Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer

HER2 receptor dimerization is a critical step in the HER2 activation process. Here, we demonstrated that heat shock protein gp96 on cell membrane interacts with HER2, facilitates HER2 dimerization and promotes cell proliferation. Cell membrane gp96 levels were observed to correlate with HER2 phosphorylation in primary breast tumors. Finally, we provide evidence that targeting gp96 with a specific monoclonal antibody led to decreased cell growth and increased apoptosis in vitro, and suppression of tumor growth in vivo. Our work represents a new therapeutic strategy for inhibiting HER2 signaling in cancer.     

血管内皮生长因子和基质金属蛋白酶-2在上皮性膀胱癌组织中的表达

目的：探讨上皮性膀胱癌组织中血管内皮生长因子（VEGF）和基质金属蛋白酶-2（MMP-2）的表达及临床意义。方法采用免疫组化S-P法检测67例上皮性膀胱癌及其癌旁组织中VEGF和MMP-2的表达,并分析两者与患者临床病理特征的关系。结果上皮性膀胱癌组织中VEGF和MMP-2的表达均高于癌旁组织（ P均＜0.05）。上皮性膀胱癌组织中VEGF和MMP-2的表达与其病理分级和临床分期有关（ P均＜0.05）。上皮性膀胱癌组织中VEGF和MMP-2的表达呈正相关关系（ r=0.468,P＜0.05）。结论上皮性膀胱癌组织中VEGF和MMP-2高表达,两者可能参与了上皮性膀胱癌的疾病进展。     

Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration

Dysregulation of SOX10 was reported to be correlated with the progression of multiple cancer types, including melanocytic tumors and tumors of the nervous system. However, the mechanisms by which SOX10 is dysregulated in these tumors are poorly understood. In this study, we report that SOX10 is a direct substrate of Fbxw7α E3 ubiquitin ligase, a tumor suppressor in multiple cancers. Fbxw7α promotes SOX10 ubiquitination-mediated turnover through CPD domain of SOX10. Besides, GSK3β phosphorylates SOX10 at CPD domain and facilitates Fbxw7α-mediated SOX10 degradation. Moreover, SOX10 protein levels were inversely correlated with Fbxw7α in melanoma cells, and modulation of Fbxw7α levels regulated the expression of SOX10 and its downstream gene MIA. More importantly, SOX10 reversed Fbxw7α-mediated suppression of melanoma cell migration. This study provides evidence that the tumor suppressor Fbxw7α is the E3 ubiquitin ligase responsible for the degradation of SOX10, and suggests that reduced Fbxw7α might contribute to the upregulation of SOX10 in melanoma cells.     

E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter

About 50–70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.