The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells

Abstract

The long non-coding RNA MALAT1, also known as MALAT-1 or NEAT2, is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using Zinc Finger Nucleases. The achieved 1000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with antisense oligonucleotides provides a potential therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target. Lastly, regulating gene expression, but not alternative splicing is the critical function of MALAT1 in lung cancer metastasis. In summary, ten years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.

Long non-coding RNA ANRIL predicts poor prognosis and promotes invasion/metastasis in serous ovarian cancer

“…For example, HOTAIR has been demonstrated to be upregulated in primary breast tumours and metastases, and elevated HOTAIR expression is an indispensable predictor of eventual metastasis and death (8). MALAT-1 has been found to promote cell motility and predict poorer clinical outcome in lung cancer (9). HULC has been implicated in the regulation of hepatoma cancer cell proliferation, and higher HULC expression can be used as a non-invasive promising novel biomarker for diagnosis and/or prognosis in hepatocellular carcinoma (32,33).…”

“…An increasing number of discoveries of misregulated lncRNA expression across numerous cancer types have suggested that aberrant lncRNA expression may be a major contributor to tumourigenesis. Further, lncRNAs may add another layer to cancer research because their potential usefulness as biomarkers (8)(9)(10)(11)(12)(13)(14)(15). Therefore, to fully understand the complex mechanisms underlying carcinogenesis and cancer metastasis, the role of lncRNAs must be considered.…”

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

“…Thus, we examined lncRNAs which are specifically dysregulated in 22RV1-miR-338-5p and 22RV1-miR-421 cells, gene expression profiling revealed several deregulated lncRNAs including MALAT1 which is associated with metastatic cancers (24) (Fig. 4A).…”

Long non-coding RNAs in cancer invasion and metastasis

“…32 One study identified a set of genes that might act to promote lung cancer metastasis, reporting that the expression of these genes depends on MALAT1. [34][35][36][37] These MALAT1 target genes were either associated with metastasis or represented critical regulators of metastasis establishment, and were strongly reduced by the loss of MALAT1. 34 These reports support the hypothesis that MALAT1 is an activator of metastasis and affects metastatic processes.…”