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Long noncoding HOXA11-AS knockdown suppresses the progression of non-small cell lung cancer by regulating miR-3619-5p/SALL4 axis

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Abstract

Accumulating evidence suggested that many long noncoding RNAs (lncRNAs) were widely involved in the development and progression of non-small cell lung cancer (NSCLC). However, the roles of lncRNA homeobox A11 antisense (HOXA11-AS) and its underlying mechanism in NSCLC remains largely unknown. The expression levels of HOXA11-AS, miR-3619-5p and sal-like protein 4 (SALL4) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was used to measure the protein levels of hexokinase II (HK2) and SALL4. Cell proliferation, apoptosis, migration and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and transwell assay, respectively. The glucose consumption and lactate production were measured using glucose assay kit and lactate assay kit, respectively. The potential binding sites between miR-3619-5p and HOXA11-AS or SALL4 were predicted by online software and verified by luciferase report assay. A xenograft tumor model was established to confirm the function of HOXA11-AS in NSCLC in vivo. HOXA11-AS and SALL4 were upregulated while miR-3619-5p was downregulated in NSCLC tissues and cells. HOXA11-AS knockdown suppressed cell proliferation, migration, invasion, and glycolysis but promoted apoptosis in NSCLC cells. Moreover, miR-3619-5p could directly bind to HOXA11-AS and its inhibition attenuated the inhibitory effect of HOXA11-AS knockdown on progression of NSCLC cells. Furthermore, SALL4 was a direct target of miR-3619-5p and its overexpression reversed the anti-tumor role of miR-3619-5p in NSCLC cells. Besides, HOXA11-AS modulated SALL4 expression via sponging miR-3619-5p. Additionally, silencing HOXA11-AS inhibited tumor growth though upregulating miR-3619-5p and downregulating SALL4. Collectively, HOXA11-AS knockdown inhibited the progression of NSCLC by regulating miR-3619-5p/SALL4 axis, which might offer a novel avenue for interpreting the mechanism of NSCLC development.

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References

  • Al-Baradie R, Yamada K, Hilaire CS, Chan W-M, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S (2002) Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 71:1195–1199

    Article  CAS  Google Scholar 

  • Bai Y, Lang L, Zhao W, Niu R (2019) Long Non-Coding RNA HOXA11-AS Promotes Non-Small Cell Lung Cancer Tumorigenesis Through microRNA-148a-3p/DNMT1 Regulatory Axis. Onco Targets Ther 12:11195–11206

    Article  CAS  Google Scholar 

  • Chen J-H, Zhou L-Y, Xu S, Zheng Y-L, Wan Y-F, Hu C-P (2017) Overexpression of lncRNA HOXA11-AS promotes cell epithelial–mesenchymal transition by repressing miR-200b in non-small cell lung cancer. Cancer Cell Int 17:64

    Article  Google Scholar 

  • Gao M, Li H, Bi Y, Zhang Z, Wang S, Li J, Yang Z, Lv X, Zhou B, Yin Z (2020) The polymorphisms of lncRNA HOXA11-AS and the risk of lung cancer in Northeastern Chinese population. J Cancer 11:592–598

    Article  CAS  Google Scholar 

  • Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703–707

    Article  CAS  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  Google Scholar 

  • Chen JH, Zhou LY, Xu S, Zhen YL, Wan YF, Hu CP (2017) Overexpression of lncRNA HOXA11-AS promotes cell epithelial-mesenchymal transition by repressing miR-200b in non-small cell lung cancer. Cancer Cell Int 17:64

    Article  Google Scholar 

  • Kobayashi D, Kuribayashi K, Tanaka M, Watanabe N (2011a) Overexpression of SALL4 in lung cancer and its importance in cell proliferation. Oncol Rep 26:965–970

    CAS  PubMed  Google Scholar 

  • Kobayashi D, Kuribayshi K, Tanaka M, Watanabe N (2011b) SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer. Int J Oncol 38:933–939

    CAS  PubMed  Google Scholar 

  • Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, Winslow MM, Downward J (2014) HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature 505:212

    Article  CAS  Google Scholar 

  • Li J, Xuan Z, Liu C (2013) Long non-coding RNAs and complex human diseases. Int J Mol Sci 14:18790–18808

    Article  CAS  Google Scholar 

  • Li S, Wang C, Yu X, Wu H, Hu J, Wang S, Ye Z (2017a) miR-3619-5p inhibits prostate cancer cell growth by activating CDKN1A expression. Oncol Rep 37:241–248

    Article  Google Scholar 

  • Li T, Xu C, Cai B, Zhang M, Gao F, Gan J (2016) Expression and clinicopathological significance of the lncRNA HOXA11-AS in colorectal cancer. Oncol Lett 12:4155–4160

    Article  CAS  Google Scholar 

  • Li W, Jia G, Qu Y, Du Q, Liu B (2017b) Long Non-coding RNA (LncRNA) HOXA11-AS promotes breast cancer invasion and metastasis by regulating epithelial-mesenchymal transition. Med Sci Monitor Int Med J Exp Clin Res 23:3393–3403

    Google Scholar 

  • Liu W, Peng X, Han W, Li W, Demiao K, Fenglei Y (2017a) MicroRNA-98 plays a suppressive role in non-small cell lung cancer through inhibition of SALL4 protein expression. Oncol Res 25:975

    Article  Google Scholar 

  • Liu W, Xiao P, Wu H, Wang L, Kong D, Yu F (2017b) MicroRNA-98 plays a suppressive role in non-small cell lung cancer through inhibition of SALL4 protein expression. Oncol Res Featur Preclin Clin Cancer Therap 25:975–988

