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JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.

Publication ,  Journal Article
Wang, S; Liang, K; Hu, Q; Li, P; Song, J; Yang, Y; Yao, J; Mangala, LS; Li, C; Yang, W; Park, PK; Hawke, DH; Zhou, J; Zhou, Y; Xia, W ...
Published in: The Journal of clinical investigation
December 2017

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.

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Published In

The Journal of clinical investigation

DOI

EISSN

1558-8238

ISSN

0021-9738

Publication Date

December 2017

Volume

127

Issue

12

Start / End Page

4498 / 4515

Related Subject Headings

  • U937 Cells
  • Tumor Microenvironment
  • Signal Transduction
  • RNA, Neoplasm
  • RNA, Long Noncoding
  • Neoplasm Proteins
  • Neoplasm Metastasis
  • NIH 3T3 Cells
  • Mice, Nude
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
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Wang, S., Liang, K., Hu, Q., Li, P., Song, J., Yang, Y., … Lin, C. (2017). JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. The Journal of Clinical Investigation, 127(12), 4498–4515. https://doi.org/10.1172/jci91553
Wang, Shouyu, Ke Liang, Qingsong Hu, Ping Li, Jian Song, Yuedong Yang, Jun Yao, et al. “JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.The Journal of Clinical Investigation 127, no. 12 (December 2017): 4498–4515. https://doi.org/10.1172/jci91553.
Wang S, Liang K, Hu Q, Li P, Song J, Yang Y, et al. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. The Journal of clinical investigation. 2017 Dec;127(12):4498–515.
Wang, Shouyu, et al. “JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.The Journal of Clinical Investigation, vol. 127, no. 12, Dec. 2017, pp. 4498–515. Epmc, doi:10.1172/jci91553.
Wang S, Liang K, Hu Q, Li P, Song J, Yang Y, Yao J, Mangala LS, Li C, Yang W, Park PK, Hawke DH, Zhou J, Zhou Y, Xia W, Hung M-C, Marks JR, Gallick GE, Lopez-Berestein G, Flores ER, Sood AK, Huang S, Yu D, Yang L, Lin C. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis. The Journal of clinical investigation. 2017 Dec;127(12):4498–4515.

Published In

The Journal of clinical investigation

DOI

EISSN

1558-8238

ISSN

0021-9738

Publication Date

December 2017

Volume

127

Issue

12

Start / End Page

4498 / 4515

Related Subject Headings

  • U937 Cells
  • Tumor Microenvironment
  • Signal Transduction
  • RNA, Neoplasm
  • RNA, Long Noncoding
  • Neoplasm Proteins
  • Neoplasm Metastasis
  • NIH 3T3 Cells
  • Mice, Nude
  • Mice