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Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling

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Abstract

Background

Lung cancer is one of the most aggressive malignancies and the efficacy of chemotherapy or concurrent chemoradiation is limited in clinical application. Curcumin has been reported to block cancer development by modulating multiple signaling pathways. However, whether curcumin can inhibit gemcitabine-resistant non-small cell lung cancer through regulation of lncRNA and the involved molecular mechanisms are rarely reported.

Materials and methods

MTT assay, clonogenic assay, apoptosis assay, qRT-PCR, Western blotting, immunohistochemistry, xenograft experiment were carried out in the present study.

Results

The results showed that curcumin suppressed gemcitabine-resistant non-small cell lung cancer cell proliferation and induced apoptosis. Curcumin upregulated the expression of lncRNA-MEG3 and PTEN, and MEG3 overexpression could increase the level of PTEN expression, while MEG3 knockdown decreased the level of PTEN expression in gemcitabine-resistant non-small cell lung cancer cells. Curcumin treatment failed to inhibit the proliferation and induce apoptosis in MEG3 knockdown or PTEN knockdown cells.

Conclusions

These findings show the antitumor activity of curcumin for potential clinical application in gemcitabine-resistant non-small cell lung cancer treatment.

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References

  1. de Oliveira JC, Oliveira LC, Mathias C, Pedroso GA, Lemos DS, Salviano-Silva A, Jucoski TS, Lobo-Alves SC, Zambalde EP, Cipolla GA, Gradia DF. Long non-coding RNAs in cancer: another layer of complexity. J Gene Med. 2019;21(1):e3065. https://doi.org/10.1002/jgm.3065.

    Article  CAS  PubMed  Google Scholar 

  2. Fernandes JCR, Acuña SM, Aoki JI, Floeter-Winter LM, Muxel SM. Long non-coding RNAs in the regulation of gene expression: physiology and disease. Noncoding RNA. 2019;5(1):E17. https://doi.org/10.3390/ncrna5010017.

    Article  CAS  PubMed  Google Scholar 

  3. Xie Y, Dang W, Zhang S, Yue W, Yang L, Zhai X, Yan Q, Lu J. The role of exosomal noncoding RNAs in cancer. Mol Cancer. 2019;18(1):37. https://doi.org/10.1186/s12943-019-0984-4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ghafouri-Fard S, Taheri M. Maternally expressed gene 3 (MEG3): a tumor suppressor long non coding RNA. Biomed Pharmacother. 2019;118:109129. https://doi.org/10.1016/j.biopha.2019.109129.

    Article  CAS  PubMed  Google Scholar 

  5. Fan FY, Deng R, Yi H, Sun HP, Zeng Y, He GC, Su Y. The inhibitory effect of MEG3/miR-214/AIFM2 axis on the growth of T-cell lymphoblastic lymphoma. Int J Oncol. 2017;51(1):316–26. https://doi.org/10.3892/ijo.2017.4006.

    Article  CAS  PubMed  Google Scholar 

  6. He Y, Luo Y, Liang B, Ye L, Lu G, He W. Potential applications of MEG3 in cancer diagnosis and prognosis. Oncotarget. 2017;8(42):73282–95. https://doi.org/10.18632/oncotarget.19931.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wu Z, He Y, Li D, Fang X, Shang T, Zhang H, Zheng X. Long noncoding RNA MEG3 suppressed endothelial cell proliferation and migration through regulating miR-21. Am J Transl Res. 2017;9(7):3326–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Z, Yang L, Liu X, Nie Z, Luo J. Long noncoding RNA MEG3 inhibits proliferation of chronic myeloid leukemia cells by sponging microRNA-21. Biomed Pharmacother. 2018;104:181–92. https://doi.org/10.1016/j.biopha.2018.05.047.

