Original Study
High Expression of Long Noncoding RNA MALAT1 Indicates a Poor Prognosis and Promotes Clinical Progression and Metastasis in Bladder Cancer

https://doi.org/10.1016/j.clgc.2017.05.001Get rights and content

Abstract

Background

Recent studies have demonstrated that the expression of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cancer cell proliferation, invasion, and metastasis in many tumor types, but the association between bladder cancer and MALAT1 remains unknown.

Materials

The expression of MALAT1 was tested by in situ hybridization (ISH) in 120 bladder cancer specimens. The association between MALAT1 expression and clinicopathological features and prognosis of the patients with bladder cancer was analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the relationship between the expression of MALAT1 and progression and metastasis of bladder cancer.

Results

ISH showed that high MALAT1 expression was associated with advanced histological grade, high tumor stage, and positive lymph nodes. Kaplan-Meier survival analysis and Cox regression analysis indicated that high tumor stage, positive lymph nodes, and high MALAT1 expression were independent prognostic indicators for overall survival (OS) of patients with bladder cancer. qRT-PCR showed that the expression of MALAT1 in bladder cancer tissues was 2.85 times higher than those measured in adjacent normal tissues (P < .001). The expression of MALAT1 was 2.673 ± 0.254 in non–muscle-invasive bladder cancer and 2.987 ± 0.381 in muscle-invasive bladder cancer (P = .018). In bladder cancer specimens with positive lymph nodes, MALAT1 expression was 3.167 ± 0.297 versus 2.896 ± 0.329 in bladder cancer specimens with negative lymph nodes (P = .020).

Conclusion

High MALAT1 expression could serve as an independent prognostic factor for OS of patients with bladder cancer and could be considered as a potential therapeutic target of bladder cancer.

Introduction

Bladder cancer (BC) arises from the urothelium of the urinary bladder. Currently, as the second most common malignancy of the urinary system after prostate cancer, BC has an enormously high incidence, with more than 76,000 new cases each year in the United States.1 Most patients are approximately 50 to 70 years of age, and the incidence in men is approximately 3.3 times that of women.2 BC can be divided into 2 types: non–muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). These 2 types show differences, such as abilities to invade, recur, and metastasize. Most new patients diagnosed with NMIBC receive surgical resection followed by bladder instillation treatment; of them, more than a half will relapse within 5 years and may upgrade to MIBC, which is highly aggressive, with a poor prognosis, and a 5-year survival rate of less than 50%.3 Therefore, it is of great importance to reveal the molecular mechanism of the development of BC, and to seek reliable biomarkers as effective therapeutic targets to improve the survival of the patients.

Whole-genome studies found that the encoding function gene of DNA accounts for only 2% of the whole genome, whereas noncoding DNA represents most of the genome. Noncoding RNA is the product of noncoding DNA transcription. According to the length of the sequence, noncoding RNA can be divided into 3 types: long-chain, medium-chain, and short-chain noncoding RNA. Long-chain noncoding RNA (lncRNA) refers those with a chain longer than 200 nt.4 In the past, lncRNA was considered only as the “noise” of gene transcription, and was paid little attention,5 but recent studies found that lncRNA has a number of functions in various human biological processes, including transcription interference, gene splicing, transcription regulation, genomic imprinting, X-chromosome inactivation, cell-cycle regulation, dyeing modification, apparent genetic modification, and immune response.6

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is located on chromosome 11q13.1, with a full length of 8.7 kb. In 2003, Ji et al7 first reported that the expression of MALAT1 was elevated in cancer cells from patients with non–small-cell lung cancer. Recent studies confirmed that the expression of MALAT1 promotes cancer cell proliferation, invasion, and metastasis in breast cancer, pancreatic cancer, colon cancer, liver cancer, and lung cancer, but the association between BC and MALAT1 remains unclear.8, 9, 10, 11, 12

Therefore, the aim of the present study was to investigate the biological and clinical function of MALAT1 in BC, and to verify whether MALAT1 could be used as a therapeutic target for BC and a biomarker to determine preoperative presence of progression and lymph node metastasis.

