Background & Aims-Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy.
Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies but the molecular genetic basis of this disease remains unclear. By using genome-wide methylation profiling analysis, we identified CLDN3 as an epigenetically regulated gene in cancer. Here, we investigated its function and clinical relevance in human HCC. CLDN3 downregulation occurred in 87/114 (76.3%) of primary HCCs, where it was correlated significantly with shorter survival of HCC patients (P=0.021). Moreover, multivariate cyclooxygenase regression analysis showed that CLDN3 was an independent prognostic factor for overall survival (P=0.014). Absent expression of CLDN3 was also detected in 67% of HCC cell lines, which was significantly associated with its promoter hypermethylation. Ectopic expression of CLDN3 in HCC cells could inhibit cell motility, cell invasiveness, and tumor formation in nude mice. Mechanistic investigations suggested through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2, CLDN3 could significantly suppress metastasis by inactivating the Wnt/β-catenin-epithelial mesenchymal transition (EMT) axis in HCC cells. Collectively, our findings demonstrated that CLDN3 is an epigenetically silenced metastasis suppressor gene in HCC. A better understanding of the molecular mechanism of CLDN3 in inhibiting liver cancer cell metastasis may lead to a more effective management of HCC patients with the inactivation of CLDN3.
We performed an integrated study of multistage hydraulic fracture stimulation of two parallel horizontal wells in the Bakken Formation in the Williston Basin, North Dakota. There are three distinct parts of this study: development of a geomechanical model for the study area, interpretation of multiarray downhole recordings of microseismic events, and interpretation of hydraulic fracturing data in a geomechanical context. We estimated the current stress state to be characterized by an NF/SS regime, with S H max oriented approximately N45°E. The microseismic events were recorded in six vertical observation wells during hydraulic fracturing of parallel wells X and Z with three unusual aspects. First, rather than occurring in proximity to the stages being pressurized, many of the events occurred along the length of well Y, a parallel well located between wells X and Z that had been in production for approximately 2.5 years at the time X and Z were stimulated. Second, relatively few fracturing stages were associated with an elongated cloud of events trending in the direction of S H max as was commonly observed during hydraulic fracturing. Instead, the microseismic events in a few stages appeared to trend approximately N75°E, approximately 30°from the direction of S H max . Earthquake focal plane mechanisms confirmed slip on faults with this orientation. Finally, the microseismic events were clustered at two distinct depths: one near the depth of the well being pressurized in the Middle Bakken Formation and the other approximately 800 ft above in the Mission Canyon Formation. We proposed that steeply dipping N75°E striking faults with a combination of normal and strike-slip movement were being stimulated during hydraulic fracturing and provided conduits for pore pressure to be transmitted to the overlaying formations. We tested a simple geomechanical analysis to illustrate how this occurred in the context of the stress field, pore pressure, and depletion in the vicinity of well Y.
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