    Article  CAS  PubMed  Google Scholar 

  9. Zheng Q, Lin Z, Xu J, Lu Y, Meng Q, Wang C, Yang Y, Xin X, Li X, Pu H, Gui X, Li T, Xiong W, Lu D. Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN. Cell Death Dis. 2018;9(3):253. https://doi.org/10.1038/s41419-018-0305-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang Y, Liu J, Lv Y, Zhang C, Guo S. LncRNA meg3 suppresses hepatocellular carcinoma in vitro and vivo studies. Am J Transl Res. 2019;11(7):4089–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shan G, Tang T, Xia Y, Qian HJ. MEG3 interacted with miR-494 to repress bladder cancer progression through targeting PTEN. J Cell Physiol. 2020;235(2):1120–8. https://doi.org/10.1002/jcp.29025.

    Article  CAS  PubMed  Google Scholar 

  12. Li J, Bian EB, He XJ, Ma CC, Zong G, Wang HL, Zhao B. Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas. Int J Oncol. 2016;48(2):723–33. https://doi.org/10.3892/ijo.2015.3285.

    Article  CAS  PubMed  Google Scholar 

  13. Xia Y, He Z, Liu B, Wang P, Chen Y. Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway. Mol Med Rep. 2015;12(3):4530–7. https://doi.org/10.3892/mmr.2015.3897.

    Article  CAS  PubMed  Google Scholar 

  14. Liu J, Wan L, Lu K, Sun M, Pan X, Zhang P, Lu B, Liu G, Wang Z. The long noncoding RNA MEG3 contributes to cisplatin resistance of human lung adenocarcinoma. PLoS ONE. 2015;10(5):e0114586. https://doi.org/10.1371/journal.pone.0114586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang P, Chen D, Ma H, Li Y. LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21–5p/SOX7 axis. Onco Targets Ther. 2017;10:5137–49. https://doi.org/10.2147/OTT.S146423.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Xia H, Qu XL, Liu LY, Qian DH, Jing HY. LncRNA MEG3 promotes the sensitivity of vincristine by inhibiting autophagy in lung cancer chemotherapy. Eur Rev Med Pharmacol Sci. 2018;22(4):1020–7. https://doi.org/10.26355/eurrev_201802_14384.

    Article  CAS  PubMed  Google Scholar 

  17. Zamani M, Sadeghizadeh M, Behmanesh M, Najafi F. Dendrosomal curcumin increases expression of the long non-coding RNA gene MEG3 via up-regulation of epi-miRs in hepatocellular cancer. Phytomedicine. 2015;22(10):961–7. https://doi.org/10.1016/j.phymed.2015.05.071.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang J, Liu J, Xu X, Li L. Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer. Cancer Chemother Pharmacol. 2017;79(3):479–87. https://doi.org/10.1007/s00280-017-3238-4.

    Article  CAS  PubMed  Google Scholar 

  19. Ye MX, Zhao YL, Li Y, Miao Q, Li ZK, Ren XL, Song LQ, Yin H, Zhang J. Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms. Phytomedicine. 2012;19(8–9):779–87. https://doi.org/10.1016/j.phymed.2012.03.005.

    Article  CAS  PubMed  Google Scholar 

  20. Ai Y, Zhu B, Ren C, Kang F, Li J, Huang Z, Lai Y, Peng S, Ding K, Tian J, Zhang Y. Discovery of new monocarbonyl ligustrazine-curcumin hybrids for intervention of drug-sensitive and drug-resistant lung cancer. J Med Chem. 2016;59(5):1747–60. https://doi.org/10.1021/acs.jmedchem.5b01203.

    Article  CAS  PubMed  Google Scholar 

  21. Chen P, Huang HP, Wang Y, Jin J, Long WG, Chen K, Zhao XH, Chen CG, Li J. Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death. J Exp Clin Cancer Res. 2019;38(1):254. https://doi.org/10.1186/s13046-019-1234-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Giordano A, Tommonaro G. Curcumin and cancer. Nutrients. 2019;11(10):2376. https://doi.org/10.3390/nu11102376.

