Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling

Authors: Jia-Kuan Li, Cheng Chen, Jia-Yi Liu, Jia-Zi Shi, Shu-Peng Liu, Bing Liu, Deng-Shuang Wu, Zi-Yu Fang, Yi Bao, Ming-Ming Jiang, Ji-Hang Yuan, Le Qu, Lin-Hui Wang

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown.

Methods

lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs.

Results

The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway.

Conclusions

MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
Ljungberg B, Cowan NC, Hanbury DC, Hora M, Kuczyk MA, Merseburger AS, Patard JJ, Mulders PF, Sinescu IC. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398–406.CrossRefPubMed
3.
4.
Shi SJ, Wang LJ, Yu B, Li YH, Jin Y, Bai XZ. LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarget. 2015;6:11652–63.CrossRefPubMedPubMedCentral
5.
Arase M, Horiguchi K, Ehata S, Morikawa M, Tsutsumi S, Aburatani H, Miyazono K, Koinuma D. Transforming growth factor-beta-induced lncRNA-Smad7 inhibits apoptosis of mouse breast cancer JygMC(A) cells. Cancer Sci. 2014;105:974–82.CrossRefPubMedPubMedCentral
6.
7.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.CrossRefPubMedPubMedCentral
8.
Han Y, Liu Y, Gui Y, Cai Z. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. J Surg Oncol. 2013;107:555–9.CrossRefPubMed
9.
Xie HW, Wu QQ, Zhu B, Chen FJ, Ji L, Li SQ, Wang CM, Tong YS, Tuo L, Wu M, et al. Long noncoding RNA SPRY4-IT1 is upregulated in esophageal squamous cell carcinoma and associated with poor prognosis. Tumour Biol. 2014;35:7743–54.CrossRefPubMed
10.
Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, Ghadessi M, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013;45:1392–8.CrossRefPubMedPubMedCentral
11.
Lelievre V, Pineau N, Hu Z, Ioffe Y, Byun JY, Muller JM, Waschek JA. Proliferative actions of natriuretic peptides on neuroblastoma cells. Involvement of guanylyl cyclase and non-guanylyl cyclase pathways. J Biol Chem. 2001;276:43668–76.CrossRefPubMed
12.
Prins BA, Weber MJ, Hu RM, Pedram A, Daniels M, Levin ER. Atrial natriuretic peptide inhibits mitogen-activated protein kinase through the clearance receptor. Potential role in the inhibition of astrocyte proliferation. J Biol Chem. 1996;271:14156–62.CrossRefPubMed
13.
Sellitti DF, Perrella G, Doi SQ, Curcio F. Natriuretic peptides increase cAMP production in human thyrocytes via the natriuretic peptide clearance receptor (NPR-C). Regul Pept. 2001;97:103–9.CrossRefPubMed
14.
Han Y, Liu Y, Nie L, Gui Y, Cai Z. Inducing cell proliferation inhibition, apoptosis, and motility reduction by silencing long noncoding ribonucleic acid metastasis-associated lung adenocarcinoma transcript 1 in urothelial carcinoma of the bladder. Urology. 2013;81:209. e201-207CrossRefPubMed
15.
Zhang H, Morisaki T, Matsunaga H, Sato N, Uchiyama A, Hashizume K, Nagumo F, Tadano J, Katano M. Protein-bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs. Clin Exp Metastasis. 2000;18:343–52.PubMed
16.
Cai Z, Zhao JS, Li JJ, Peng DN, Wang XY, Chen TL, Qiu YP, Chen PP, Li WJ, Xu LY, et al. A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism. Mol Cell Proteomics. 2010;9:2617–28.CrossRefPubMedPubMedCentral
17.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.CrossRefPubMedPubMedCentral
18.
Ho MY, Liang SM, Hung SW, Liang CM. MIG-7 controls COX-2/PGE2-mediated lung cancer metastasis. Cancer Res. 2013;73:439–49.CrossRefPubMed
19.
Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, et al. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008;172:1717–28.CrossRefPubMedPubMedCentral
20.
