MALAT-1 Modulates Epithelial–Mesenchymal Transition in Cancer: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Gnanasekar Munirathinam.

Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long intergenic non-coding RNA (lncRNA) located on chr11q13. It is overexpressed in several cancers and controls gene expression through chromatin modification, transcriptional regulation, and post-transcriptional regulation. Importantly, MALAT-1 stimulates cell proliferation, migration, and metastasis and serves a vital role in driving the epithelial-to-mesenchymal transition (EMT), subsequently acquiring cancer stem cell-like properties and developing drug resistance. MALAT-1 modulates EMT by interacting with various intracellular signaling pathways, notably the phosphoinositide 3-kinase (PI3K)/Akt and Wnt/β-catenin pathways. It also behaves like a sponge for microRNAs, preventing their interaction with target genes and promoting EMT. 

  • MALAT-1
  • epithelial-to-mesenchymal transition (EMT)
  • metastasis
  • chemoresistance

1. Introduction

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][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][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].
Figure 1. MALAT-1 is an RNA gene encoded by chromosome 11q13. MALAT-1 is initially transcribed as a precursor immature transcript, which the enzyme RNAase P processes to produce mature MALAT-1. MALAT-1 decreases gene expression in many ways, including interfering with a transcription factor, interfering with RNA Pol II, therefore inhibiting transcription, interfering with mRNA splicing, interfering with epigenetic regulation leading to gene silencing and competing with miRNAs, and preventing mRNA transcriptions. Figure 1 created with BioRender.com (Accessed on 27 December 2023).
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][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][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][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.
Figure 2. Depicts the comparison of MALAT-1 gene expression. MALAT-1 gene expression between tumor samples (denoted in red color) and non-cancerous samples (blue color) across different cancers through the UALCAN database online portal (https://ualcan.path.uab.edu/) (Accessed on 26 December 2023). The tumor sample shows high expression in various tumors such as esophageal carcinoma, CC, HCC, sarcoma, and melanoma compared to normal patients’ samples.
MALAT-1 is a promising diagnostic marker for detecting endometrial, breast, NSCLC, bladder, and nasopharyngeal carcinoma (NPC) [27,28,29,30,31][27][28][29][30][31]. However, there is a discrepancy in reporting the diagnostic accuracy of MALAT-1 [29,30,31][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][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][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][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][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.