Section snippets

Specimens

BC specimens (n = 120) were obtained from consecutive patients operated at the Xiangya Hospital between January 2008 and December 2012. All the patients were treated by surgery, including transurethral resection of bladder tumor and radical resection of the bladder. The tumor specimens were staged according to the 2009 seventh version of the Union International Contre le Cancer TNM staging system, and graded according to the 2004 World Health Organization classification. All patients were

Expression Intensity of MALAT1 in BC

The expression intensity of MALAT1 was classified as negative, weakly positive, moderately positive, and strongly positive (scored 1 to 4, respectively). Samples were tested in quadruplicate; 2 doctors examined the slides in a double-blind manner to determine the staining intensity of each specimen. The average value was taken as the corresponding MALAT1 expression intensity.

Among the 120 specimens, the results showed that MALAT1 expression was negative in 24 cases, weakly positive in 32,

Discussion

Accumulating evidence suggests the importance of lncRNA MALAT1 in various human cancers,8, 9, 10, 11, 12 but the associations between MALAT1 and a mechanistic role in driving BC, especially lymph node metastasis, was unclear. In the present study, ISH was used to detect the expression of MALAT1 in paraffin BC sections, and the relationship between MALAT1 expression and clinical progression, lymph node metastasis, and prognosis of BC were retrospectively analyzed. qRT-PCR was used to detect the

Conclusion

This study examined the underlying association between MALAT1 and BC from the pathogenic aspect. Elevated expression of MALAT1 could be involved in the progression and metastasis of BC, and could therefore be considered as a prognostic factor for patients with BC. With better understanding of the potential pathogenic mechanism of BC, MALAT1 could serve as a new biomarker and potential molecular therapeutic target for estimating tumor progression and lymph node metastasis of BC.

Disclosure

The authors declare that they have no conflicts of interests.

Acknowledgments

Funding for this work was provided by the Hunan Province Funds for Distinguished Young Scientists of China (2016JJ1026).

References (29)

  • R.R. Pandey et al.

    Transcriptional and posttranscriptional programming by long noncoding RNAs

    Prog Mol Subcell Biol

    (2011)
  • P. Ji 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)
  • M.C. Lai et al.

    Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation

    Med Oncol

    (2012)
  • E.J. Pang et al.

    Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer

    Tumour Biol

    (2015)
  • Cited by (63)

    • Increased expression of urinary exosomal LnCRNA TUG-1 in early bladder cancer

      2021, Gene Reports
      Citation Excerpt :

      In a recent study performed on ovarian carcinoma by Michael A Gordon et al. they also showed that MALAT-1 was not significantly upregulated in early stages but higher expression of MALAT-1 is associated with end stages (stage III and IV) as well as with recurrence (Gordon et al., 2019). Moreover, Chao Li et al. showed that the MALAT-1 expression was significantly higher in patients with advanced histological grade in compared to low grade BC patients (p = 0.023) (Li et al., 2017). MALAT-1 has an important role in cancer progression through different mechanism especially metastasis and migration which mediate through processes such as EMT, cell signaling and extracellular matrix degradation (Sun and Ma, 2019).

    • Non-coding RNA in bladder cancer

      2020, Cancer Letters
      Citation Excerpt :

      When these findings are considered together, the tumor suppressor role of GAS5 could be a potential therapeutic target in the treatment of bladder cancer. There is emerging evidence that MALAT1, first identified as the prognostic marker in lung cancer, is linked to other cancers such as liver cancer [96], pancreatic cancer [97,98], bladder cancer [99], and prostate cancer [100]. The overexpression of MALAT1 promotes uncontrolled cell proliferation, migration, and clonality in bladder cancer [101].

    • Long non-coding RNA in bladder cancer

      2020, Clinica Chimica Acta
      Citation Excerpt :

      Moreover, H19 directly binds to miR-29b-3p (miR-29b) and inhibits the expression of its target DNMT3B to exert malignant transformation effects [72]. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was associated with high tumour stage, advanced histological grade and positive lymph node metastasis [73]. One possible mechanism demonstrates that MALAT1-mediated bladder cancer progression is partly associated with specific suppression of miR-125b and activates target genes through the “MALAT1-miR-125b-Bcl-2/MMP-13” axis [74].

    View all citing articles on Scopus
    View full text