LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis.

Abstract

BACKGROUND:

Recent genome-wide profiling by sequencing and distinctive chromatin signatures has identified thousands of long non-coding RNA (lncRNA) species (>200 nt). LncRNAs have emerged as important regulators of gene expression, involving in both developmental and pathological processes. While altered expression of lncRNAs has been observed in breast cancer development, their roles in breast cancer progression and metastasis are still poorly understood.

METHODS:

To identify novel breast cancer-associated lncRNA candidates, we employed a high-density SNP array-based approach to uncover intergenic lncRNA genes that are aberrantly expressed in breast cancer. We first evaluated the potential value as a breast cancer prognostic biomarker for one breast cancer-associated lncRNA, LincIN, using a breast cancer cohort retrieved from The Cancer Genome Atlas (TCGA) Data Portal. Then we characterized the role of LincIN in breast cancer progression and metastasis by in vitro invasion assay and a mouse tail vein injection metastasis model. To study the action of LincIN, we identified LincIN-interacting protein partner(s) by RNA pull-down experiments followed with protein identification by mass spectrometry.

RESULTS:

High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancer. Importantly, analysis of TCGA data further suggest that high expression of LincIN is associated with poor overall survival in patients with breast cancer (P = 0.044 and P = 0.011 after adjustment for age). The functional experiments demonstrate that knockdown of LincIN inhibits tumor cell migration and invasion in vitro, which is supported by the results of transcriptome analysis in the LincIN-knockdown cells. Furthermore, knockdown of LincIN diminishes lung metastasis in a mouse tail vein injection model. We also identified a LincIN-binding protein, NF90, through which overexpression of LincIN may repress p21 protein expression by inhibiting its translation, and upregulation of p21 by LincIN knockdown may be associated with less aggressive metastasis phenotypes.

CONCLUSIONS:

Our studies provide clear evidence to support LincIN as a new regulator of tumor progression-metastasis at both transcriptional and translational levels and as a promising prognostic biomarker for breast cancer.

• Authors: Zhengyu Jiang, Carolyn M Slater, Yan Zhou, Karthik Devarajan, Karen J Ruth, Yueran Li, Kathy Q Cai, Mary Daly, Xiaowei Chen
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 19 Issue 1 Pg. 62 (05 30 2017) ISSN: 1465-542X [Electronic] England
• PMID: 28558830 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ILF3 protein, human
• Nuclear Factor 90 Proteins
• RNA, Long Noncoding

Topics

• Animals
• Breast Neoplasms (genetics, mortality, pathology)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Gene Expression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Mice
• Neoplasm Metastasis
• Neoplasm Staging
• Nuclear Factor 90 Proteins (metabolism)
• Prognosis
• Protein Binding
• Protein Processing, Post-Translational
• RNA, Long Noncoding (genetics, metabolism)