Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long non-coding intergenic RNA of 12,820 bases on chr11q13. It is initially transcribed as a precursor transcript, followed by enzymatic processing by RNase P to form the mature long non-coding RNA [1,2]. A triple helical structure at the 3′ end stabilizes the structure of MALAT-1 and compensates for the missing poly-A tail. It regulates gene expression by various mechanisms, including modulating gene transcription through the repression of promoters of target genes, regulating RNA-binding proteins or activating mesenchymal transcription factors, modifying the chromatin, and regulating post-transcriptional processing (Figure 1) [3,4,5,6]. In addition, it is involved in DNA repair and cell death [7]. Targeting MALAT-1 induces DNA damage and sensitizes cancer to chemotherapy treatment [8].

MALAT-1 induces cancer proliferation, invasion, migration, and metastasis to distant sites. Recently, several studies highlighted the immunomodulatory role of MALAT-1 and how it can enable cancer cells to escape immune surveillance by exerting an immunosuppressive effect and regulating the expression of several molecules associated with the tumor microenvironment [9,10]. In the triple-negative breast cancer (TNBC) cell model, MALAT-1 knockdown results in a marked induction in MHC class I chain-related proteins A/B expression and the repression of the checkpoint molecules PD-L1 and B7-H4 [11]. In addition, MALAT1 also modulates its suppressive effect by negatively modulating Myeloid-derived suppressor cells (MDSCs) and decreasing peripheral blood mononuclear cells (PBMCs) in cancer patients [12]. Indeed, MALAT-1 knockdown using MALAT-1 antisense oligonucleotides (ASO) in an immune-competent mouse model results in a decrease in MDSC as well as immunosuppressive tumor-associated macrophages (TAM). In contrast, an increase in cytotoxic CD8⁺ T cells was also observed, which opened new avenues in understanding the conspicuous role of MALAT-1 in modulating carcinogenesis [13]. Various studies have reported MALAT-1 overexpression in numerous cancers such as esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, breast cancer (BC), and hepatocellular carcinoma (HCC) [14,15,16,17,18,19,20,21,22,23,24]. Using the online portal of the University of Alabama at Birmingham (UALCAN) (https://ualcan.path.uab.edu/) (Accessed on 26 December 2023), researchers analyzed MALAT-1 gene expression across different cancers using data from The Cancer Genome Atlas (TCGA) [25,26]. The expression levels of MALAT-1 between samples of different cancers and normal patients show that high expression of MALAT-1 is a prevalent event in various tumors such as ESCC, HCC, cholangiocarcinoma, cervical cancer (CC), sarcoma, and melanoma (Figure 2). Moreover, plausible differences in the expression of MALAT-1 between normal and cancerous samples were observed in other cancers, such as bladder carcinoma, thyroid carcinoma, and stomach adenocarcinoma (Figure 2). Contradictory to the disparity in MALAT-1 expression between normal and cancerous samples that are generally observed, samples having approximately the same MALAT-1 expression levels also exist. This ambiguity implies that MALAT-1 has a pleiotropic effect in cancer cells.

MALAT-1 is a promising diagnostic marker for detecting endometrial, breast, NSCLC, bladder, and nasopharyngeal carcinoma (NPC) [27,28,29,30,31]. However, there is a discrepancy in reporting the diagnostic accuracy of MALAT-1 [29,30,31]. A pooled analysis including 17 studies with 3255 subjects demonstrated that MALAT-1 exhibits moderate accuracy in detecting and diagnosing cancer, and it was strongly associated with the metastasis of early-stage NSCLC [32]. A wealth of evidence has revealed that the role of MALAT-1 is pivotal in modulating EMT, driving cells to become cancer stem cells (CSCs) or acquire stem cell–like properties, develop chemoresistance, and metastasize to distant places in the body [17,33,34,35,36]. Albeit the role of MALAT-1 in cancer has been extensively studied, molecular mechanisms that regulate MALAT-1 are scarcely reported. Several reports examined the expression level of MALAT-1 and its significance as a diagnostic, prognostic, and, recently, as a novel drug target. However, the underlying mechanisms that induce MALAT-1 to play its role are still largely unknown.

In EMT, epithelial cells display migratory and invasive features and become mesenchymal cells via the downregulation of E-cadherin, desmosomes, and claudin, and the upregulation of mesenchymal markers such as N-cadherin, fibronectin, and vimentin [37,38,39,40,41,42]. EMT increases the invasiveness and plasticity of cancer cells, which results in cancer cell dissemination to distant sites through the basement membrane, thereby inducing metastasis. Tumor-associated stroma upregulates the expression of various growth factors such as PDGF, EGF, HGF, and TGF-β, which in turn induces the activation of a series of transcription factors, including SNAI1, Slug, Twist, Zinc finger E-box binding homeobox1 (ZEB1), Goosecoid, and FOXC2, consequently initiating the EMT process [43,44,45,46,47,48]. Several reports demonstrate that EMT is crucial in stimulating cancer progression and metastasis and acquiring drug-resistant properties by modulating alternative cell signaling pathways [49,50,51,52,53]. Essential player proteins like Akt, ERK, MAPK, PI3K, β-catenin, and SMAD are essential in modulating EMT by central cell-signaling pathways [54]. Furthermore, microRNAs also have a crucial role in the cellular signaling circuitry that controls the EMT process. MALAT-1 serves as a competitive endogenous RNA (ceRNA) for tumor-suppressive microRNA and consequently downregulates their gene expression.