    Google Scholar 

  • Lu CW, Zhou DD, Xie T, Hao JL, Pant OP, Lu CB, Liu XF (2018) HOXA 11 antisense long noncoding RNA (HOXA 11-AS): a promising lnc RNA in human cancers. Cancer Med 7:3792–3799

    Article  CAS  Google Scholar 

  • Lu KH, Wei L, Liu XH, Ming S, Zhang ML, Wu WQ, Xie WP, Hou YY (2013) Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer 13:461–461

    Article  Google Scholar 

  • Nie W, Ge H-j, Yang X-q, Sun X, Huang H, Tao X, Chen W-s, Li B (2016) LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett 371:99–106

    Article  CAS  Google Scholar 

  • Niu X, Liu S, Jia L, Chen J (2015) Role of MiR-3619-5p in β-catenin-mediated non-small cell lung cancer growth and invasion. Cell Physiol Biochem 37:1527–1536

    Article  CAS  Google Scholar 

  • Prensner JR, Chinnaiyan AM (2011) The emergence of lncRNAs in cancer biology. Cancer Discov 1:391

    Article  CAS  Google Scholar 

  • Qiu M, Xu Y, Yang X, Wang J, Hu J, Xu L, Yin R (2014) CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer. Tumor Biology 35:5375–5380

    Article  CAS  Google Scholar 

  • Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146:353–358

    Article  CAS  Google Scholar 

  • Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S (2014) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 64:252–271

    Article  Google Scholar 

  • Sun M, Nie F, Wang Y, Zhang Z, Hou J, He D, Xie M, Xu L, De W, Wang Z (2016) LncRNA HOXA11-AS promotes proliferation and invasion of gastric cancer by scaffolding the chromatin modification factors PRC2, LSD1, and DNMT1. Cancer Res 76:6299–6310

    Article  CAS  Google Scholar 

  • Tan A, Li Q, Chen L (2019) CircZFR promotes hepatocellular carcinoma progression through regulating miR-3619–5p/CTNNB1 axis and activating Wnt/β-catenin pathway. Arch Biochem Biophys 661:196–202

    Article  CAS  Google Scholar 

  • Tay Y, Rinn J, Pandolfi PP (2014) The multilayered complexity of ceRNA crosstalk and competition. Nature 505:344–352

    Article  CAS  Google Scholar 

  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  Google Scholar 

  • Wan L, Sun M, Liu GJ, Wei CC, Zhang EB, Kong R, Xu TP, Huang MD, Wang ZX (2016) Long noncoding RNA PVT1 promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression. Mol Cancer Ther 15:1082–1094

    Article  CAS  Google Scholar 

  • Wang Q, Zhang J, Liu Y, Zhang W, Zhou J, Duan R, Pu P, Kang C, Han L (2016) A novel cell cycle-associated lncRNA, HOXA11-AS, is transcribed from the 5-prime end of the HOXA transcript and is a biomarker of progression in glioma. Cancer Lett 373:251–259

    Article  CAS  Google Scholar 

  • Yan G, Su Y, Ma Z, Yu L, Chen N (2019) Long noncoding RNA LINC00202 promotes tumor progression by sponging miR-3619-5p in retinoblastoma. Cell Struct Funct 44:51–60

    Article  Google Scholar 

  • Yang J, Lin J, Liu T, Chen T, Pan S, Huang W, Li S (2014) Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer 85:110–115

    Article  Google Scholar 

  • Yuan X, Zhang X, Zhang W, Liang W, Xu W (2016) SALL4 promotes gastric cancer progression through activating CD44 expression. Oncogenesis 5:e268

    Article  CAS  Google Scholar 

  • Zhang Q, Miao S, Han X, Li C, Zhang M, Cui K, Xiong T, Chen Z, Wang C, Xu H (2018) MicroRNA-3619-5p suppresses bladder carcinoma progression by directly targeting β-catenin and CDK2 and activating p21. Cell Death Dis 9:960

    Article  Google Scholar 

  • Zhang Y, He R-q, Dang Y-w, Zhang X-l, Wang X, Huang S-n, Huang W-t, Jiang M-t, Gan X-n, Xie Y (2016) Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells. Cancer Cell Int 16:89

    Article  CAS  Google Scholar 

  • Zhang Y, Yuan Y, Li Y, Zhang P, Chen P, Sun S (2019) An inverse interaction between HOXA11 and HOXA11-AS is associated with cisplatin resistance in lung adenocarcinoma. Epigenetics 14:949–960

    Article  Google Scholar 

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Funding

The study was completed by the author at his own expense.

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Author notes

  1. Hongwei Xia and Qingling Niu contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Qingpu Branch of Zhongshan Hospital Affiliated To Fudan University, No.1158, Gongyuan East Road, Qingpu District, Shanghai, 210700, China

    Hongwei Xia, Yanguang Ding, Zhiqiang Zhang, Jun Yuan & Wei Jin

  2. Department of Pediatrics, Qingpu Branch, Zhongshan Hospital Affiliated To Fudan University, Shanghai, China

    Qingling Niu

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  1. Hongwei Xia
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  2. Qingling Niu
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  3. Yanguang Ding
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  4. Zhiqiang Zhang
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  5. Jun Yuan
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  6. Wei Jin
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Correspondence to Wei Jin.

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Xia, H., Niu, Q., Ding, Y. et al. Long noncoding HOXA11-AS knockdown suppresses the progression of non-small cell lung cancer by regulating miR-3619-5p/SALL4 axis. J Mol Histol 52, 729–740 (2021). https://doi.org/10.1007/s10735-021-09981-1

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  • DOI: https://doi.org/10.1007/s10735-021-09981-1

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