originated from the same parental cell and share a similar genetic background. In the current study, we identified 3 differentially expressed proteins in 95C and 95D cell lines, namely, PAI-RBP1, C1orf142, and COTL1, by using 2-dimensional electrophoresis proteomics analysis. We found that PAI-RBP1 and C1orf142 expression levels were higher in 95D than in 95C cells, whereas COTL1 expression level was lower in 95D when compared to 95C cells. We also confirmed these results by reverse transcription-polymerase chain reaction and immunoblotting analyses. The messenger RNA and protein levels of PAI-RBP1 and C1orf142 were much higher in 95D than in 95C cells, and COTL1 expression level was lower in 95D than in 95C cells. The PAI-RBP1 expression was assessed by immunohistochemistry in 70 NSCLC and 7 normal lung tissue samples from patients. PAI-RBP1 expression level was higher in tumor tissues (positive staining in 87.1% of cases [61/70]) than in normal tissues (positive staining in 14.3% of cases [1/7]). In conclusion, by studying protein expression in NSCLC cell lines with high and low metastasis as well as in human lung cancer tissues, we have identified 3 proteins, namely, PAI-RBP1, C1orf142, and COTL1, which were differentially expressed in NSCLC cell lines with different metastatic potential. In addition, we also found that PAI-RBP1 might contribute to NSCLC development.
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