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Published in: Journal of Neuro-Oncology 1/2015

01-01-2015 | Laboratory Investigation

Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer

Authors: Liqin Shen, Lei Chen, Yongsheng Wang, Xiaochun Jiang, Hongping Xia, Zhixiang Zhuang

Published in: Journal of Neuro-Oncology | Issue 1/2015

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Abstract

Brain metastasis often has a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Therefore, it is urgent to identify factors associated with lung cancer brain metastasis. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) also known as noncoding nuclear-enriched abundant transcript 2 is a long noncoding RNA, which is highly conserved amongst mammals. It has been shown to be increased in a variety of tumors including NSCLC and regulate the expression of metastasis-associated genes. However, the role of MALAT1 in lung cancer brain metastasis has not been investigated. In this study, we examined the level of MALAT1 in 78 cases of NSCLC samples with 19 brain metastasis and 59 non-brain metastasis by qRT-PCR. We observed that the level of MALAT1 was significantly higher in brain metastasis than that of non brain metastasis samples (P < 0.001). The level of MALAT1 was associated with patients’ survival. To investigate the role of MALAT1 in brain metastasis, we established a highly invasive and metastatic cell subline using the brain metastasis lung cancer cell H1915. We found that MALAT1 is increased in highly invasive subline of brain metastasis lung cancer cells. Further functional studies indicate that silencing MALAT1 inhibits highly invasive subline of brain metastasis lung cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, increased level of long noncoding RNA MALAT1 promotes lung cancer brain metastasis by inducing EMT, which may be a promising prognosis factor and therapeutic target to treat lung cancer brain metastasis in future.
Literature
1.
go back to reference Nolte SM, Venugopal C, McFarlane N, Morozova O, Hallett RM, O’Farrell E, Manoranjan B, Murty NK, Klurfan P, Kachur E (2013) A cancer stem cell model for studying brain metastases from primary lung cancer. J Natl Cancer Inst 105:551–562PubMedCrossRef Nolte SM, Venugopal C, McFarlane N, Morozova O, Hallett RM, O’Farrell E, Manoranjan B, Murty NK, Klurfan P, Kachur E (2013) A cancer stem cell model for studying brain metastases from primary lung cancer. J Natl Cancer Inst 105:551–562PubMedCrossRef
2.
go back to reference Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, Johnson BE (2010) Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 16:5873–5882PubMedCentralPubMedCrossRef Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, Johnson BE (2010) Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 16:5873–5882PubMedCentralPubMedCrossRef
3.
go back to reference Xia M, Hu M (2010) The role of microRNA in tumor invasion and metastasis. J Cancer Mol 5:33–39 Xia M, Hu M (2010) The role of microRNA in tumor invasion and metastasis. J Cancer Mol 5:33–39
4.
go back to reference Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, Kratzke R, Watson MA, Kelley M, Ginsburg GS (2006) A genomic strategy to refine prognosis in early-stage non–small-cell lung cancer. N Engl J Med 355:570–580PubMedCrossRef Potti A, Mukherjee S, Petersen R, Dressman HK, Bild A, Koontz J, Kratzke R, Watson MA, Kelley M, Ginsburg GS (2006) A genomic strategy to refine prognosis in early-stage non–small-cell lung cancer. N Engl J Med 355:570–580PubMedCrossRef
5.
go back to reference Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198PubMedCrossRef Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198PubMedCrossRef
6.
go back to reference Chen H-Y, Yu S-L, Chen C-H, Chang G-C, Chen C-Y, Yuan A, Cheng C-L, Wang C-H, Terng H-J, Kao S-F (2007) A five-gene signature and clinical outcome in non–small-cell lung cancer. N Engl J Med 356:11–20PubMedCrossRef Chen H-Y, Yu S-L, Chen C-H, Chang G-C, Chen C-Y, Yuan A, Cheng C-L, Wang C-H, Terng H-J, Kao S-F (2007) A five-gene signature and clinical outcome in non–small-cell lung cancer. N Engl J Med 356:11–20PubMedCrossRef
7.
go back to reference Nguyen DX, Chiang AC, Zhang XH-F, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massague J (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62PubMedCentralPubMedCrossRef Nguyen DX, Chiang AC, Zhang XH-F, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massague J (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62PubMedCentralPubMedCrossRef
10.
