From junk to master regulators of invasion: lncRNA functions in migration, EMT and metastasis

Abstract

Metastasis is a multistep process that involves the dissemination of cells from the primary tumor and colonization of distant secondary organs. Epithelial cells at the invasive front of a carcinoma acquire an enhanced migratory phenotype in a process called epithelial-to-mesenchymal transition (EMT). This cellular plasticity seems to drive the initiation of metastasis. Identifying important molecules and understanding their molecular mechanisms is a key to cancer prognosis and the development of therapeutics for late stage malignancies. Recent advances in sequencing technology uncovered that the mammalian genome is pervasively transcribed into many nonprotein-coding RNAs including the class of long noncoding RNA, a.k.a. lncRNA. Several lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we review the diverse molecular mechanisms, cellular roles and regulatory patterns that are becoming apparent for the noncoding transcriptome. Chromatin modification, epigenetic regulation, alternative splicing and translational control by MALAT1, HOTAIR and TRE lncRNAs represent important examples of lncRNA-mediated control of cell migration and invasion, EMT and metastasis. Beyond these better characterized examples, numerous additional transcripts have been associated with cancer metastasis, but their functional roles await their discovery.Metastasis is a key process in cancer progression, wherein cells in a primary tumor acquire invasive properties and disseminate to other sites in the body to initiate secondary lesions. 1 This complex process involves most of the transdifferentiation steps unique to embryonic development. While aberrant proliferation is a necessity for tumor initiation, a second hit which changes the migratory properties and cell-cell contacts is crucial for the spread of tumor cells in the body. 2 Epithelial-to-mesenchymal transition (EMT) is a key step by which epithelium-derived cancer cells lose their intercellular contacts, upregulate components of the contractile cytoskeleton and move out of the benign primary tumor. 3,4 On the contrary, a reverse of this process (MET) is required for migrating cells to colonize a secondary site. In addition, effective metastasis requires suppression of anoikis and upregulation of multiple matrix degrading enzymes. 2,5 A complex interplay of signals regulate these processes in ways unique to different types of cancers 6 and identification of novel players in the process of tumor dissemination is crucial for cancer prognosis and the development of therapeutics for late stage malignancies. While the majority of these studies focus on protein effectors of metastasis, the importance of noncoding RNAs is now being appreciated. 7 LncRNAs are generally defined as RNA transcripts longer than 200 nucleotides (nt) with no protein-coding potential. Recent advances in sequencing technologies have revealed that the human genome is pervasively transcribed while only <2% transcripts code for proteins...

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

“…Of the thousands of IncRNAs discovered, a few have been shown to play crucial roles in different biological processes through chromatin modification, epigenetic regulation, alternative splicing, and translational control [26, 27]. In particular, a number of IncRNAs are emerging as critical regulators of tumor progression and metastasis [28, 29]. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear-enriched abundant transcript 2 (NEAT2), is a large, ubiquitously expressed IncRNA [30].…”

“…The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear-enriched abundant transcript 2 (NEAT2), is a large, ubiquitously expressed IncRNA [30]. Extensive studies have indicated that MALAT1 plays an oncogenic role in various cancers via multiple mechanisms, including triggering EMT in tumor cells and promoting tumor metastasis [28, 31]. Importantly, MALAT1 has been found to be induced by TGF-β1 and mediate TGF-β1-triggered EMT in retinal pigment epithelial cells [32].…”

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

“…LncRNAs are very abundant with estimates of 430 000 lncRNAs transcripts in the human genome. [71][72][73][74][75][76][77] One group of investigators estimated that there were close to 60 000 lncRNAs including 8000 oncologic lncRNAs. 74 A growing number of these lncRNAs are being isolated and characterized from thyroid and other cancers.…”

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

“…LncRNAs, which are emerging as pivotal regulation factors of cell biological behavior, can alter tumor growth kinetics, Author Manuscript Published OnlineFirst on December 11, 2017; DOI: 10.1158/0008-5472. CAN-17-2356 promote lymphangiogenesis and distant metastasis of cancer by interacting with RNA, DNA, or proteins [14,15]. In recent years, the expression of certain lncRNAs has been frequently reported to be functionally important for cervical cancer, including lincRNA-p21 [16], HOXA11-AS [17], HOTAIR [18] and ANRIL [19].…”