2. MALAT-1 Modulates EMT and Promotes Cancer Metastasis, Stemness, and Chemoresistance

2.1. MALAT-1 Induces Cancer Progression and Metastasis by Modulating EMT

The overexpression of MALAT-1 enhances the ability of tumor cells to migrate, invade, metastasize, and escape the cytotoxic effect of chemotherapy. One study reported that MALAT-1 inhibition decreases the progression and metastasis of CC in vitro and in vivo [56][55]. MALAT-1 knockdown upregulates the epithelial markers and downregulates the mesenchymal markers, contributing to an active EMT process [56][55]. In addition, the EMT regulator SNAI1 was markedly downregulated, indicating that SNAI1 regulates the expression of E-cadherin in response to MALAT-1 knockdown [56][55].
Furthermore, MALAT-1 downregulation inhibits cancer cell proliferation, invasion, and metastasis in GC cells in vitro and in vivo. MALAT-1 silencing upregulates E-cadherin while downregulating vimentin and reverses the EMT process, indicating that MALAT-1 has a role in inducing GC cells to undergo EMT [58][56]. Jiao et al. [21] demonstrated that MALAT-1 was highly expressed in cell lines and tissue samples of pancreatic cancer, and its knockdown was shown to induce apoptosis and suppress cell migration and invasion in pancreatic cancer [21]. Furthermore, MALAT-1 knockdown increased the expression of the epithelial marker E-cadherin and decreased the expression of the mesenchymal markers N-cadherin, SNAI1, Slug, and metalloproteinases (MMP2 and MMP9), indicating that EMT was inhibited [21].
Additionally, in lung cancer, Shen et al. [17] demonstrated that MALAT-1 expression was markedly higher in lung tumor samples with brain metastasis than those without brain metastasis, indicating EMT in metastatic samples [17]. MALAT-1 silencing inhibited the invasion and metastasis of a highly invasive subline of brain-metastatic lung cancer cells in vitro and in vivo. Intriguingly, E-cadherin and vimentin expression increased in this study, concluding that MALAT-1 promoted brain metastasis of lung cancer cells by inducing EMT [17]. Furthermore, researchers analyzed MALAT-1 RNA-Seq expression data using the TNM plot online portal (https://tnmplot.com/analysis/) (Accessed on 26 December 2023) in normal, tumor, and metastatic samples of CC, head and neck squamous cell carcinoma (HNSCC), pheochromocytoma and paraganglioma, thyroid carcinoma, and breast invasive carcinoma (Figure 3) [60][57]. Indeed, the analysis illustrated that MALAT-1 expression is significantly higher in metastatic samples than in tumor and normal samples, affirming the fundamental role of MALAT-1 in inducing cancer metastasis. Intriguingly, the graph in Figure 3 shows a difference in the distribution between normal and tumor samples and a remarkably high expression in metastatic samples, implying that MALAT-1 plays an essential role in inducing metastasis.
Figure 3. Illustrates the boxplot of the MALAT-1 expression. The analysis of MALAT-1 expression data through the online TNM plot portal (https://tnmplot.com/analysis/) (Accessed on 26 December 2023) compares the different expressions between normal, tumor, and metastatic samples in CC, HNSCC, pheochromocytoma and paraganglioma, thyroid carcinoma, and breast invasive carcinoma. 

2.2. MALAT-1 Promotes Chemoresistance via Modulating EMT

Several studies have discussed the role of MALAT-1 in facilitating chemoresistance in cancer [33,34,35,59][33][34][35][58]. Li et al. [59][58] revealed that a higher level of MALAT-1 in glioblastoma cells is associated with drug resistance through the upregulation of ZEB1 [59][58]. Knockdown of MALAT-1 markedly enhanced the sensitivity of multi-resistant glioblastoma cells to Temozolomide (TMZ) by decreasing the expression level of the resistance genes MDR1, MRP5, and LRP1 as well as the mesenchymal markers ZEB1, α-SMA, and fibronectin. These results affirm the pivotal role of MALAT-1 in modulating chemoresistance in cancer [59][58].
Another study investigates the role of MALAT-1 in modulating chemoresistance in CRC. Xiong et al. [33] established Oxymatrine-resistant CRC cells and showed that chemo-resistant cell lines possess many characteristics associated with EMT. The cells lose their polarity, downregulate E-cadherin, and upregulate vimentin [33]. MALAT-1 was also shown to be highly expressed in Oxymatrine-resistant CRC cells. Therefore, MALAT-1 silencing resulted in a significant upregulation of epithelial markers and downregulation of mesenchymal markers. Hence, MALAT-1 knockdown may reverse the EMT process and reduce chemotherapy resistance [33].
Moreover, another study conducted by Wu et al. [34] illustrated that the expression of MALAT-1 was higher in Trastuzumab-resistant HER2+ cells and metastatic TNBC cells than in normal cells. MALAT-1 silencing was associated with a more robust response to Trastuzumab treatment and decreased cell proliferation and invasion [34]. The overexpression of MALAT-1 was correlated with higher expression of EMT markers. Thus, MALAT-1 was proposed to induce resistance to Cisplatin through EMT [35]. MALAT-1 silencing reduces Cisplatin resistance in OSCC by reversing EMT and enhancing cell apoptosis [35]. In addition, another study reported that MALAT-1 knockdown in diffuse large B cell lymphoma cells resistant to Adriamycin induces autophagy-related death, accompanied by enhanced chemosensitivity [57][59]. Moreover, MALAT-1 knockdown promotes chemosensitivity to Gemcitabine in pancreatic cancer [36]. MALAT-1 tethered EZH2 to the CDH1 promoter and inhibited miR-218, resulting in resistance to oxaliplatin in CRC [61][60].
EMT acquisition has induced resistance to EGFR-TKIs in advanced NSCLC [62][61]. In addition, MALAT-1 has also been shown to induce resistance to the newly developed EGFR-TKI targeted therapy, Gefitinib [63][62]. In lung adenocarcinoma A549 cells that are resistant to Gefitinib, MALAT-1 expression was significantly higher than in normal cells [63][62]. MiR-200a has been reported to increase sensitivity to Gefitinib treatment in NSCLC [64][63]. MALAT-1 was shown to sponge miR-200a in Gefitinib-resistant A549 cells that inhibit EMT by targeting ZEB1 and ZEB2 [63,65][62][64]. Therefore, knockdown of MALAT-1 by shMALAT-1 significantly decreases cell proliferation and resistance to Gefitinib [63][62]. Collectively, the role of MALAT-1 in promoting chemoresistance is monumental and involves interference with several mechanisms that facilitate the development of resistance, including DNA damage and repair pathways, drug efflux, cell cycle, apoptosis, autophagy, stemness, and EMT reviewed extensively by Hou et al. [66][65].

2.3. MALAT-1 Drives Cancer Cells toward More Stem Cell-like Features by Inducing EMT

Tumor heterogeneity is mainly caused by a minor subpopulation called CSCs, which is responsible for tumor plasticity, angiogenesis, invasion, and resistance to cancer treatment. CSC populations respond to the adjacent microenvironment by interacting with transcriptional, post-transcriptional, and metabolic factors [67,68][66][67]. Various lncRNAs have been associated with initiating, maintaining, and regulating CSCs, including HOTAIR, MALAT-1, HOTTIP, and H19 [69][68]. Jiao et al. [36] examined MALAT-1 expression in the pancreatic CSC population and showed that it was overexpressed in CSCs. Knockdown of MALAT-1 resulted in a decrease in the CD133+ subpopulation [36]. In addition, the induction of EMT using TGF-β increased the expression of MALAT-1 in the CD133+ subpopulation compared to the CD133- subpopulation, indicating that MALAT-1 was upregulated in pancreatic CSCs. MALAT-1 knockdown decreases sphere formation, colony formation, and tumor size [36].
Furthermore, another study demonstrated that MALAT-1 promoted CSC-like phenotypes in the MCF7 cell line. MALAT-1 was markedly overexpressed in the CD133+ subpopulation compared to the rest of the MCF7 cells [55][69]. MALAT-1 silencing subsequently leads to a decrease in the CD133+ CSC population. In addition, the sphere formation rate, proliferation, colony formation, migration, and invasion of CSCs also decreased [55][69]. In conclusion, MALAT-1 promotes cell proliferation, migration, invasion, metastasis, and chemoresistance by promoting EMT, which may give rise to CSCs. However, further studies are required to decipher the mechanisms underlying inducing a CSC-like phenotype.

References

  1. Ji, P.; Diederichs, S.; Wang, W.; Boing, S.; Metzger, R.; Schneider, P.M.; Tidow, N.; Brandt, B.; Buerger, H.; Bulk, E.; et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003, 22, 8031–8041.
  2. Li, Z.X.; Zhu, Q.N.; Zhang, H.B.; Hu, Y.; Wang, G.; Zhu, Y.S. MALAT1: A potential biomarker in cancer. Cancer Manag. Res. 2018, 10, 6757–6768.
  3. Dueva, R.; Akopyan, K.; Pederiva, C.; Trevisan, D.; Dhanjal, S.; Lindqvist, A.; Farnebo, M. Neutralization of the Positive Charges on Histone Tails by RNA Promotes an Open Chromatin Structure. Cell Chem. Biol. 2019, 26, 1436–1449.e1435.
  4. Blank-Giwojna, A.; Postepska-Igielska, A.; Grummt, I. lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators. Cell Rep. 2019, 26, 2904–2915.e2904.
  5. Seila, A.C.; Calabrese, J.M.; Levine, S.S.; Yeo, G.W.; Rahl, P.B.; Flynn, R.A.; Young, R.A.; Sharp, P.A. Divergent transcription from active promoters. Science 2008, 322, 1849–1851.
  6. Hartford, C.C.R.; Lal, A. When Long Noncoding Becomes Protein Coding. Mol. Cell Biol. 2020, 40, e00528-19.
  7. Hu, Y.; Lin, J.; Fang, H.; Fang, J.; Li, C.; Chen, W.; Liu, S.; Ondrejka, S.; Gong, Z.; Reu, F.; et al. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia 2018, 32, 2250–2262.
  8. Huang, J.; Lin, C.; Dong, H.; Piao, Z.; Jin, C.; Han, H.; Jin, D. Targeting MALAT1 induces DNA damage and sensitize non-small cell lung cancer cells to cisplatin by repressing BRCA1. Cancer Chemother. Pharmacol. 2020, 86, 663–672.
  9. Anbiyaee, O.; Moalemnia, A.; Ghaedrahmati, F.; Shooshtari, M.K.; Khoshnam, S.E.; Kempisty, B.; Halili, S.A.; Farzaneh, M.; Morenikeji, O.B. The functions of long non-coding RNA (lncRNA)-MALAT-1 in the pathogenesis of renal cell carcinoma. BMC Nephrol. 2023, 24, 380.
  10. Hou, Z.H.; Xu, X.W.; Fu, X.Y.; Zhou, L.D.; Liu, S.P.; Tan, D.M. Long non-coding RNA MALAT1 promotes angiogenesis and immunosuppressive properties of HCC cells by sponging miR-140. Am. J. Physiol. Cell Physiol. 2020, 318, C649–C663.
  11. Mekky, R.Y.; Ragab, M.F.; Manie, T.; Attia, A.A.; Youness, R.A. MALAT-1: Immunomodulatory lncRNA hampering the innate and the adaptive immune arms in triple negative breast cancer. Transl. Oncol. 2023, 31, 101653.
  12. Zhou, Q.; Tang, X.; Tian, X.; Tian, J.; Zhang, Y.; Ma, J.; Xu, H.; Wang, S. LncRNA MALAT1 negatively regulates MDSCs in patients with lung cancer. J. Cancer 2018, 9, 2436–2442.
  13. Adewunmi, O.; Shen, Y.; Zhang, X.H.; Rosen, J.M. Targeted Inhibition of lncRNA Malat1 Alters the Tumor Immune Microenvironment in Preclinical Syngeneic Mouse Models of Triple-Negative Breast Cancer. Cancer Immunol. Res. 2023, 11, 1462–1479.
  14. Hu, L.; Wu, Y.; Tan, D.; Meng, H.; Wang, K.; Bai, Y.; Yang, K. Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma. J. Exp. Clin. Cancer Res. 2015, 34, 7.
  15. Okugawa, Y.; Toiyama, Y.; Hur, K.; Toden, S.; Saigusa, S.; Tanaka, K.; Inoue, Y.; Mohri, Y.; Kusunoki, M.; Boland, C.R.; et al. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis. Carcinogenesis 2014, 35, 2731–2739.
  16. Djebali, S.; Davis, C.A.; Merkel, A.; Dobin, A.; Lassmann, T.; Mortazavi, A.; Tanzer, A.; Lagarde, J.; Lin, W.; Schlesinger, F.; et al. Landscape of transcription in human cells. Nature 2012, 489, 101–108.
