Tumor invasion and metastasis are complex biological processes. Matriptase and its endogenous inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1) are involved in invasion and metastasis. To evaluate the ratio of matriptase/HAI-1 and their potential therapeutic value in ovarian cancer, HO-8910 human ovarian cancer cells and the homologous high-metastatic HO-8910PM cells were used as in vitro cellular models ovarian cancer. The invasive and metastatic abilities, and the expression of matriptase and HAI-1 in these cells were detected using scratch assays, Transwell chamber assays, reverse transcription-quantitative polymerase chain reaction, western blotting and fluorescent immunocytochemistry. Following infection with lentivirus-mediated matriptase-targeting small interfering RNA (siRNA), cell cycle progression and apoptosis were also analyzed. The migration distance and number of invading HO-8910PM cells were significantly increased compared with HO-8910 cells. HO-8910PM cells exhibited a significantly higher ratio of matriptase/HAI-1 mRNA levels compared with HO-8910 cells (0.51 vs. 0.24, ~2.2 fold increase). Compared with HO-8910 cells, the matriptase mRNA level was increased by ~3.6 fold in HO-8910PM cells, whereas the HAI-1 mRNA level was increased by ~1.7 fold. Similar increases in protein expression levels were also observed in HO-8910PM cells compared with HO-8910 cells. Migration and invasiveness were positively correlated with matriptase expression level (r=0.994, P<0.01) and the ratio of matriptase/HAI-1 (r=0.929, P<0.01). Downregulation of matriptase using siRNA resulted in inhibition of the invasive and metastatic abilities of HO-8910PM cells, cell cycle arrest in the G0/G1 phase and increased apoptosis. The present study demonstrated that ovarian cancer cell metastasis and invasion were more dependent on upregulation of matriptase levels than downregulation of HAI-1. Matriptase may be a potential adjuvant therapeutic target for inhibiting ovarian cancer invasion and metastasis.
As a notable feature of malignant tumors, invasion and metastasis are important events in the process of tumor progression. Amiloride, a synthetic inhibitor of urokinase plasminogen activator (uPA), is involved in these events. To evaluate the therapeutic value of amiloride in cervical cancer, HeLa cells were used as in vitro cellular models. The migration and invasion abilities of HeLa cells, in addition to the mRNA expression of matriptase, uPA, uPA receptor and 72 kDa type IV collagenase (MMP-2), were detected using scratch assays, Transwell chamber assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results of RT-qPCR demonstrated that the mRNA expression of uPA and MMP-2 in HeLa cells was downregulated significantly in a dose-dependent manner when incubated with various concentrations of amiloride for 24 h. The migration distance of HeLa cells was significantly shorter at 6, 12 and 24 h following incubation with amiloride (P<0.01), and there was a positive correlation between cell migratory ability and cellular uPA protein expression level (r=0.955, P<0.01). The number of HeLa cells that penetrated the Matrigel following incubation for 24 h with different concentrations of amiloride decreased significantly compared with the control group, indicating that cell invasiveness was positively correlated with the protein expression level of uPA in the cells (r=0.993, P<0.01). The present study demonstrated that amiloride was able to specifically inhibit the mRNA expression levels of uPA in HeLa cells, and sequentially downregulate the mRNA expression of downstream MMP-2 in the uPA system, thereby suppressing the migratory and invasive ability of HeLa cells. Therefore, amiloride may be a promising therapeutic target for the treatment of cervical cancer.
Background: Lower serum homocysteine (Hcy) levels are found to correlate with a better chance of clinical pregnancy and better embryo grades in assisted reproductive technology (ART). However, there is little knowledge on the association between Hcy level and unexplained infertility until now. Methods:A total of 388 infertile women undergoing IVF/ICSI treatments were recruited, including 129 women with unexplained causes (case group) and 259 women with known causes (control group), and the case group was further divided into subgroups A (≤8 μmol/L), B (>8 and <15 μmol/L), and C (≥15 μmol/L) based on the serum Hcy level. The associations between serum Hcy level and IVF/ICSI pregnancy outcomes were examined in infertile women with unknown causes.Results: A significantly higher serum Hcy level was measured in the case group than in the control group (P = .008). Subgroup analysis revealed a significant difference in the total number of oocytes retrieved among subgroups A, B, and C (P = .031), and no significant difference was seen among these three groups in terms of age, BMI, E 2 level on the hCG day, number of M-II oocytes, number of fertilized oocytes, or total number of high-quality embryos (P > .05). Spearman correlation analysis revealed a negative correlation between serum Hcy level and total number of oocytes retrieved (r = −.406, P = .019). Univariate and multivariate linear regression analyses revealed that serum Hcy level had no correlations with any IVF/ICSI outcomes. Conclusion:Serum Hcy level has no associations with IVF/ICSI pregnancy outcomes. K E Y W O R D Sassociation study, homocysteine, in vitro fertilization/intracytoplasmic sperm injection, unexplained infertility
Background To determine the relationship between the levels of stress biomarkers in cord blood and preeclampsia in a hospital-based population of pregnant patients, and to evaluate the resulting effects on pregnancy outcomes. Measures: This prospective case-control study included a total of 282 severe preeclamptic and 534 normal pregnant women. Fetal blood was collected from the umbilical cord at delivery and was utilized for Malonaldehyde (MDA), reactive oxygen species (ROS, superoxide dismutase (SOD) and homocysteine (Hcy) analysis. For a better assessment, we performed a univariate general linear regression model to control for potential confounders and determined the underlying influencing factors for high MDA and ROS. Moreover, a receiver operating characteristic curve analysis was conducted to determine the cutoff values for identifying severe preeclampsia. Further, the severe PE group was divided into the low or high MDA and low or high ROS subgroups according to their cut-off values. Finally, we created logistic regression models to estimate the adjusted odds ratio for each perinatal outcome in high-MDA and -ROS subgroup. Results MDA and ROS levels are higher in women with severe preeclampsia than in normotensive pregnant patients. However, when adjusted for cord blood Hcy levels, the difference is insignificant. Additionally, both MDA (r = 0.359, p < 0.001) and ROS (r = 0.473, p < 0.001) are positively correlated with cord blood Hcy level. The AUCs of MDA and ROS levels were 0.65 (95% CI: 0.60–0.69) and 0.88 (95% CI: 0.86–0.90), respectively, for predicting severe PE. Higher MDA and ROS levels are associated with increased risks of low Apgar score, admission to the NICU, and assisted ventilation for the newborn. Conclusion Increased levels of cord blood oxidative stress markers are significantly associated with negative effects on newborns. High cord blood Hcy levels might be involved in the observed elevated MDA and ROS concentrations in women with severe PE.
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