The Journal of clinical investigation, 2017-12, Vol.127 (12), p.4498-4515
- Wang, Shouyu
- Liang, Ke
- Hu, Qingsong
- Li, Ping
- Song, Jian
- Yang, Yuedong
- Yao, Jun
- Mangala, Lingegowda Selanere
- Li, Chunlai
- Yang, Wenhao
- Park, Peter K
- Hawke, David H
- Zhou, Jianwei
- Zhou, Yan
- Xia, Weiya
- Hung, Mien-Chie
- Marks, Jeffrey R
- Gallick, Gary E
- Lopez-Berestein, Gabriel
- Flores, Elsa R
- Sood, Anil K
- Huang, Suyun
- Yu, Dihua
- Yang, Liuqing
- Lin, Chunru
2017
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- Autor(en) / Beteiligte
- Wang, Shouyu
- Liang, Ke
- Hu, Qingsong
- Li, Ping
- Song, Jian
- Yang, Yuedong
- Yao, Jun
- Mangala, Lingegowda Selanere
- Li, Chunlai
- Yang, Wenhao
- Park, Peter K
- Hawke, David H
- Zhou, Jianwei
- Zhou, Yan
- Xia, Weiya
- Hung, Mien-Chie
- Marks, Jeffrey R
- Gallick, Gary E
- Lopez-Berestein, Gabriel
- Flores, Elsa R
- Sood, Anil K
- Huang, Suyun
- Yu, Dihua
- Yang, Liuqing
- Lin, Chunru
- Titel
- JAK2-binding long noncoding RNA promotes breast cancer brain metastasis
- Ist Teil von
- The Journal of clinical investigation, 2017-12, Vol.127 (12), p.4498-4515
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M- and IL-6-triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/JCI91553Titel-ID: cdi_proquest_journals_1974540763
- Format
- –
- Schlagworte
- Analysis, Animal models, Animals, Biomedical research, Blood-brain barrier, Brain, Brain cancer, Brain Neoplasms - genetics, Brain Neoplasms - metabolism, Brain Neoplasms - pathology, Brain Neoplasms - secondary, Breast cancer, Breast Neoplasms - genetics, Breast Neoplasms - metabolism, Breast Neoplasms - pathology, Cancer metastasis, Care and treatment, Cell adhesion & migration, Chemoresistance, Development and progression, Diagnosis, Female, Gene expression, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Intercellular adhesion molecule 1, Interleukin 6, Janus kinase 2, Janus Kinase 2 - genetics, Janus Kinase 2 - metabolism, Kinases, Macrophages, MCF-7 Cells, Metastases, Metastasis, Mice, Mice, Nude, Monocyte chemoattractant protein 1, Nanoparticles, Neoplasm Metastasis, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, NIH 3T3 Cells, Oncostatin M, Phosphorylation, Proteins, Ribonucleic acid, RNA, RNA, Long Noncoding - genetics, RNA, Long Noncoding - metabolism, RNA, Neoplasm - genetics, RNA, Neoplasm - metabolism, Signal Transduction - genetics, siRNA, Stat3 protein, Tumor Microenvironment - genetics, Tumors, U937 Cells