  17. Shen, L.; Chen, L.; Wang, Y.; Jiang, X.; Xia, H.; Zhuang, Z. Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J. Neurooncol. 2015, 121, 101–108.
  18. Zheng, H.T.; Shi, D.B.; Wang, Y.W.; Li, X.X.; Xu, Y.; Tripathi, P.; Gu, W.L.; Cai, G.X.; Cai, S.J. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer. Int. J. Clin. Exp. Pathol. 2014, 7, 3174–3181.
  19. Lai, M.C.; Yang, Z.; Zhou, L.; Zhu, Q.Q.; Xie, H.Y.; Zhang, F.; Wu, L.M.; Chen, L.M.; Zheng, S.S. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med. Oncol. 2012, 29, 1810–1816.
  20. Xu, S.; Sui, S.; Zhang, J.; Bai, N.; Shi, Q.; Zhang, G.; Gao, S.; You, Z.; Zhan, C.; Liu, F.; et al. Downregulation of long noncoding RNA MALAT1 induces epithelial-to-mesenchymal transition via the PI3K-AKT pathway in breast cancer. Int. J. Clin. Exp. Pathol. 2015, 8, 4881–4891.
  21. Jiao, F.; Hu, H.; Yuan, C.; Wang, L.; Jiang, W.; Jin, Z.; Guo, Z.; Wang, L. Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol. Rep. 2014, 32, 2485–2492.
  22. Dong, Y.; Liang, G.; Yuan, B.; Yang, C.; Gao, R.; Zhou, X. MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol. 2015, 36, 1477–1486.
  23. Tee, A.E.; Ling, D.; Nelson, C.; Atmadibrata, B.; Dinger, M.E.; Xu, N.; Mizukami, T.; Liu, P.Y.; Liu, B.; Cheung, B.; et al. The histone demethylase JMJD1A induces cell migration and invasion by up-regulating the expression of the long noncoding RNA MALAT1. Oncotarget 2014, 5, 1793–1804.
  24. Glover, A.R.; Zhao, J.T.; Ip, J.C.; Lee, J.C.; Robinson, B.G.; Gill, A.J.; Soon, P.S.; Sidhu, S.B. Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence. Endocr. Relat. Cancer 2015, 22, 99–109.
  25. (UALCAN), The University of Alabama at Birmingham. MALAT-1 Gene Expression across Different Cancers Using Data from The Cancer Genome Atlas (TCGA). Available online: http://ualcan.path.uab.edu/analysis.html (accessed on 20 May 2022).
  26. Chandrashekar, D.S.; Karthikeyan, S.K.; Korla, P.K.; Patel, H.; Shovon, A.R.; Athar, M.; Netto, G.J.; Qin, Z.S.; Kumar, S.; Manne, U.; et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia 2022, 25, 18–27.
  27. Peng, H.; Wang, J.; Li, J.; Zhao, M.; Huang, S.K.; Gu, Y.Y.; Li, Y.; Sun, X.J.; Yang, L.; Luo, Q.; et al. A circulating non-coding RNA panel as an early detection predictor of non-small cell lung cancer. Life Sci. 2016, 151, 235–242.
  28. Duan, W.; Du, L.; Jiang, X.; Wang, R.; Yan, S.; Xie, Y.; Yan, K.; Wang, Q.; Wang, L.; Zhang, X.; et al. Identification of a serum circulating lncRNA panel for the diagnosis and recurrence prediction of bladder cancer. Oncotarget 2016, 7, 78850–78858.
  29. Huang, S.K.; Luo, Q.; Peng, H.; Li, J.; Zhao, M.; Wang, J.; Gu, Y.Y.; Li, Y.; Yuan, P.; Zhao, G.H.; et al. A Panel of Serum Noncoding RNAs for the Diagnosis and Monitoring of Response to Therapy in Patients with Breast Cancer. Med. Sci. Monit. 2018, 24, 2476–2488.
  30. He, B.; Zeng, J.; Chao, W.; Chen, X.; Huang, Y.; Deng, K.; Huang, Z.; Li, J.; Dai, M.; Chen, S.; et al. Serum long non-coding RNAs MALAT1, AFAP1-AS1 and AL359062 as diagnostic and prognostic biomarkers for nasopharyngeal carcinoma. Oncotarget 2017, 8, 41166–41177.
  31. Eissmann, M.; Gutschner, T.; Hammerle, M.; Gunther, S.; Caudron-Herger, M.; Gross, M.; Schirmacher, P.; Rippe, K.; Braun, T.; Zornig, M.; et al. Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol. 2012, 9, 1076–1087.
