MALAT1 long non-coding RNA is overexpressed in multiple myeloma and may serve as a marker to predict disease progression

BMC Cancer

Shih-Feng Cho¹  Yuli Christine Chang²  Chao-Sung Chang⁵  Sheng-Fung Lin³  Yi-Chang Liu³  Hui-Hua Hsiao³  Jan-Gowth Chang⁴  Ta-Chih Liu¹ 

[1] Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan

[2] Department of Laboratory Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan

[3] Faculty of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan

[4] School of Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 404, Taiwan

[5] Graduate Institute of Healthcare Administration, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan

关键词: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1);    Long non-coding RNA;    Multiple myeloma;   

Others  :  1120236
DOI  :  10.1186/1471-2407-14-809

 received in 2014-07-10, accepted in 2014-10-23,  发布年份 2014

【 摘 要 】

Background

The pathogenesis of multiple myeloma involves complex genetic and epigenetic events. This study aimed to investigate the role and clinical relevance of the long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in multiple myeloma.

Methods

Bone marrow mononuclear cells were collected for analysis. The samples of multiple myeloma were taken from 45 patients at diagnosis, 61 post-treatment, and 18 who relapsed or had progression. Control samples were collected from 20 healthy individuals. Real-time quantitative reverse transcription polymerase chain reactions were performed to evaluate the expression of MALAT1. The clinical relevance of MALAT1 expression was also explored.

Results

MALAT1 was overexpressed in the newly diagnosed patients compared with post-treatment patients (mean ∆C_T: -5.54 ± 0.16 vs. -3.84 ± 0.09, 3.25-fold change; p < 0.001) and healthy individuals (mean ∆C_T: -5.54 ± 0.16 vs. -3.95 ± 0.21, 3.01-fold change; p < 0.001). The expression of MALAT1 strongly correlated with disease status, and the magnitude of change in MALAT1 post-treatment had prognostic relevance. The patients with early progression had a significantly smaller change in MALAT1 after treatment (mean ∆C_T change: 1.26 ± 1.06 vs. 2.09 ± 0.79, p = 0.011). A cut-off value of the change in MALAT1 (∆C_T change: 1.5) was obtained, and the patients with a greater decrease in MALAT1 (difference in ∆C_T >1.5) had significantly longer progression-free survival compared with the patients with a smaller MALAT1 change (24 months vs. 11 months; p = 0.001). For the post-treatment patients, the risk of early progression could be predicted using this cut-off value.

Conclusions

MALAT1 was overexpressed in patients with myeloma and may play a role in its pathogenesis. In addition, MALAT1 may serve as a molecular predictor of early progression.

