Cross-cell DNA methylation annotation and analysis for pan-cancer study

Pan-cancer study can uncover cell- and tissue-specific genomic loci and regions with underlying biological functions, as one of fundamental procedures toward precision medicine. We utilized the online curated resource of DNA methylation annotation knowledgebase, to implement the cross-cell interrogation of pan-cancer study of breast cancer. The study revealed genome-wide differentially-methylated loci and regions by the reduced representation bisulfite sequencing profiling. The knowledgebase contains three level of curated information across multiple cancer and normal cells from the ENCODE Consortium. The reference base covers all identified differentially-methylation CpG sites and regions of interest, further annotated gene information, together with tumor suppressor gene and methylation level. Lastly, it includes the inferred functional association network and related Gene Ontology analysis results based on all the tumor suppressor genes identified from the differentially-methylated regions of interest. Our knowledgebase and analysis results provide a thorough reference source for biomedical researchers and clinicians. The cross-cell analysis results are deposited at: http://github.com/gladex/DMAK.

Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network

The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were inversely correlated with expression of Hsp47 and ECM network genes in human breast cancer tissues. We found that miR-29 repressed expression of Hsp47 along with multiple ECM network genes. Ectopic expression of miR-29b suppressed malignant phenotypes of breast cancer cells in 3D culture. Clinically, increased expression of Hsp47 and reduced levels of miR-29b and -29c were associated with poor survival outcomes in breast cancer patients. Our results show that Hsp47 is regulated by miR-29 during breast cancer development and progression, and that increased Hsp47 expression promotes cancer progression in part by enhancing deposition of ECM proteins

Hsp47 Promotes Cancer Metastasis by Enhancing Collagen-Dependent Cancer Cell-Platelet Interaction

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs

On the Rights and Obligations of Military Activities in the Exclusive Economic Zone

*李广义,西安政治学院军事法学系武装冲突法教研室教授。电子邮箱:mmm19880215 @yahoo.com.cn。 **万彬华,西安政治学院国际军事法专业研究生。 ***朱宏杰,西安政治学院国际军事法专业研究生。［文摘］世界主要海洋国为拓展其在沿海国专属经济区军事活动的自由空间,对《联合国海洋法公约》专属经济区有关规定,做出了自私性和扩大性解释。这是违背海洋法公约本意的。任何国家在沿海国专属经济区的军事活动,都是受限制的;军事活动必须体现“和平目的”和相互尊重合法权利;军事活动必须优先“适当顾及”沿海国的权利;在“剩余权利”的分配上,沿海国处于主导和优先地位。［Abstract］To justify the expansion of military activities onto the exclusive economic zone of coastal States,some of the world’s major maritime powers have adopted one-sided,extended interpretations over relevant provisions on the exclusive economic zone in UNCLOS,which go against the original intention of the Convention.According to this document,any military activity of any State in any exclusive economic zone of any coastal State shall be subject to restriction;any military activity must reflect“peaceful purposes”and mutual respect of legitimate rights;any military activity shall give“due regard”to the rights of coastal States;and in terms of allocating“residual rights”,coastal States shall occupy the dominant and preferential position

Autocrine Epiregulin Activates EGFR Pathway for Lung Metastasis Via EMT in Salivary Adenoid Cystic Carcinoma

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation