Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway.

Glioblastoma (GBM) recurrence is attributed to the presence of therapy-resistant glioblastoma stem cells. Steroid receptor coactivator-1 (SRC-1) acts as an oncogenic regulator in many human tumors. The relationship between SRC-1 and GBM has not yet been studied. Herein, we investigate the role of SRC-1 in GBM. In this study, we found that SRC-1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient's prognosis. Steroid receptor coactivator-1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC-1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X-inactive specific transcript (XIST) is regulated by SRC-1 at the posttranscriptional level and mediates the function of SRC-1 in promoting stemness-like properties of GBM. Steroid receptor coactivator-1 can promote the expression of Kruppel-like factor 4 (KLF4) through the XIST/microRNA (miR)-152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC-1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR-152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

Aqp-1 Gene Knockout Attenuates Hypoxic Pulmonary Hypertension of Mice.

Objective- Hypoxic pulmonary hypertension (HPH) is characterized by proliferative vascular remodeling. Abnormal pulmonary artery smooth muscle cells proliferation and endothelial dysfunction are the primary cellular bases of vascular remodeling. AQP1 (aquaporin-1) is regulated by oxygen level and has been observed to play a role in the proliferation and migration of pulmonary artery smooth muscle cells. The role of AQP1 in HPH pathogenesis has not been directly determined to date. To determine the possible roles of AQP1 in the pathogenesis of HPH and explore its possible mechanisms. Approach and Results- Aqp1 knockout mice were used, and HPH model was established in this study. Primary pulmonary artery smooth muscle cells, primary mouse lung endothelial cells, and lung tissue sections from HPH model were used. Immunohistochemistry, immunofluorescence and Western blot, cell cycle, apoptosis, and migration analysis were performed in this study. AQP1 expression was upregulated by chronic hypoxia exposure, both in pulmonary artery endothelia and medial smooth muscle layer of mice. Aqp1 deficiency attenuated the elevation of right ventricular systolic pressures and mitigated pulmonary vascular structure remodeling. AQP1 deletion reduced abnormal cell proliferation in pulmonary artery and accompanied with accumulation of HIF (hypoxia-inducible factor). In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration ability of primary cultured pulmonary artery smooth muscle cells and repressed HIF-1α protein stability. Furthermore, Aqp1 deficiency protected lung endothelial cells from apoptosis in response to hypoxic injury. Conclusions- Our data showed that Aqp1 deficiency could attenuate hypoxia-induced vascular remodeling in the development of HPH. AQP1 may be a potential target for pulmonary hypertension treatment.

Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides.

Malignant pleural mesothelioma is a rare and aggressive tumor characterized by rapid progression, late metastases, and poor prognosis. In this study, we investigated the expression of survivin, a member of the inhibitors of apoptosis protein gene family, in mesothelioma and an antisense oligonucleotide-based gene therapy for mesothelioma using survivin as a target. Initially, we documented the expression of survivin in human mesothelioma cell lines and fresh tissues using reverse transcription-PCR and Western blot analysis. Our results showed that survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed. To investigate the use of survivin as a therapeutic target on mesothelioma, we carried out transfections with antisurvivin oligonucleotides to induce apoptosis in mesothelioma cell lines MS-1 and H28. Results from cellular transfection and subsequent analysis using the flow cytometry demonstrated that antisurvivin oligonucleotides induced significantly greater apoptosis rates in the survivin-positive mesothelioma cell line H28 (42.5%) as compared with the control oligonucleotides (16.2%; P < 0.001). The survivin-negative cell line LRK1A (survivin-/-) did not apoptose with antisense oligonucleotides. Furthermore, time course evaluation by Western blot analysis showed that survivin was inhibited by antisurvivin oligonucleotides within 12 h after transfection. Our results show, for the first time, that survivin, an inhibitors of apoptosis protein family gene member, is highly overexpressed in malignant pleural mesothelioma. Down-regulation of survivin by a targeted antisense oligonucleotide appears to be an effective gene therapy approach to the treatment of mesothelioma.

HIV-1 protease cleavage site prediction based on two-stage feature selection method.

Knowledge of the mechanism of HIV protease cleavage specificity is critical to the design of specific and effective HIV inhibitors. Searching for an accurate, robust, and rapid method to correctly predict the cleavage sites in proteins is crucial when searching for possible HIV inhibitors. In this article, HIV-1 protease specificity was studied using the correlation-based feature subset (CfsSubset) selection method combined with Genetic Algorithms method. Thirty important biochemical features were found based on a jackknife test from the original data set containing 4,248 features. By using the AdaBoost method with the thirty selected features the prediction model yields an accuracy of 96.7% for the jackknife test and 92.1% for an independent set test, with increased accuracy over the original dataset by 6.7% and 77.4%, respectively. Our feature selection scheme could be a useful technique for finding effective competitive inhibitors of HIV protease.