Increased lncRNA HOTAIR expression promotes the chemoresistance of multiple myeloma to dexamethasone by regulating cell viability and apoptosis by mediating the JAK2/STAT3 signaling pathway

  • Authors:
    • Rongyan Guan
    • Wei Wang
    • Bin Fu
    • Yujun Pang
    • Ye Lou
    • Hong Li
  • View Affiliations

  • Published online on: August 22, 2019     https://doi.org/10.3892/mmr.2019.10603
  • Pages: 3917-3923
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Abstract

Multiple studies have shown that HOX antisense intergenic RNA (HOTAIR), an oncogenic long non‑coding RNA (lncRNA), is dysregulated in leukemia and is involved in tumor progression. The aim of the present study was to determine whether HOTAIR could serve as a novel biomarker for the diagnosis of multiple myeloma (MM), and to investigate its role in regards to MM cell viability and chemoresistance to dexamethasone (DEX). The results revealed that the expression of HOTAIR was significantly upregulated in serum, bone marrow and primary CD138+ cells from MM patients compared with those from normal controls as determined by qPCR. HOTAIR expression was obviously increased in MM cell lines compared to that in normal plasma cells. ROC curve analysis showed that the serum level of HOTAIR exhibited a higher diagnostic value for MM. Furthermore, loss‑of‑functional assays indicated that HOTAIR inhibition suppressed MM cell viability by arresting the cell cycle at the G0/G1 phase as determined by cell viability assay and flow cytometry. An in‑depth study revealed that knockdown of HOTAIR led to decreased chemoresistance of DEX in MM cells by regulating the JAK2/STAT3 signaling pathway. Taken together, our findings suggest that upregulation of serum HOTAIR may prove to be a novel biomarker for the diagnosis of MM. HOTAIR promoted MM cell viability and increased chemoresistance of MM to DEX via the JAK2/STAT3 signaling pathway, indicating HOTAIR may also serve as a potential therapeutic target for MM.

References

1 

Spizzo R, Almeida MI, Colombatti A and Calin GA: Long non-coding RNAs and cancer: A new frontier of translational research? Oncogene. 31:4577–4587. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Nobili L, Ronchetti D, Agnelli L, Taiana E, Vinci C and Neri A: Long non-coding RNAs in multiple myeloma. Genes (Basel). 9(pii): E692018. View Article : Google Scholar : PubMed/NCBI

3 

Wang H, Wang J, Liang CF and Zhou T: Expression of long non-coding RNA PRAL as a potential biomarker for diagnosis in non-small-cell lung cancer patients is associated with the inhibition of cell proliferation and metastasis. Clin Lab. 64:1341–1348. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Zhang ZS, Wang J, Zhu BQ and Ge L: Long noncoding RNA UCA1 promotes multiple myeloma cell growth by targeting TGF-β. Eur Rev Med Pharmacol Sci. 22:1374–1379. 2018.PubMed/NCBI

5 

Chen L, Hu N, Wang C, Zhao H and Gu Y: Long non-coding RNA CCAT1 promotes multiple myeloma progression by acting as a molecular sponge of miR-181a-5p to modulate HOXA1 expression. Cell Cycle. 17:319–329. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Spitzer TR, Sachs DH and Cosimi B: Multiple myeloma. N Engl J Med. 364:23642011. View Article : Google Scholar : PubMed/NCBI

7 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Kuehl WM and Bergsagel PL: Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest. 122:3456–3463. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Anderson KC: Progress and paradigms in multiple myeloma. Clin Cancer Res. 22:5419–5427. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Robak P, Drozdz I, Szemraj J and Robak T: Drug resistance in multiple myeloma. Cancer Treat Rev. 70:199–208. 2018. View Article : Google Scholar : PubMed/NCBI

11 

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

12 

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

13 

Tang Q and Hann SS: HOTAIR: An oncogenic long non-coding RNA in human cancer. Cell Physiol Biochem. 47:893–913. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Xing CY, Hu XQ, Xie FY, Yu ZJ, Li HY, Bin-Zhou, Wu JB, Tang LY and Gao SM: Long non-coding RNA HOTAIR modulates c-KIT expression through sponging miR-193a in acute myeloid leukemia. FEBS Lett. 589:1981–1987. 2015. View Article : Google Scholar : PubMed/NCBI

15 

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

16 

Wu Y and Wang H: LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR-193a/MCL1 pathway. J Biochem Mol Toxicol. 32:Jan;2018.doi: 10.1002/jbt.22008. View Article : Google Scholar :

17 

Li QY, Chen L, Hu N and Zhao H: Long non-coding RNA FEZF1-AS1 promotes cell growth in multiple myeloma via miR-610/Akt3 axis. Biomed Pharmacother. 103:1727–1732. 2018. View Article : Google Scholar : PubMed/NCBI

18 

Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, Gay F and Anderson KC: Multiple myeloma. Nat Rev Dis Primers. 3:170462017. View Article : Google Scholar : PubMed/NCBI