    Article  CAS  PubMed Central  Google Scholar 

  23. Willenbacher E, Khan SZ, Mujica SCA, Trapani D, Hussain S, Wolf D, Willenbacher W, Spizzo G, Seeber A. Curcumin: new insights into an ancient ingredient against cancer. Int J Mol Sci. 2019;20(8):1808. https://doi.org/10.3390/ijms20081808.

    Article  CAS  PubMed Central  Google Scholar 

  24. Wu GQ, Chai KQ, Zhu XM, Jiang H, Wang X, Xue Q, Zheng AH, Zhou HY, Chen Y, Chen XC, Xiao JY, Ying XH, Wang FW, Rui T, Liao YJ, Xie D, Lu LQ, Huang DS. Anti-cancer effects of curcumin on lung cancer through the inhibition of EZH2 and NOTCH1. Oncotarget. 2016;7(18):26535–50. https://doi.org/10.18632/oncotarget.8532.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liao H, Wang Z, Deng Z, Ren H, Li X. Curcumin inhibits lung cancer invasion and metastasis by attenuating GLUT1/MT1-MMP/MMP2 pathway. Int J Clin Exp Med. 2015;8(6):8948–57.

    PubMed  PubMed Central  Google Scholar 

  26. Zhu JY, Yang X, Chen Y, Jiang Y, Wang SJ, Li Y, Wang XQ, Meng Y, Zhu MM, Ma X, Huang C, Wu R, Xie CF, Li XT, Geng SS, Wu JS, Zhong CY, Han HY. Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and sonic hedgehog pathways. Phytother Res. 2017;31(4):680–8. https://doi.org/10.1002/ptr.5791.

    Article  CAS  PubMed  Google Scholar 

  27. Feng C, Xia Y, Zou P, Shen M, Hu J, Ying S, Pan J, Liu Z, Dai X, Zhuge W, Liang G, Ruan Y. Curcumin analog L48H37 induces apoptosis through ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells. Mol Carcinog. 2017;56(7):1765–77. https://doi.org/10.1002/mc.22633.

    Article  CAS  PubMed  Google Scholar 

  28. Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y. Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep. 2018;39(3):1523–31. https://doi.org/10.3892/or.2018.6188.

    Article  CAS  PubMed  Google Scholar 

  29. Dai X, Zhang J, Guo G, Cai Y, Cui R, Yin C, Liu W, Vinothkumar R, Zhang T, Liang G, Zhang X. A mono-carbonyl analog of curcumin induces apoptosis in drug-resistant EGFR-mutant lung cancer through the generation of oxidative stress and mitochondrial dysfunction. Cancer Manag Res. 2018;10:3069–82. https://doi.org/10.2147/CMAR.S159660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wei F, Ma C, Zhou T, Dong X, Luo Q, Geng L, Ding L, Zhang Y, Zhang L, Li N, Li Y, Liu Y. Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p. Mol Cancer. 2017;16(1):132. https://doi.org/10.1186/s12943-017-0694-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang H, Zhao PJ, Su D, Feng J, Ma SL. Paris saponin I induces apoptosis via increasing the Bax/Bcl-2 ratio and caspase-3 expression in gefitinib-resistant non-small cell lung cancer in vitro and in vivo. Mol Med Rep. 2014;9(6):2265–72.

    Article  CAS  PubMed  Google Scholar 

  32. Jiang H, Zhao P, Feng J, Su D, Ma S. Effect of Paris saponin I on radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line. Oncol Lett. 2014;7(6):2059–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhao P, Jiang H, Su D, Feng J, Ma S, Zhu X. Inhibition of cell proliferation by mild hyperthermia at 43 C with Paris Saponin I in the lung adenocarcinoma cell line PC-9. Mol Med Rep. 2015;11(1):327–32.

    Article  CAS  PubMed  Google Scholar 

  34. Zhu X, Jiang H, Li J, Xu J, Fei Z. Anticancer effects of paris saponins by apoptosis and PI3K/AKT pathway in gefitinib-resistant non-small cell lung cancer. Med Sci Monit. 2016;22:1435–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao PJ, Song SC, Du LW, Zhou GH, Ma SL, Li JH, Feng JG, Zhu XH, Jiang H. Paris Saponins enhance radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line by inducing apoptosis and G2/M cell cycle phase arrest. Mol Med Rep. 2016;13(3):2878–84.

    Article  CAS  PubMed  Google Scholar 

  36. Song S, Du L, Jiang H, Zhu X, Li J, Xu J. Paris saponin i sensitizes gastric cancer cell lines to cisplatin via cell cycle arrest and apoptosis. Med Sci Monit. 2016;22:3798–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng R, Jiang H, Li J, Liu X, Xu H. Polyphyllin II restores sensitization of the resistance of PC-9/ZD cells to gefitinib by a negative regulation of the PI3K/Akt/mTOR signaling pathway. Curr Cancer Drug Targets. 2017;17(4):376–85.

    Article  CAS  PubMed  Google Scholar 

  38. Wang H, Fei Z, Jiang H. Polyphyllin increases sensitivity to gefitinib by modulating the elevation of P21 in acquired gefitinib resistant non-small cell lung cancer. J Pharmacol Sci. 2017;134(3):190–6.

    Article  PubMed  Google Scholar 

  39. Yang Q, Chen W, Xu Y, Lv X, Zhang M, Jiang H. Polyphyllin I modulates MALAT1/STAT3 signaling to induce apoptosis in gefitinib-resistant non-small cell lung cancer. Toxicol Appl Pharmacol. 2018;356:1–7.

    Article  CAS  PubMed  Google Scholar 

  40. Hong F, Jiang J, Liu X, Jiang H. Anticancer activity of Polyphyllin I in nasopharyngeal carcinoma by modulation of lncRNA ROR and P53 signaling. J Drug Target. 2019;27(7):806–11.

    Article  CAS  PubMed  Google Scholar 

  41. Zang F, Rao Y, Zhu X, Wu Z, Jiang H. Shikonin suppresses NEAT1 and Akt signaling in treating paclitaxel-resistant non-small cell of lung cancer. Mol Med. 2020;26(1):28. https://doi.org/10.1186/s10020-020-00152-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang Z, Liu T, Wang K, Qu X, Pang Z, Liu S, Liu Q, Du J. Down-regulation of long non-coding RNA MEG3 indicates an unfavorable prognosis in non-small cell lung cancer: evidence from the GEO database. Gene. 2017;30(630):49–58. https://doi.org/10.1016/j.gene.2017.08.001.

    Article  CAS  Google Scholar 

  43. Dai Y, Wan Y, Qiu M, Wang S, Pan C, Wang Y, Ou J. lncRNA MEG3 suppresses the tumorigenesis of hemangioma by sponging miR-494 and Regulating PTEN/ PI3K/AKT pathway. Cell Physiol Biochem. 2018;51(6):2872–86. https://doi.org/10.1159/000496040.

    Article  CAS  PubMed  Google Scholar 

  44. Wang J, Xu W, He Y, Xia Q, Liu S. LncRNA MEG3 impacts proliferation, invasion, and migration of ovarian cancer cells through regulating PTEN. Inflamm Res. 2018;67(11–12):927–36. https://doi.org/10.1007/s00011-018-1186-z.

    Article  CAS  PubMed  Google Scholar 

  45. Yang NQ, Luo XJ, Zhang J, Wang GM, Guo JM. Crosstalk between Meg3 and miR-1297 regulates growth of testicular germ cell tumor through PTEN/PI3K/AKT pathway. Am J Transl Res. 2016;8(2):1091–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

The authors acknowledge Hangzhou Cancer Hospital to support the research.

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Correspondence to J. Ding.

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The animal experiment was approved by the ethics committee of Hangzhou Cancer Hospital.

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Gao, L., Shao, T., Zheng, W. et al. Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling. Clin Transl Oncol 23, 1386–1393 (2021). https://doi.org/10.1007/s12094-020-02531-3

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