Identifying the crosstalk of dysfunctional pathways mediated by lncRNAs in breast cancer subtypes

Abstract

Crosstalk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. How long non-coding RNAs (lncRNAs) participate in the regulation of an abnormal pathway crosstalk in human cancer is largely unknown. Here, we proposed a strategy that integrates mRNA and lncRNA expression profiles for systematic identification of lncRNA-mediated crosstalk among risk pathways in different breast cancer subtypes. We identified 12 to 44 crosstalking pathway pairs mediated by 28 to 49 lncRNAs in four breast cancer subtypes. An LncRNA-mediated crosstalking pathway network in each breast cancer subtype was then constructed. We observed a number of breast cancer subtype-specific crosstalks of risk pathways. These subtype-specific lncRNA-mediated pathway crosstalks largely determined subtype-selective functions. Notably, we observed that lncRNAs mediated the crosstalk of pathways by cooperating with known important protein-coding genes, which play core roles in the deterioration of breast cancer. And we also identified key lncRNAs contributing to the crosstalk network in each subtype. As an example, the low expression of LIFR-AS1 was associated with poor survival in LumB subtype, and its cooperated genes IL1R and TGFBR located at the most upstream of the MAPK signaling pathway shared a common cascade path (p38 MAPKs-MEF2C) that can result in proliferation, differentiation and apoptosis. In summary, we offer an effective way to characterize complex crosstalks mediated by lncRNAs in breast cancer subtypes, which can be applied to other diseases and provide useful information for understanding the pathogenesis of human cancer.

<p>Long noncoding RNA Linc00460 promotes breast cancer progression by regulating the miR-489-5p/FGF7/AKT axis</p>

“…Nevertheless, the clinical relevance and underlying mechanisms of lncRNAs have not been fully understood in breast cancer. Linc00460 (ID in NCBI database: 728192), a newly identified lncRNA, was reported to be dysregulated in various cancer types, including parapharyngeal schwannoma, renal cell carcinoma, head and neck squamous cell carcinoma and breast cancer 12,13,14. Repression of Linc00460 significantly inhibited the proliferation of esophageal and nasopharyngeal carcinoma cells 15,16.…”

Plasma long non-coding RNA MALAT1 is associated with distant metastasis in patients with epithelial ovarian cancer

“…There are a large number of non-protein-coding RNAs in the human genome, which do not encode proteins and were once considered as ‘noise’ in genome transcription ( 13 , 14 ). Previous studies have found that these non-protein coding RNAs regulate cell differentiation, growth and metabolism, in addition to numerous other biological processes, at the transcriptional, post-transcriptional or translational levels, and at the DNA, RNA or protein levels ( 15 – 18 ). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the few well-studied long non-coding RNAs (lncRNAs), which presents high expression and enhanced activity in numerous tumor tissues and cells ( 19 – 21 ), playing a critical role in tumor invasion and metastasis ( 22 ).…”

Puerarin Induces Hepatocellular Carcinoma Cell Apoptosis Modulated by MAPK Signaling Pathways in a Dose-dependent Manner

“…More intriguingly, increasing published evidence demonstrates the apparent crosstalk of MAPK signaling with other signal transduction pathways in tumorigenesis, chondrogenesis, as well as other physiological and pathological processes, thus implicating proliferation, differentiation and apoptosis (29)(30)(31). Consequently, we reasonably assumed that puerarin exhibits dual biological effects on cell apoptosis via MAPK pathways by interacting with additional divergent pathways.…”