Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

Gao,Caihua; Zhang,Jianying; Wang,Qingyan; Ren,Chunhua

doi:10.3892/ol.2016.4738

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

Authors:
- Caihua Gao
- Jianying Zhang
- Qingyan Wang
- Chunhua Ren
View Affiliations

Affiliations: Department of Medical Services, Weihai Maternal and Child Health Hospital, Weihai, Shandong 264200, P.R. China, Department of Emergency, Weihai Maternal and Child Health Hospital, Weihai, Shandong 264200, P.R. China, Happy Sisters Family Service Centre, Weihai Maternal and Child Health Hospital, Weihai, Shandong 264200, P.R. China
Published online on: June 16, 2016 https://doi.org/10.3892/ol.2016.4738
Pages: 1051-1057

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Leukemia is a heterogeneous clonal disorder in which early hematopoietic cells fail to differentiate and do not undergo programmed cell death or apoptosis. Less than one‑third of adult patients with leukemia are managed using current therapies due to the emergence of multidrug resistance (MDR), emphasizing the need for newer and more robust approaches. Recent reports have suggested that long non‑coding RNAs (lncRNAs) contribute to selective gene expression and, hence, could be manipulated effectively to halt the progression of cancer. However, little is known regarding the role of lncRNA in leukemia. Nuclear paraspeckle assembly transcript 1 (NEAT1) is a nuclear‑restricted lncRNA involved in the pathogenesis of certain types of cancer. Deregulated expression of NEAT1 has been reported in a number of human malignancies, including leukemia and other solid tumors. The present study aimed to characterize the role of NEAT1 in the regulation of MDR in leukemia. Using reverse transcription‑quantitative polymerase chain reaction, it was demonstrated that NEAT1 messenger RNA (mRNA) expression levels were significantly downregulated in leukemia patient samples compared with those from healthy donors. Furthermore, NEAT1 mRNA expression was repressed in a number of leukemia cell lines, including K562, THP‑1, HL‑60 and Jurkat cells, compared with peripheral white blood control cells, consistent with the expression observed in patients with leukemia. In addition, the transfection of a NEAT1 overexpression plasmid into K562 and THP‑1 leukemia cell lines alleviated MDR induced by cytotoxic agents, such as Alisertib and Bortezomib, through inhibition of ATP‑binding cassette G2. Although more robust studies are warranted, the current findings provide the basis for the use of NEAT1 as a novel promising target in the treatment of leukemia.