19 

Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E, Moine P, Bourin P, Moos M, Corre J, et al: CD200 is a new prognostic factor in multiple myeloma. Blood. 108:4194–4197. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Perosa F, Minoia C, Favoino E, Prete M and Dammacco F: Staging multiple myeloma patients with active disease using serum levels of beta2m-free HLA class I heavy chain together with IgM or platelet count. Blood Cells Mol Dis. 42:71–76. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Bhan A, Soleimani M and Mandal SS: Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77:3965–3981. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Bolha L, Ravnik-Glavač M and Glavač D: Long noncoding RNAs as biomarkers in cancer. Dis Markers. 2017:72439682017. View Article : Google Scholar : PubMed/NCBI

23 

Shen X, Zhang Y, Wu X, Guo Y, Shi W, Qi J, Cong H, Wang X, Wu X and Ju S: Upregulated lncRNA-PCAT1 is closely related to clinical diagnosis of multiple myeloma as a predictive biomarker in serum. Cancer Biomark. 18:257–263. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Li N, Wang Y, Liu X, Luo P, Jing W, Zhu M and Tu J: Identification of circulating long noncoding RNA HOTAIR as a novel biomarker for diagnosis and monitoring of non-small cell lung cancer. Technol Cancer Res Treat. Jan 1–2017.doi: 10.1177/1533034617723754 (Epub ahead of print). View Article : Google Scholar

25 

Elsayed ET, Salem PE, Darwish AM and Fayed HM: Plasma long non-coding RNA HOTAIR as a potential biomarker for gastric cancer. Int J Biol Markers. Apr 1–2018.doi: 10.1177/1724600818760244 (Epub ahead of print). View Article : Google Scholar : PubMed/NCBI

26 

Tan SK, Pastori C, Penas C, Komotar RJ, Ivan ME, Wahlestedt C and Ayad NG: Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme. Mol Cancer. 17:742018. View Article : Google Scholar : PubMed/NCBI

27 

Wang W, He X, Zheng Z, Ma X, Hu X, Wu D and Wang M: Serum HOTAIR as a novel diagnostic biomarker for esophageal squamous cell carcinoma. Mol Cancer. 16:752017. View Article : Google Scholar : PubMed/NCBI

28 

Das M: Lenalidomide plus dexamethasone in multiple myeloma. Lancet Oncol. 19:e122018. View Article : Google Scholar : PubMed/NCBI

29 

Zhao JJ, Chu ZB, Hu Y, Lin J, Wang Z, Jiang M, Chen M, Wang X, Kang Y, Zhou Y, et al: Targeting the miR-221-222/PUMA/BAK/BAX pathway abrogates dexamethasone resistance in multiple myeloma. Cancer Res. 75:4384–4397. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Arora L, Kumar AP, Arfuso F, Chng WJ and Sethi G: The role of signal transducer and activator of transcription 3 (STAT3) and its targeted inhibition in hematological malignancies. Cancers (Basel). 10(pii): E3272018. View Article : Google Scholar : PubMed/NCBI

31 

Liu T, Fei Z, Gangavarapu KJ, Agbenowu S, Bhushan A, Lai JC, Daniels CK and Cao S: Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells. Leuk Res. 37:1322–1328. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Zhu S, Wang Z, Li Z, Peng H, Luo Y, Deng M, Li R, Dai C, Xu Y, Liu S and Zhang G: Icaritin suppresses multiple myeloma, by inhibiting IL-6/JAK2/STAT3. Oncotarget. 6:10460–10472. 2015. View Article : Google Scholar : PubMed/NCBI

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October 2019
Volume 20 Issue 4

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Copy and paste a formatted citation
APA
Guan, R., Wang, W., Fu, B., Pang, Y., Lou, Y., & Li, H. (2019). Increased lncRNA HOTAIR expression promotes the chemoresistance of multiple myeloma to dexamethasone by regulating cell viability and apoptosis by mediating the JAK2/STAT3 signaling pathway. Molecular Medicine Reports, 20, 3917-3923. https://doi.org/10.3892/mmr.2019.10603
MLA
Guan, R., Wang, W., Fu, B., Pang, Y., Lou, Y., Li, H."Increased lncRNA HOTAIR expression promotes the chemoresistance of multiple myeloma to dexamethasone by regulating cell viability and apoptosis by mediating the JAK2/STAT3 signaling pathway". Molecular Medicine Reports 20.4 (2019): 3917-3923.
Chicago
Guan, R., Wang, W., Fu, B., Pang, Y., Lou, Y., Li, H."Increased lncRNA HOTAIR expression promotes the chemoresistance of multiple myeloma to dexamethasone by regulating cell viability and apoptosis by mediating the JAK2/STAT3 signaling pathway". Molecular Medicine Reports 20, no. 4 (2019): 3917-3923. https://doi.org/10.3892/mmr.2019.10603