Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Knock-down of LncRNA-XIST induced glioma cell death and inhibited tumorigenesis by regulating miR-137/SLC1A5 axis-mediated ROS production


Glioma seriously degrades the life quality of afflicted human beings. Uncovering the underlying mechanisms of the pathogenesis of glioma is a step needed to help provide new therapeutic agents for clinical treatments. This study aimed to explore the role of the LncRNA-XIST/miR-137/SLC1A5 axis in influencing the regulation of development of glioma. Our results indicated that LncRNA-XIST and SLC1A5 were expressed at high levels and contrastingly indicated that miR-137 was expressed at low levels in glioma cells when compared results for normal human astrocytes (NHAs). Further, our findings indicated that downregulation of LncRNA-XIST promoted both glioma cell apoptosis and ROS production as well as inhibited cell proliferation. All these effects were reversed by treating cells with ROS scavenger N-acetyl-L-Cysteine (NAC). In addition, inducing the knock-down of LncRNA-XIST was found to have decreased the expression levels of SLC1A5 by sponging miR-137 in glioma cells. Notably, both the knocking down of miR-137 and/or induced overexpression of SLC1A5 abrogated the effects of downregulated LncRNA-XIST on glioma cell proliferation, apoptosis, and ROS production. Furthermore, in vivo experiments validated that LncRNA-XIST deficiency inhibited tumorigenesis of glioma cells in examinations of nude mice and these effects were reversible by way of either downregulating miR-137 or upregulating SLC1A5. Taken together, knocking down LncRNA-XIST induced the inhibition of the progression of glioma by way of triggering ROS production in a miR-137/SLC1A5 axis-dependent manner.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. Bi WP, Xia M, Wang XJ (2018) miR-137 suppresses proliferation, migration and invasion of colon cancer cell lines by targeting TCF4. Oncol Lett 15:8744–8748.

  2. Bjersand K, Seidal T, Sundstrom-Poromaa I, Akerud H, Skirnisdottir I (2017) The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer. PLoS One 12:e0179363.

  3. Chen R, Zhang Y, Zhang C, Wu H, Yang S (2017) miR-137 inhibits the proliferation of human non-small cell lung cancer cells by targeting SRC3. Oncol Lett 13:3905–3911.

  4. Chen F, Luo N, Hu Y, Li X, Zhang K (2018) MiR-137 suppresses triple-negative breast cancer stemness and tumorigenesis by perturbing BCL11A-DNMT1 interaction. Cell Physiol Biochem 47:2147–2158.

  5. Chen H, Li Q, Liang J, Jin M, Lu A (2019) LncRNA CPS1-IT1 serves as anti-oncogenic role in glioma. Biomed Pharmacother 118:109277.

  6. Cormerais Y, Massard PA, Vucetic M, Giuliano S, Tambutte E, Durivault J, Vial V, Endou H, Wempe MF, Parks SK, Pouyssegur J (2018) The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem 293:2877–2887.

  7. Dong J, Xiao D, Zhao Z, Ren P, Li C, Hu Y, Shi J, Su H, Wang L, Liu H, Li B, Gao P, Qing G (2017) Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism. Oncogenesis 6:e356.

  8. Dong ZQ, Guo ZY, Xie J (2019) The lncRNA EGFR-AS1 is linked to migration, invasion and apoptosis in glioma cells by targeting miR-133b/RACK1. Biomed Pharmacother 118:109292.

  9. Du P, Zhao H, Peng R, Liu Q, Yuan J, Peng G, Liao Y (2017) LncRNA-XIST interacts with miR-29c to modulate the chemoresistance of glioma cell to TMZ through DNA mismatch repair pathway. Biosci Rep 37.

  10. El-Ansari R, Craze ML, Alfarsi L, Soria D, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR (2019) The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer. Breast Cancer Res Treat 175:27–38.

  11. Ergun S, Guney S, Temiz E, Petrovic N, Gunes S (2018) Significance of miR-15a-5p and CNKSR3 as novel prognostic biomarkers in non-small cell lung cancer. Anti Cancer Agents Med Chem 18:1695–1701.

  12. Jin J, Zhang S, Hu Y, Zhang Y, Guo C, Feng F (2019) SP1 induced lncRNA CASC11 accelerates the glioma tumorigenesis through targeting FOXK1 via sponging miR-498. Biomed Pharmacother 116:108968.

  13. Li C, Hu G, Wei B, Wang L, Liu N (2019) lncRNA LINC01494 promotes proliferation, migration and invasion in Glioma through miR-122-5p/CCNG1 axis. OncoTargets Ther 12:7655–7662.

  14. Liang ML, Hsieh TH, Ng KH, Tsai YN, Tsai CF, Chao ME, Liu DJ, Chu SS, Chen W, Liu YR, Liu RS, Lin SC, Ho DM, Wong TT, Yang MH, Wang HW (2016) Downregulation of miR-137 and miR-6500-3p promotes cell proliferation in pediatric high-grade gliomas. Oncotarget 7:19723–19737.

  15. Liu Y, Yang L, An H, Chang Y, Zhang W, Zhu Y, Xu L, Xu J (2015) High expression of solute carrier family 1, member 5 (SLC1A5) is associated with poor prognosis in clear-cell renal cell carcinoma. Sci Rep 5:16954.

  16. Liu X, Cui L, Hua D (2018) Long noncoding RNA XIST regulates miR-137-EZH2 axis to promote tumor metastasis in colorectal cancer. Oncol Res 27:99–106.

  17. Liu J, Yao L, Zhang M, Jiang J, Yang M, Wang Y (2019a) Downregulation of LncRNA-XIST inhibited development of non-small cell lung cancer by activating miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death. Aging 11:7830–7846.

  18. Liu JG, Wang HB, Wan G, Yang MZ, Jiang XJ, Yang JY (2019b) Long noncoding RNA ZFPM2-AS1 promotes the tumorigenesis of renal cell cancer via targeting miR-137. Eur Rev Med Pharmacol Sci 23:5675–5681.

  19. Luo M, Wu L, Zhang K, Wang H, Zhang T, Gutierrez L, O'Connell D, Zhang P, Li Y, Gao T, Ren W, Yang Y (2018) miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ 25:1457–1472.

  20. Luo H, Xu R, Chen B, Dong S, Zhou F, Yu T, Xu G, Zhang J, Wang Y, You Y (2019) MicroRNA-940 inhibits glioma cells proliferation and cell cycle progression by targeting CKS1. Am J Transl Res 11:4851–4865

  21. Neault M, Mallette FA, Richard S (2016) miR-137 modulates a tumor suppressor network-inducing senescence in pancreatic cancer cells. Cell Rep 14:1966–1978.

  22. Ong DST, Hu B, Ho YW, Sauve CG, Bristow CA, Wang Q, Multani AS, Chen P, Nezi L, Jiang S, Gorman CE, Monasterio MM, Koul D, Marchesini M, Colla S, Jin EJ, Sulman EP, Spring DJ, Yung WA, Verhaak RGW, Chin L, Wang YA, DePinho RA (2017) PAF promotes stemness and radioresistance of glioma stem cells. Proc Natl Acad Sci U S A 114:E9086–e9095.

  23. Peng G, Yang C, Liu Y, Shen C (2019) miR-25-3p promotes glioma cell proliferation and migration by targeting FBXW7 and DKK3. Exp Ther Med 18:769–778.

  24. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O'Toole SA, Rasko JE, Holst J (2016) ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 35:3201–3208.

  25. Wang Z, Yuan J, Li L, Yang Y, Xu X, Wang Y (2017) Long non-coding RNA XIST exerts oncogenic functions in human glioma by targeting miR-137. Am J Transl Res 9:1845–1855

  26. Wang X, Zhang G, Cheng Z, Dai L, Jia L, Jing X, Wang H, Zhang R, Liu M, Jiang T, Yang Y, Yang M (2018) Knockdown of LncRNA-XIST suppresses proliferation and TGF-beta1-induced EMT in NSCLC through the notch-1 pathway by regulation of miR-137. Genet Test Mol Biomarkers 22:333–342.

  27. Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, Xia H, Zhou J, Li G, Li J, Li W, Wei S, Vatan L, Zhang H, Szeliga W, Gu W, Liu R, Lawrence TS, Lamb C, Tanno Y, Cieslik M, Stone E, Georgiou G, Chan TA, Chinnaiyan A, Zou W (2019) CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569:270–274.

  28. Wu C, Su J, Wang X, Wang J, Xiao K, Li Y, Xiao Q, Ling M, Xiao Y, Qin C, Long W, Zhang F, Pan Y, Xiang F, Liu Q (2019) Overexpression of the phospholipase A2 group V gene in glioma tumors is associated with poor patient prognosis. Cancer Manag Res 11:3139–3152.

  29. Yu H, Xue Y, Wang P, Liu X, Ma J, Zheng J, Li Z, Li Z, Cai H, Liu Y (2017) Knockdown of long non-coding RNA XIST increases blood-tumor barrier permeability and inhibits glioma angiogenesis by targeting miR-137. Oncogenesis 6:e303.

  30. Zhang L, Yang H, Zhang W, Liang Z, Huang Q, Xu G, Zhen X, Zheng LT (2017) Clk1-regulated aerobic glycolysis is involved in glioma chemoresistance. J Neurochem 142:574–588.

  31. Zhang R, Wang Z, Yu Q, Shen J, He W, Zhou D, Yu Q, Fan J, Gao S, Duan L (2019) Atractylenolide II reverses the influence of lncRNA XIST/miR-30a-5p/ROR1 axis on chemo-resistance of colorectal cancer cells. J Cell Mol Med 23:3151–3165.

  32. Zhao Y, Li S, Xia N, Shi Y, Zhao CM (2018) Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model. J Cell Physiol 233:4307–4316.

Download references

Author contribution statement

ZXH conceived and designed research. SYF and LB conducted experiments and analyzed data. SYF wrote the manuscript. All authors read and approved the manuscript.

Author information

Correspondence to Xianhong Zhang.

Ethics declarations

All aspects of the design and experimentation which related to live animals were in accordance with institutional guidelines of the Jining First People’s Hospital (China).

Conflict of interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sun, Y., Lv, B. & Zhang, X. Knock-down of LncRNA-XIST induced glioma cell death and inhibited tumorigenesis by regulating miR-137/SLC1A5 axis-mediated ROS production. Naunyn-Schmiedeberg's Arch Pharmacol (2020).

Download citation


  • Glioma
  • miR-137
  • SLC1A5
  • ROS