go back to reference Eißmann M, Gutschner T, Hämmerle M, Günther S, Caudron-Herger M, Groß M, Schirmacher P, Rippe K, Braun T, Diederichs S (2012) Loss of the abundant nuclear noncoding RNA MALAT1 is compatible with life and development. RNA Biol 9:1076–1087PubMedCentralPubMedCrossRef Eißmann M, Gutschner T, Hämmerle M, Günther S, Caudron-Herger M, Groß M, Schirmacher P, Rippe K, Braun T, Diederichs S (2012) Loss of the abundant nuclear noncoding RNA MALAT1 is compatible with life and development. RNA Biol 9:1076–1087PubMedCentralPubMedCrossRef
11.
go back to reference Schmidt LH, Spieker T, Koschmieder S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A, Hillejan L (2011) The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol 6:1984–1992PubMedCrossRef Schmidt LH, Spieker T, Koschmieder S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A, Hillejan L (2011) The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol 6:1984–1992PubMedCrossRef
12.
go back to reference Gutschner T, Hämmerle M, Eißmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Groß M, Zörnig M, MacLeod AR, Spector DL, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73:1180–1189. doi:10.1158/0008-5472.can-12-2850 PubMedCentralPubMedCrossRef Gutschner T, Hämmerle M, Eißmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Groß M, Zörnig M, MacLeod AR, Spector DL, Diederichs S (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73:1180–1189. doi:10.​1158/​0008-5472.​can-12-2850 PubMedCentralPubMedCrossRef
13.
go back to reference Grinberg-Rashi H, Ofek E, Perelman M, Skarda J, Yaron P, Hajdúch M, Jacob-Hirsch J, Amariglio N, Krupsky M, Simansky DA (2009) The expression of three genes in primary non–small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res 15:1755–1761PubMedCrossRef Grinberg-Rashi H, Ofek E, Perelman M, Skarda J, Yaron P, Hajdúch M, Jacob-Hirsch J, Amariglio N, Krupsky M, Simansky DA (2009) The expression of three genes in primary non–small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res 15:1755–1761PubMedCrossRef
14.
go back to reference Berkhout B, Jeang K-T (2007) RISCy business: microRNAs, pathogenesis, and viruses. J Biol Chem 282:26641–26645PubMedCrossRef Berkhout B, Jeang K-T (2007) RISCy business: microRNAs, pathogenesis, and viruses. J Biol Chem 282:26641–26645PubMedCrossRef
15.
go back to reference Yu S-L, Chen H-Y, Chang G-C, Chen C-Y, Chen H-W, Singh S, Cheng C-L, Yu C-J, Lee Y-C, Chen H-S, Su T-J, Chiang C-C, Li H-N, Hong Q-S, Su H-Y, Chen C-C, Chen W-J, Liu C-C, Chan W-K, Chen WJ, Li K-C, Chen JJW, Yang P-C (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57PubMedCrossRef Yu S-L, Chen H-Y, Chang G-C, Chen C-Y, Chen H-W, Singh S, Cheng C-L, Yu C-J, Lee Y-C, Chen H-S, Su T-J, Chiang C-C, Li H-N, Hong Q-S, Su H-Y, Chen C-C, Chen W-J, Liu C-C, Chan W-K, Chen WJ, Li K-C, Chen JJW, Yang P-C (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57PubMedCrossRef
16.
go back to reference Arora S, Ranade AR, Tran NL, Nasser S, Sridhar S, Korn RL, Ross JT, Dhruv H, Foss KM, Sibenaller Z (2011) MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration. Int J Cancer 129:2621–2631PubMedCentralPubMedCrossRef Arora S, Ranade AR, Tran NL, Nasser S, Sridhar S, Korn RL, Ross JT, Dhruv H, Foss KM, Sibenaller Z (2011) MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration. Int J Cancer 129:2621–2631PubMedCentralPubMedCrossRef
17.
go back to reference Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E (2003) MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22:8031–8041PubMedCrossRef Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E (2003) MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22:8031–8041PubMedCrossRef
18.
go back to reference Gutschner T, Hämmerle M, Diederichs S (2013) MALAT1—a paradigm for long noncoding RNA function in cancer. J Mol Med 91:791–801PubMedCrossRef Gutschner T, Hämmerle M, Diederichs S (2013) MALAT1—a paradigm for long noncoding RNA function in cancer. J Mol Med 91:791–801PubMedCrossRef
19.
go back to reference Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y (2010) MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet 6:e1000879PubMedCentralPubMedCrossRef Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y (2010) MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet 6:e1000879PubMedCentralPubMedCrossRef
20.
go back to reference Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K, Akimitsu N (2010) MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett 584:4575–4580PubMedCrossRef Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K, Akimitsu N (2010) MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett 584:4575–4580PubMedCrossRef
21.
Metadata
Title
Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer
Authors
Liqin Shen
Lei Chen
Yongsheng Wang
Xiaochun Jiang
Hongping Xia
Zhixiang Zhuang
Publication date
01-01-2015
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 1/2015
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-014-1613-0

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