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Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk. Methodology/principal findings Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion. Conclusions In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.

Background Angiogenesis is essential for the progression of osteoarthritis (OA). Hepatocyte growth factor (HGF) is an angiogenic mediator, and it shows elevated levels in regions of OA. However, the relationship between HGF and vascular endothelial growth factor (VEGF-A) in OA synovial fibroblasts (OASFs) is mostly unknown. Methodology/Principal Findings Here we found that stimulation of OASFs with HGF induced concentration- and time-dependent increases in VEGF-A expression. Pretreatment with PI3K inhibitor (Ly294002), Akt inhibitor, or mTORC1 inhibitor (rapamycin) blocked the HGF-induced VEGF-A production. Treatment of cells with HGF also increased PI3K, Akt, and mTORC1 phosphorylation. Furthermore, HGF increased the stability and activity of HIF-1 protein. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that c-Met, PI3K, Akt, and mTORC1 signaling pathways were potentially required for HGF-induced HIF-1α activation. Conclusions/Significance Taken together, our results provide evidence that HGF enhances VEGF-A expression in OASFs by an HIF-1α-dependent mechanism involving the activation of c-Met/PI3K/Akt and mTORC1 pathways.

Background: Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs). Methodology/Principal Findings: Stimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCd inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCd and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCd, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer. Conclusions/Significance: Our results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCd, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.