Long non-coding RNA LINC00504 regulates the Warburg effect in ovarian cancer through inhibition of miR-1244

  • Ya Liu
  • Xiaocui He
  • Yuli Chen
  • Dan CaoEmail author


Ovarian cancer (OC) is the most lethal gynecologic malignancy and long non-coding RNAs (lncRNAs) have been acknowledged as important regulators in human OC. This study aimed to investigate the function and underlying mechanisms of LINC00504 in OC. The expression levels of LINC00504 in human OC tissues and cell lines were investigated by qRT-PCR analysis. The OC cell proliferation, and apoptosis were evaluated by MTT assay, colony-formation assay, Caspase-3 activity assay, and nucleosome ELISA assay, respectively. The metabolic shift in OC cells was examined by aerobic glycolysis analysis. Dual-luciferase activity reporter assay and mRNA–miRNA pull-down assay were conducted to validate the interaction between LINC00504 and miR-1244. LINC00504 was upregulated in OC cell lines and specimens. Knockdown of LINC00504 inhibited cell proliferation, enhanced apoptosis, decreased glycolysis-related gene (PKM2, HK2, and PDK1) expression, and altered aerobic glycolysis in OC cells and vice versa. LINC00504 downregulated miR-1244 expression levels by acting as an endogenous sponge of miR-1244. Inhibition of miR-1244 diminished the effects of LINC00504 on OC cells. Our study shows that LINC00504 promotes OC cell progression and stimulates aerobic glycolysis by interacting with miR-1244, which indicates that LINC00504 might act as a promising therapeutic target for OC treatment.


Ovarian cancer (OC) Long non-coding RNAs (lncRNAs) LINC00504 Aerobic glycolysis miR-1244 




Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of Heze Municipal Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

All participants in this study were informed and gave a written consent.