【 授权许可】

   
2014 Cho et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Palumbo A, Anderson K: Multiple myeloma. N Engl J Med 2011, 364:1046-1060.
• [2]Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009, 113:5418-5422.
• [3]Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV: Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009, 113:5412-5417.
• [4]Kuehl WM, Bergsagel PL: Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002, 2:175-187.
• [5]Seidl S, Kaufmann H, Drach J: New insights into the pathophysiology of multiple myeloma. Lancet Oncol 2003, 4:557-564.
• [6]Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005, 23:6333-6338.
• [7]Morgan GJ, Walker BA, Davies FE: The genetic architecture of multiple myeloma. Nat Rev Cancer 2012, 12:335-348.
• [8]Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, Greipp PR, Rajkumar SV: Expression of VEGF and its receptors by myeloma cells. Leukemia 2003, 17:2025-2031.
• [9]Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI: Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004, 103:3503-3510.
• [10]Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC: Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007, 7:585-598.
• [11]Bertone P, Stolc V, Royce TE, Rozowsky JS, Urban AE, Zhu X, Rinn JL, Tongprasit W, Samanta M, Weissman S, Gerstein M, Snyder M: Global identification of human transcribed sequences with genome tiling arrays. Science 2004, 306:2242-2246.
• [12]International Human Genome Sequencing C: Finishing the euchromatic sequence of the human genome. Nature 2004, 431:931-945.
• [13]Hauptman N, Glavac D: Long non-coding RNA in cancer. Int J Mol Sci 2013, 14:4655-4669.
• [14]Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, Thomas M, Berdel WE, Serve H, Muller-Tidow C: 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.
• [15]Guru SC, Agarwal SK, Manickam P, Olufemi SE, Crabtree JS, Weisemann JM, Kester MB, Kim YS, Wang Y, Emmert-Buck MR, Liotta LA, Spiegel AM, Boguski MS, Roe BA, Collins FS, Marx SJ, Burns L, Chandrasekharappa SC: A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus. Genome Res 1997, 7:725-735.
• [16]van Asseldonk M, Schepens M, de Bruijn D, Janssen B, Merkx G, Geurts van Kessel A: Construction of a 350-kb sequence-ready 11q13 cosmid contig encompassing the markers D11S4933 and D11S546: mapping of 11 genes and 3 tumor-associated translocation breakpoints. Genomics 2000, 66:35-42.
• [17]Wilusz JE, Freier SM, Spector DL: 3' end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 2008, 135:919-932.
• [18]Friedel CC, Dolken L, Ruzsics Z, Koszinowski UH, Zimmer R: Conserved principles of mammalian transcriptional regulation revealed by RNA half-life. Nucleic Acids Res 2009, 37:e115.
• [19]Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A: A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 2007, 8:39. BioMed Central Full Text
• [20]Miyagawa R, Tano K, Mizuno R, Nakamura Y, Ijiri K, Rakwal R, Shibato J, Masuo Y, Mayeda A, Hirose T, Akimitsu N: Identification of cis- and trans-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles. RNA 2012, 18:738-751.
• [21]Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV: The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 2010, 39:925-938.
• [22]Yang F, Yi F, Han X, Du Q, Liang Z: MALAT-1 interacts with hnRNP C in cell cycle regulation. FEBS Lett 2013, 587:3175-3181.
• [23]Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, Zhang Y, Gorospe M, Prasanth SG, Lal A, Prasanth KV: Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet 2013, 9:e1003368.
• [24]Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A, Hillejan L, Wiebe K, Berdel WE, Wiewrodt R, Muller-Tidow C: 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 2011, 6:1984-1992.
• [25]Xu C, Yang M, Tian J, Wang X, Li Z: MALAT-1: a long non-coding RNA and its important 3' end functional motif in colorectal cancer metastasis. Int J Oncol 2011, 39:169-175.
• [26]Ying L, Chen Q, Wang Y, Zhou Z, Huang Y, Qiu F: Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. Mol Biosyst 2012, 8:2289-2294.
• [27]Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, Zornig M, MacLeod AR, Spector DL, Diederichs S: The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 2013, 73:1180-1189.
• [28]Lane L, Argoud-Puy G, Britan A, Cusin I, Duek PD, Evalet O, Gateau A, Gaudet P, Gleizes A, Masselot A, Zwahlen C, Bairoch A: neXtProt: a knowledge platform for human proteins. Nucleic Acids Res 2012, 40:D76-83.
• [29]Wu C, Macleod I, Su AI: BioGPS and MyGene.info: organizing online, gene-centric information. Nucleic Acids Res 2013, 41:D561-565.
• [30]Isin M, Ozgur E, Cetin G, Erten N, Aktan M, Gezer U, Dalay N: Investigation of circulating lncRNAs in B-cell neoplasms. Clin Chim Acta 2014, 431:255-259.
• [31]Chanan-Khan AA, Giralt S: Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol 2010, 28:2612-2624.
• [32]Moreau P, Attal M, Pegourie B, Planche L, Hulin C, Facon T, Stoppa AM, Fuzibet JG, Grosbois B, Doyen C, Ketterer N, Sebban C, Kolb B, Chaleteix C, Dib M, Voillat L, Fontan J, Garderet L, Jaubert J, Mathiot C, Esseltine D, Avet-Loiseau H, Harousseau JL, investigators IFMs: Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial. Blood 2011, 117:3041-3044.