View Figures

View References

1	Coombs CC, Tavakkoli M and Tallman MS: Acute promyelocytic leukemia: Where did we start, where are we now and the future. Blood Cancer J. 5:e3042015. View Article : Google Scholar : PubMed/NCBI
2	Ozben T: Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett. 580:2903–2909. 2006. View Article : Google Scholar : PubMed/NCBI
3	Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H and Haga N: Molecular targeting therapy of cancer: Drug resistance, apoptosis and survival signal. Cancer Sci. 94:15–21. 2003. View Article : Google Scholar : PubMed/NCBI
4	Fung KL and Gottesman MM: A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta. 1794:860–871. 2009. View Article : Google Scholar : PubMed/NCBI
5	Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM and Roninson IB: Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 47:381–389. 1986. View Article : Google Scholar : PubMed/NCBI
6	Tatsuta T, Naito M, Oh-hara T, Sugawara I and Tsuruo T: Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem. 267:20383–20391. 1992.PubMed/NCBI
7	Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I and Willingham MC: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA. 84:7735–7738. 1987. View Article : Google Scholar : PubMed/NCBI
8	Flynn RA and Chang HY: Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 14:752–761. 2014. View Article : Google Scholar : PubMed/NCBI
9	Rinn JL and Chang HY: Genome regulation by long noncoding RNAs. Annu Rev Biochem. 81:145–166. 2012. View Article : Google Scholar : PubMed/NCBI
10	Wang KC and Chang HY: Molecular mechanisms of long noncoding RNAs. Mol Cell. 43:904–914. 2011. View Article : Google Scholar : PubMed/NCBI
11	Huarte M and Rinn JL: Large non-coding RNAs: Missing links in cancer? Hum Mol Genet. 19:R152–R161. 2010. View Article : Google Scholar : PubMed/NCBI
12	Lee JT: Epigenetic regulation by long noncoding RNAs. Science. 338:1435–1439. 2012. View Article : Google Scholar : PubMed/NCBI
13	Batista PJ and Chang HY: Long noncoding RNAs: Cellular address codes in development and disease. Cell. 152:1298–1307. 2013. View Article : Google Scholar : PubMed/NCBI
14	Sunwoo H, Dinger ME, Wilusz JE, Amaral PP, Mattick JS and Spector DL: MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19:347–359. 2009. View Article : Google Scholar : PubMed/NCBI
15	Naganuma T and Hirose T: Paraspeckle formation during the biogenesis of long non-coding RNAs. RNA Biol. 10:456–461. 2013. View Article : Google Scholar : PubMed/NCBI
16	Chen LL and Carmichael GG: Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: Functional role of a nuclear noncoding RNA. Mol Cell. 35:467–478. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zeng C, Xu Y, Xu L, Yu X, Cheng J, Yang L, Chen S and Li Y: Inhibition of long non-coding RNA NEAT1 impairs myeloid differentiation in acute promyelocytic leukemia cells. BMC Cancer. 14:6932014. View Article : Google Scholar : PubMed/NCBI
18	Wadleigh M and Tefferi A: Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. Int J Hematol. 91:174–179. 2010. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Rahgozar S, Moafi A, Abedi M, Entezar-E-Ghaem M, Moshtaghian J, Ghaedi K, Esmaeili A and Montazeri F: mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther. 15:35–41. 2014. View Article : Google Scholar : PubMed/NCBI
21	Gromicho M, Dinis J, Magalhães M, Fernandes AR, Tavares P, Laires A, Rueff J and Rodrigues AS: Development of imatinib and dasatinib resistance: Dynamics of expression of drug transporters ABCB1, ABCC1, ABCG2, MVP and SLC22A1. Leuk Lymphoma. 52:1980–1990. 2011. View Article : Google Scholar : PubMed/NCBI
22	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
24	Saxena A and Carninci P: Long non-coding RNA modifies chromatin: Epigenetic silencing by long non-coding RNAs. Bioessays. 33:830–839. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kaikkonen MU, Lam MT and Glass CK: Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res. 90:430–440. 2011. View Article : Google Scholar : PubMed/NCBI
26	Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E and Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science. 329:689–693. 2010. View Article : Google Scholar : PubMed/NCBI
27	Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E and Chang HY: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007. View Article : Google Scholar : PubMed/NCBI
28	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. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI
29	Zhang H, Chen Z, Wang X, Huang Z, He Z and Chen Y: Long non-coding RNA: A new player in cancer. J Hematol Oncol. 6:372013. View Article : Google Scholar : PubMed/NCBI
30	Zhuang Y, Wang X, Nguyen HT, Zhuo Y, Cui X, Fewell C, Flemington EK and Shan B: Induction of long intergenic non-coding RNA HOTAIR in lung cancer cells by type I collagen. J Hematol Oncol. 6:352013. View Article : Google Scholar : PubMed/NCBI
31	Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB and Chess A: A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics. 8:392007. View Article : Google Scholar : PubMed/NCBI
32	Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N and Hirose T: Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 31:4020–4034. 2012. View Article : Google Scholar : PubMed/NCBI
33	Sasaki YT, Ideue T, Sano M, Mituyama T and Hirose T: MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles. Proc Natl Acad Sci USA. 106:2525–2530. 2009. View Article : Google Scholar : PubMed/NCBI
34	Chakravarty D, Sboner A, Nair SS, Giannopoulou E, Li R, Hennig S, Mosquera JM, Pauwels J, Park K, Kossai M, et al: The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun. 5:53832014. View Article : Google Scholar : PubMed/NCBI
35	Pan LJ, Zhong TF, Tang RX, Li P, Dang YW, Huang SN and Chen G: Upregulation and clinicopathological significance of long non-coding NEAT1 RNA in NSCLC tissues. Asian Pac J Cancer Prev. 16:2851–2855. 2015. View Article : Google Scholar : PubMed/NCBI
36	Zhao W, An Y, Liang Y and Xie XW: Role of HOTAIR long noncoding RNA in metastatic progression of lung cancer. Eur Rev Med Pharmacol Sci. 18:1930–1936. 2014.PubMed/NCBI
37	Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, Becker-Santos DD, MacAulay CE, Lam S, Brown CJ and Lam WL: Human cancer long non-coding RNA transcriptomes. PloS One. 6:e259152011. View Article : Google Scholar : PubMed/NCBI
38	Bergmann JH and Spector DL: Long non-coding RNAs: Modulators of nuclear structure and function. Curr Opin Cell Biol. 26:10–18. 2014. View Article : Google Scholar : PubMed/NCBI
39	Wang F, Wang XK, Shi CJ, Zhang H, Hu YP, Chen YF and Fu LW: Nilotinib enhances the efficacy of conventional chemotherapeutic drugs in CD34⁺CD38⁻ stem cells and ABC transporter overexpressing leukemia cells. Molecules. 19:3356–3375. 2014. View Article : Google Scholar : PubMed/NCBI
40	Wang XK, He JH, Xu JH, Ye S, Wang F, Zhang H, Huang ZC, To KK and Fu LW: Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells. Cancer Res. 74:4431–4445. 2014. View Article : Google Scholar : PubMed/NCBI
41	Liu J, Wan L, Lu K, Sun M, Pan X, Zhang P, Lu B, Liu G and Wang Z: The long noncoding RNA MEG3 contributes to cisplatin resistance of human lung adenocarcinoma. PloS One. 10:e01145862015. View Article : Google Scholar : PubMed/NCBI
42	Zhang XW, Bu P, Liu L, Zhang XZ and Li J: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun. 462:227–232. 2015. View Article : Google Scholar : PubMed/NCBI
43	Hang Q, Sun R, Jiang C and Li Y: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs. 26:632–640. 2015.PubMed/NCBI
44	Stromskaya TP, Rybalkina EY, Zabotina TN, Shishkin AA and Stavrovskaya AA: Influence of RARalpha gene on MDR1 expression and P-glycoprotein function in human leukemic cells. Cancer Cell Int. 5:152005. View Article : Google Scholar : PubMed/NCBI