  1. 1.
    Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424CrossRefGoogle Scholar
  2. 2.
    Rauh-Hain JA et al (2011) Ovarian cancer screening and early detection in the general population. Rev Obstet Gynecol 4(1):15–21PubMedPubMedCentralGoogle Scholar
  3. 3.
    Reid BM, Permuth JB, Sellers TA (2017) Epidemiology of ovarian cancer: a review. Cancer Biol Med 14(1):9–32PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Desai A et al (2014) Epithelial ovarian cancer: an overview. World J Transl Med 3(1):1–8PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Doubeni CA, Doubeni AR, Myers AE (2016) Diagnosis and management of ovarian cancer. Am Fam Physician 93(11):937–944PubMedGoogle Scholar
  6. 6.
    Orr B, Edwards RP (2018) Diagnosis and treatment of ovarian cancer. Hematol Oncol Clin North Am 32(6):943–964PubMedCrossRefGoogle Scholar
  7. 7.
    Bhoola S, Hoskins WJ (2006) Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol 107(6):1399–1410PubMedCrossRefGoogle Scholar
  8. 8.
    Lee JY et al (2018) Changes in ovarian cancer survival during the 20 years before the era of targeted therapy. BMC Cancer 18(1):601PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Torre LA et al (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68(4):284–296PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Razi S et al (2016) The incidence and mortality of ovarian cancer and their relationship with the Human Development Index in Asia. Ecancermedicalscience 10:628PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Thin KZ et al (2018) LncRNA-DANCR: a valuable cancer related long non-coding RNA for human cancers. Pathol Res Pract 214(6):801–805PubMedCrossRefGoogle Scholar
  12. 12.
    Schmitt AM, Chang HY (2016) Long noncoding RNAs in cancer pathways. Cancer Cell 29(4):452–463PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ji D et al (2018) The role of long non-coding RNA AFAP1-AS1 in human malignant tumors. Pathol Res Pract 214(10):1524–1531PubMedCrossRefGoogle Scholar
  14. 14.
    Dianatpour A, Ghafouri-Fard S (2017) Long non coding RNA expression intersecting cancer and spermatogenesis: a systematic review. Asian Pac J Cancer Prev 18(10):2601–2610PubMedPubMedCentralGoogle Scholar
  15. 15.
    Zampetaki A, Albrecht A, Steinhofel K (2018) Long non-coding RNA structure and function: is there a link? Front Physiol 9:1201PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fang Y, Fullwood MJ (2016) Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genomics Proteomics Bioinform 14(1):42–54CrossRefGoogle Scholar
  17. 17.
    Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43(6):904–914PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Cao J (2014) The functional role of long non-coding RNAs and epigenetics. Biol Proced Online 16:11PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Mattick JS, Makunin IV (2006) Non-coding RNA. Hum Mol Genet 15(1):R17–R29PubMedCrossRefGoogle Scholar
  20. 20.
    Yang JX, Rastetter RH, Wilhelm D (2016) Non-coding RNAs: an introduction. Adv Exp Med Biol 886:13–32PubMedCrossRefGoogle Scholar
  21. 21.
    Paraskevopoulou MD, Hatzigeorgiou AG (2016) Analyzing miRNA–LncRNA interactions. Methods Mol Biol 1402:271–286PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang Y et al (2017) Decoding noncoding RNAs: role of microRNAs and long noncoding RNAs in ocular neovascularization. Theranostics 7(12):3155–3167PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Hube F, Francastel C (2018) Coding and non-coding RNAs, the frontier has never been so blurred. Front Genet 9:140PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Huang B, Zhang R (2014) Regulatory non-coding RNAs: revolutionizing the RNA world. Mol Biol Rep 41(6):3915–3923PubMedCrossRefGoogle Scholar
  25. 25.
    Liu SP et al (2013) Identification of differentially expressed long non-coding RNAs in human ovarian cancer cells with different metastatic potentials. Cancer Biol Med 10(3):138–141PubMedPubMedCentralGoogle Scholar
  26. 26.
    Qiu JJ et al (2014) Expression and clinical significance of estrogen-regulated long non-coding RNAs in estrogen receptor alpha-positive ovarian cancer progression. Oncol Rep 31(4):1613–1622PubMedCrossRefGoogle Scholar
  27. 27.
    Zeng S et al (2019) Upregulation of lncRNA AB073614 functions as a predictor of epithelial ovarian cancer prognosis and promotes tumor growth in vitro and in vivo. Cancer Biomark 24(4):421–428PubMedCrossRefGoogle Scholar
  28. 28.
    Gao J et al (2015) Long non-coding RNA growth arrest-specific transcript 5 is involved in ovarian cancer cell apoptosis through the mitochondria-mediated apoptosis pathway. Oncol Rep 34(6):3212–3221PubMedCrossRefGoogle Scholar
  29. 29.
    Li J et al (2017) LncRNA GAS5 suppresses ovarian cancer by inducing inflammasome formation. Biosci Rep. PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ma N et al (2018) Long non-coding RNA GAS5 inhibits ovarian cancer cell proliferation via the control of microRNA-21 and SPRY2 expression. Exp Ther Med 16(1):73–82PubMedPubMedCentralGoogle Scholar
  31. 31.
    Feng J et al (2019) A noncoding RNA LINC00504 interacts with c-Myc to regulate tumor metabolism in colon cancer. J Cell Biochem 120(9):14725–14734PubMedCrossRefGoogle Scholar
  32. 32.
    Yu Y et al (2017) A novel mechanism of lncRNA and miRNA interaction: CCAT2 regulates miR-145 expression by suppressing its maturation process in colon cancer cells. Mol Cancer 16(1):155PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Xu JH et al (2018) The mRNA, miRNA and lncRNA networks in hepatocellular carcinoma: an integrative transcriptomic analysis from Gene Expression Omnibus. Mol Med Rep 17(5):6472–6482PubMedPubMedCentralGoogle Scholar
  34. 34.
    Wei C et al (2017) Differentially expressed lncRNAs and miRNAs with associated ceRNA networks in aged mice with postoperative cognitive dysfunction. Oncotarget 8(34):55901–55914PubMedPubMedCentralGoogle Scholar
  35. 35.
    Gao Y et al (2015) LncRNA-HOST2 regulates cell biological behaviors in epithelial ovarian cancer through a mechanism involving microRNA let-7b. Hum Mol Genet 24(3):841–852PubMedCrossRefGoogle Scholar
  36. 36.
    Lei R et al (2017) Long noncoding RNA MALAT1-regulated microRNA 506 modulates ovarian cancer growth by targeting iASPP. Onco Targets Ther 10:35–46PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GynecologyHeze Municipal HospitalHezeChina
  2. 2.Department of Gynecology and ObstetricsHeze Municipal HospitalHezeChina

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