Kim T, Jeon YJ, Cui R, Lee JH, Peng Y, Kim SH, Tili E, Alder H, Croce CM. Role of MYC-regulated long noncoding RNAs in cell cycle regulation and tumorigenesis. J Natl Cancer Inst. 2015;107:dju505.
21.
Kim T, Cui R, Jeon YJ, Lee JH, Lee JH, Sim H, Park JK, Fadda P, Tili E, Nakanishi H, et al. Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5. Proc Natl Acad Sci U S A. 2014;111:4173–8.CrossRefPubMedPubMedCentral
22.
Kim T, Cui R, Jeon YJ, Fadda P, Alder H, Croce CM. MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression. Oncotarget. 2015;6:18780–9.CrossRefPubMedPubMedCentral
23.
Lin MF, Jungreis I, Kellis M. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics. 2011;27:i275–82.CrossRefPubMedPubMedCentral
24.
Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, Chen W, Liu F, Sun W, Li XF, et al. Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Cancer Cell. 2016;29:653–68.CrossRefPubMed
25.
Sun L, Luo H, Bu D, Zhao G, Yu K, Zhang C, Liu Y, Chen R, Zhao Y. Utilizing sequence intrinsic composition to classify protein-coding and long non-coding transcripts. Nucleic Acids Res. 2013;41:e166.CrossRefPubMedPubMedCentral
26.
Juang SH, Xie K, Xu L, Shi Q, Wang Y, Yoneda J, Fidler IJ. Suppression of tumorigenicity and metastasis of human renal carcinoma cells by infection with retroviral vectors harboring the murine inducible nitric oxide synthase gene. Hum Gene Ther. 1998;9:845–54.CrossRefPubMed
27.
Tang J, Li Z, Lu L, Cho CH. beta-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy. Semin Cancer Biol. 2013;23:533–42.CrossRefPubMed
28.
Breckler M, Berthouze M, Laurent AC, Crozatier B, Morel E, Lezoualc'h F. Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cell Signal. 2011;23:1257–66.CrossRefPubMed
29.
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106:11667–72.CrossRefPubMedPubMedCentral
30.
Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, Cheunsuchon P, Louis DN, Klibanski A. Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 2010;70:2350–8.CrossRefPubMedPubMedCentral
31.
Ji-hang Yuan FY, Wang F, Ma J-z, Guo Y-j, Tao Q-f, et al. A Long Noncoding RNA Activated by TGF-β Promotes the Invasion-Metastasis Cascade in Hepatocellular Carcinoma. Cancer Cell. 2014;25:666–81.CrossRefPubMed
32.
Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS, Resau JH, Teh BT. Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Res. 2008;68:81–8.CrossRefPubMed
33.
Ward Y, Wang W, Woodhouse E, Linnoila I, Liotta L, Kelly K. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol Cell Biol. 2001;21:5958–69.CrossRefPubMedPubMedCentral
34.
Webb CP, Taylor GA, Jeffers M, Fiscella M, Oskarsson M, Resau JH, Vande Woude GF. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene. 1998;17:2019–25.CrossRefPubMed
35.
36.
Pasini D, Bracken AP, Helin K. Polycomb group proteins in cell cycle progression and cancer. Cell Cycle. 2004;3:396–400.CrossRefPubMed
Metadata
Title
Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling
Authors
Jia-Kuan Li
Cheng Chen
Jia-Yi Liu
Jia-Zi Shi
Shu-Peng Liu
Bing Liu
Deng-Shuang Wu
Zi-Yu Fang
Yi Bao
Ming-Ming Jiang
Ji-Hang Yuan
Le Qu
Lin-Hui Wang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0681-0

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

MicroRNA-29c functions as a tumor suppressor by targeting VEGFA in lung adenocarcinoma

Research

Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1

Research

Hsp90β promoted endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma

Review

Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells

Research

Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ

Review

Neutrophils in cancer: prognostic role and therapeutic strategies
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits