Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer

Abstract

MALAT1 (metastasis associated lung adenocarcinoma transcript1) is a conserved long non-coding RNA, known to regulate gene expression by modulating transcription and post-transcriptional pre-mRNA processing of a large number of genes. MALAT1 expression is deregulated in various tumors, including breast cancer. However, the significance of such abnormal expression is yet to be fully understood. In this study, we demonstrate that regulation of aggressive breast cancer cell traits by MALAT1 is not predicted solely based on an elevated expression level but is context specific. By performing loss- and gain-of-function studies, both under in vitro and in vivo conditions, we demonstrate that MALAT1 facilitates cell proliferation, tumor progression and metastasis of triple-negative breast cancer (TNBC) cells despite having a comparatively lower expression level than ER or HER2-positive breast cancer cells. Furthermore, MALAT1 regulates the expression of several cancer metastasis-related genes, but displays molecular subtype specific correlations with such genes. Assessment of the prognostic significance of MALAT1 in human breast cancer (n=1992) revealed elevated MALAT1 expression was associated with decreased disease-specific survival in ER negative, lymph node negative patients of the HER2 and TNBC molecular subtypes. Multivariable analysis confirmed MALAT1 to have independent prognostic significance in the TNBC lymph node negative patient subset (HR=2.64, 95%CI 1.35 − 5.16, p=0.005). We propose that the functional significance of MALAT1 as a metastasis driver and its potential use as a prognostic marker is most promising for those patients diagnosed with ER negative, lymph node negative breast cancer who might otherwise mistakenly be stratified to have low recurrence risk.

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

“…MALAT has been found to be highly overexpressed in several human malignancies and has been associated with tumor invasion and metastasis in various cancers. [78][79][80][81][82][83][84] Jiao et al 78 reported that MALAT1 could increase the proportion of pancreatic CSCs, maintain self-renewal capacity, decrease chemosensitivity to anticancer drugs and promote angiogenesis in vitro in pancreatic cancer cell lines. Downregulation of MALAT1 reduced self-renewal-associated factors, such as SOX2, Bmi and Nanog.…”

LncRNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation by Inhibiting MicroRNA-9 in MCF-7 Cells

“…LncRNAs are defined as transcripts longer than 200 nucleotides with no protein-coding potential. To date, several lncRNAs have been found to be dysregulated in breast cancer and to be closely associated with the diagnosis and prognosis of breast cancer, such as metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ), nuclear enriched abundant transcript 1 ( NEAT1 ), and breast cancer antiestrogen resistance 4 ( BCAR4 ) [567]. LncRNA taurine upregulated gene 1 ( TUG1 ) was initially identified as an essential gene for retinal development in the developing mouse eye [8].…”

LINC00978 predicts poor prognosis in breast cancer patients

“…For example, lncRNA HOX transcriptantisense RNA (HOTAIR) functions as an oncogene and an independent biomarker for diagnosis and prognosis prediction in various tumors including hepatocellular carcinoma1718, lung cancer1920, gastric cancer2122, and colorectal cancer23. LncRNA metastasis-associated in lung adenocarcinoma transcript 1 (MALAT1) can also be used as a prognostic factor for survival and metastasis in various cancers7242526. H19 is aberrantly regulated in a great deal of cancers, it can serve as a biomarker for poor prognosis in patients with several tumor types2728 as well.…”