  32. Zhao, Y.; Yu, Y.Q.; You, S.; Zhang, C.M.; Wu, L.; Zhao, W.; Wang, X.M. Long Non-Coding RNA MALAT1 as a Detection and Diagnostic Molecular Marker in Various Human Cancers: A Pooled Analysis Based on 3255 Subjects. Onco Targets Ther. 2020, 13, 5807–5817.
  33. Xiong, Y.; Wang, J.; Zhu, H.; Liu, L.; Jiang, Y. Chronic oxymatrine treatment induces resistance and epithelialmesenchymal transition through targeting the long non-coding RNA MALAT1 in colorectal cancer cells. Oncol. Rep. 2018, 39, 967–976.
  34. Wu, Y.; Sarkissyan, M.; Ogah, O.; Kim, J.; Vadgama, J.V. Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers. Cancers 2020, 12, 1918.
  35. Wang, R.; Lu, X.; Yu, R. lncRNA MALAT1 Promotes EMT Process and Cisplatin Resistance of Oral Squamous Cell Carcinoma via PI3K/AKT/m-TOR Signal Pathway. Onco Targets Ther. 2020, 13, 4049–4061.
  36. Jiao, F.; Hu, H.; Han, T.; Yuan, C.; Wang, L.; Jin, Z.; Guo, Z.; Wang, L. Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. Int. J. Mol. Sci. 2015, 16, 6677–6693.
  37. Iderzorig, T.; Kellen, J.; Osude, C.; Singh, S.; Woodman, J.A.; Garcia, C.; Puri, N. Comparison of EMT mediated tyrosine kinase inhibitor resistance in NSCLC. Biochem. Biophys. Res. Commun. 2018, 496, 770–777.
  38. Lee, J.M.; Dedhar, S.; Kalluri, R.; Thompson, E.W. The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J. Cell Biol. 2006, 172, 973–981.
  39. Thiery, J.P.; Sleeman, J.P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 2006, 7, 131–142.
  40. Puram, S.V.; Tirosh, I.; Parikh, A.S.; Patel, A.P.; Yizhak, K.; Gillespie, S.; Rodman, C.; Luo, C.L.; Mroz, E.A.; Emerick, K.S.; et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 2017, 171, 1611–1624.e1624.
  41. Jang, M.H.; Kim, H.J.; Kim, E.J.; Chung, Y.R.; Park, S.Y. Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome. Hum. Pathol. 2015, 46, 1267–1274.
  42. Dong, J.; Hu, Y.; Fan, X.; Wu, X.; Mao, Y.; Hu, B.; Guo, H.; Wen, L.; Tang, F. Single-cell RNA-seq analysis unveils a prevalent epithelial/mesenchymal hybrid state during mouse organogenesis. Genome Biol. 2018, 19, 31.
  43. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454.
  44. Jechlinger, M.; Grunert, S.; Beug, H. Mechanisms in epithelial plasticity and metastasis: Insights from 3D cultures and expression profiling. J. Mammary Gland. Biol. Neoplasia 2002, 7, 415–432.
  45. Shi, Y.; Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003, 113, 685–700.
  46. Niessen, K.; Fu, Y.; Chang, L.; Hoodless, P.A.; McFadden, D.; Karsan, A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J. Cell Biol. 2008, 182, 315–325.
  47. Medici, D.; Hay, E.D.; Olsen, B.R. Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol. Biol. Cell 2008, 19, 4875–4887.
  48. Kokudo, T.; Suzuki, Y.; Yoshimatsu, Y.; Yamazaki, T.; Watabe, T.; Miyazono, K. Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J. Cell Sci. 2008, 121, 3317–3324.
  49. Patel, M.; Eckburg, A.; Gantiwala, S.; Hart, Z.; Dein, J.; Lam, K.; Puri, N. Resistance to Molecularly Targeted Therapies in Melanoma. Cancers 2021, 13, 1115.
  50. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428.
  51. Garside, V.C.; Chang, A.C.; Karsan, A.; Hoodless, P.A. Co-ordinating Notch, BMP, and TGF-beta signaling during heart valve development. Cell Mol. Life Sci. 2013, 70, 2899–2917.
  52. Micalizzi, D.S.; Farabaugh, S.M.; Ford, H.L. Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J. Mammary Gland. Biol. Neoplasia 2010, 15, 117–134.
  53. Wells, A.; Yates, C.; Shepard, C.R. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin. Exp. Metastasis 2008, 25, 621–628.
  54. Tse, J.C.; Kalluri, R. Mechanisms of metastasis: Epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J. Cell Biochem. 2007, 101, 816–829.
  55. Sun, R.; Qin, C.; Jiang, B.; Fang, S.; Pan, X.; Peng, L.; Liu, Z.; Li, W.; Li, Y.; Li, G. Down-regulation of MALAT1 inhibits cervical cancer cell invasion and metastasis by inhibition of epithelial-mesenchymal transition. Mol. Biosyst. 2016, 12, 952–962.
  56. Chen, D.; Liu, L.; Wang, K.; Yu, H.; Wang, Y.; Liu, J.; Guo, Y.; Zhang, H. The role of MALAT-1 in the invasion and metastasis of gastric cancer. Scand. J. Gastroenterol. 2017, 52, 790–796.
  57. Bartha, A.; Gyorffy, B. TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int. J. Mol. Sci. 2021, 22, 2622.
  58. Li, H.; Yuan, X.; Yan, D.; Li, D.; Guan, F.; Dong, Y.; Wang, H.; Liu, X.; Yang, B. Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide. Cell Physiol. Biochem. 2017, 42, 1192–1201.
  59. Li, L.J.; Chai, Y.; Guo, X.J.; Chu, S.L.; Zhang, L.S. The effects of the long non-coding RNA MALAT-1 regulated autophagy-related signaling pathway on chemotherapy resistance in diffuse large B-cell lymphoma. Biomed. Pharmacother. 2017, 89, 939–948.
  60. Li, P.; Zhang, X.; Wang, H.; Wang, L.; Liu, T.; Du, L.; Yang, Y.; Wang, C. MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2. Mol. Cancer Ther. 2017, 16, 739–751.
  61. Zhou, J.; Wang, J.; Zeng, Y.; Zhang, X.; Hu, Q.; Zheng, J.; Chen, B.; Xie, B.; Zhang, W.M. Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer. Oncotarget 2015, 6, 44332–44345.
  62. Feng, C.; Zhao, Y.; Li, Y.; Zhang, T.; Ma, Y.; Liu, Y. LncRNA MALAT1 Promotes Lung Cancer Proliferation and Gefitinib Resistance by Acting as a miR-200a Sponge. Arch Bronconeumol. 2019, 55, 627–633.
  63. Zhen, Q.; Liu, J.; Gao, L.; Liu, J.; Wang, R.; Chu, W.; Zhang, Y.; Tan, G.; Zhao, X.; Lv, B. MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer. Cytogenet. Genome Res. 2015, 146, 1–8.
  64. Bracken, C.P.; Gregory, P.A.; Kolesnikoff, N.; Bert, A.G.; Wang, J.; Shannon, M.F.; Goodall, G.J. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008, 68, 7846–7854.
  65. Hou, J.; Zhang, G.; Wang, X.; Wang, Y.; Wang, K. Functions and mechanisms of lncRNA MALAT1 in cancer chemotherapy resistance. Biomark. Res. 2023, 11, 23.
  66. Huang, T.; Song, X.; Xu, D.; Tiek, D.; Goenka, A.; Wu, B.; Sastry, N.; Hu, B.; Cheng, S.Y. Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics 2020, 10, 8721–8743.
  67. Nassar, D.; Blanpain, C. Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Annu. Rev. Pathol. 2016, 11, 47–76.
  68. Castro-Oropeza, R.; Melendez-Zajgla, J.; Maldonado, V.; Vazquez-Santillan, K. The emerging role of lncRNAs in the regulation of cancer stem cells. Cell Oncol. 2018, 41, 585–603.
  69. Zeng, L.; Cen, Y.; Chen, J. Long non-coding RNA MALAT-1 contributes to maintenance of stem cell-like phenotypes in breast cancer cells. Oncol. Lett. 2018, 15, 2117–2122.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback