Cancer Research Journal最新文献

Serous ovarian cancer (SOC) is usually diagnosed at late stage and stage-adjusted five year survival rate is low. Mortality is relatively heavy on African-Americans/Black (AA) affected with SOC compared to their Caucasian counterparts, though the cause for the disparity remains unclear. DNA damage induced by oxidative stress has been linked to ovarian cancer, but the role of oxidative stress in distinguishing differences in aggressive SOC tumors among patients is yet to be determined. This study aims to determine the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reactive carbonyl groups and antioxidants in primary SOC normal, precancerous (cystadenoma, borderline) and invasive (III/IV) tissue samples obtained from AA and Caucasian subgroups. Additionally, the study seeks to investigate significant changes in the level of ROS between AA and Caucasian SOC samples. A fluorogenic probe, dichlorodihydrofluorescein (DCFH-DiOxyQ), was used to scavenge reactive oxygen species in SOC normal, precancerous and malignant stages III/IV tissue samples. Malondialdehyde (MDA), a lipid peroxidation marker, and reactive carbonyl groups were measured as indicators of oxidative injury. Moreover, antioxidant status was assessed by estimating glutathione peroxidase 3 (GPX3) enzyme levels. Results indicate ROS concentration was approximately 96% higher in the malignant tissues in comparative to the normal non-diseased controls. In addition, ROS concentration among AA women was approximately 9% higher than Caucasian women. MDA levels increased exponentially from non-disease control and precancerous tissues relative to malignant tissues. Furthermore, malignant serous ovarian samples showed significantly higher reactive carbonyl content compared to the non-disease controls (p=0.009), while GPX3 levels decreased considerably in serous cystadenoma and malignant tissue samples, and non-diseased control compared to borderline disease. The results suggest accumulation of ROS and MDA levels may be a causative factor for SOC. Elevated levels of MDA and reactive carbonyl proteins could override the GPX3 enzyme capacity therefore, initiating serous ovarian neoplasm.

Human epidermal growth factor receptor 2 (HER2)/ErbB2 is a receptor tyrosine kinase belonging to the EGFR/ErbB family and is overexpressed in 20-30% of human breast cancers. Since there is a growing effort to develop pharmacological inhibitors of the HER2 kinase for the treatment of breast cancer, it is clinically valuable to rationalize how specific mutations impact the molecular mechanism of receptor activation. Although several crystal structures of the ErbB kinases have been solved, the precise mechanism of HER2 activation remains unknown, and it has been suggested that HER2 is unique in its requirement for phosphorylation of Y877, a key tyrosine residue located in the activation loop (A-loop). In our studies, discussed here, we have investigated the mechanisms that are important in HER2 kinase domain regulation and compared them with the other ErbB family members, namely EGFR and ErbB4, to determine the molecular basis for HER2's unique mode of activation. We apply computational simulation techniques at the atomic level and at the electronic structure (quantum mechanical) level to elucidate details of the mechanisms governing the kinase domains of these ErbB members. Through analysis of our simulation results, we have discovered potential regulatory mechanisms common to EGFR, HER2, and ErbB4, including a tight coupling between the A-loop and catalytic loop that may contribute to alignment of residues required for catalysis in the active kinase. We further postulate an autoinhibitory mechanism whereby the inactive kinase is stabilized through sequestration of catalytic residues. In HER2, we also predict a role for phosphorylated Y877 in bridging a network of hydrogen bonds that fasten the A-loop in its active conformation, suggesting that HER2 may be unique among the ErbB members in requiring A-loop tyrosine phosphorylation for functionality. In EGFR, HER2, and ErbB4, we discuss the possible effects of activating mutations. Delineation of the activation mechanism of HER2 in the context of the other ErbB members is crucial for understanding how the activated kinase might interact with downstream molecules and couple to signaling cascades that promote cancer. Our comparative analysis furthers insight into the mechanics of activation of the HER2 kinase and enables us to predict the effect of an identified insertion mutation on HER2 activation. Further understanding of the mechanism of HER2 kinase activation at the atomic scale and how it couples to downstream signaling at the cellular scale will elucidate predictive molecular phenotypes that may indicate likelihood of response to specific therapies for HER2-mediated cancers.