VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane.

Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.

rs77283072 influences breast cancer susceptibility by regulating CDKN2A expression.

Breast cancer is the cancer type with the highest morbidity rates in women, and previous genome-wide association studies (GWASs) have suggested that the single nucleotide polymorphism (SNP) rs1011970 is significantly associated with this disease. An analysis of data from the 1000 Genomes Project demonstrated that there is an SNP, rs77283072, in almost complete linkage disequilibrium with rs1011970, which should therefore present the same signal in a GWAS. However, the actual causal SNP and its associated underlying mechanism have yet to be elucidated. Therefore, the present study evaluated the role of rs77283072 in terms of its association with breast cancer. A dual-luciferase assay was performed, which demonstrated that the two alleles of rs1011970 did not exhibit significantly different reporter gene activity. However, the A allele of rs77283072 exhibited a significant increase in relative luciferase activity compared with the G allele, which suggested that rs77283072 was the causal SNP for breast cancer. Chromosome conformation capture demonstrated that the enhancer containing rs77283072 interacted with the promoter of cyclin-dependent kinase inhibitor 2A (CDKN2A). Furthermore, expression quantitative trait locus analysis demonstrated that the expression of CDKN2A was dependent on the genotype of rs77283072. Taken together, the findings of the present study provided novel insights into the mechanism underlying how the genetic variation in this locus was able to influence breast cancer susceptibility and further the treatment for this disease.

Asbestos-Induced Lung Cancer-Associated SNP rs13383928 Regulates PTH2R Expression in Lung Tissue.

BACKGROUND: Lung cancer is one of the most common malignant tumors, and asbestos exposure was suggested to contribute to a proportion of lung cancer cases. Previous genome-wide gene-environment interaction analysis reported that rs13383928 was associated with asbestos-related lung cancer. However, the mechanism of this association was still unclear. METHODS: In the present study, we retrieved the genotype data from the 1,000 Genomes Project on single-nucleotide polymorphisms (SNPs) surrounding rs13383928 and analyzed the linkage disequilibrium (LD) pattern of this region. Further functional genomics analyses were performed. RESULTS: The result indicated that no other SNPs were in LD with rs13383928, suggesting that rs13383928 is the causal one. The following dual luciferase assay disclosed that the T allele of rs13383928 presented significantly higher enhancer activity than G in lung cells, thus verifying that this SNP was functional in the lung. Through chromosome conformation capture, the PTH2R (parathyroid hormone 2 receptor)promoter was identified to interact with the segment surrounding rs13383928. By chromatin immunoprecipitation, it was observed that the region spanning rs13383928 could bind transcription factor FOXJ2 (forkhead box J2). CONCLUSION: Our functional genomics evidence supports a link between rs13383928 and asbestos-related lung cancer through regulating PTH2R.