Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4

  • Authors:
    • Pin Guo
    • Yanan Yu
    • Zibin Tian
    • Yingying Lin
    • Yongming Qiu
    • Weicheng Yao
    • Lijuan Zhang
  • View Affiliations

  • Published online on: July 23, 2018     https://doi.org/10.3892/ijo.2018.4498
  • Pages: 1591-1600
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Abstract

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and it is characterized by extremely poor therapeutic response and overall survival. Adjuvant radiotherapy remains the standard of care following surgical resection. Thus, elucidating the mechanisms conferring radioresistance in GBM is extremely urgent. In the present study, miR-96 was demonstrated to be significantly upregulated in radioresistant GBM cells. Knockdown of miR-96 in the radioresistant GBM cells T98G elevated the % of apoptotic cells and reduced their clonogenic formation ability following radiotherapy. By contrast, overexpression of miR-96 in the radiosensitive GBM cells U87-MG reduced the % of apoptotic cells and increased their clonogenic formation ability following radiotherapy. Results from phosphorylated-H2A histone family member X (γH2AX) foci staining and comet assays revealed that miR-96 enhanced the DNA repair processes. Furthermore, miR-96 overexpression conferred radioresistance by downregulating programmed cell death protein 4 (PDCD4). Luciferase assay results revealed that miR-96 bound to the 3'UTR of PDCD4 mRNA. Finally, U87-MG cells regained radiosensitivity following PDCD4 overexpression. Taken together, the present is the first study to establish that upregulation of miR-96 in GBM cells confers radioresistance via targeting PDCD4, which might be a potential therapeutic target for GBM.

References

1 

Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Kirkpatrick JP, Laack NN, Shih HA and Gondi V: Management of GBM: A problem of local recurrence. J Neurooncol. 134:487–493. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Fidoamore A, Cristiano L, Antonosante A, d'Angelo M, Di Giacomo E, Astarita C, Giordano A, Ippoliti R, Benedetti E and Cimini A: Glioblastoma stem cells microenvironment: The paracrine roles of the niche in drug and radioresistance. Stem Cells Int. 2016:68091052016. View Article : Google Scholar : PubMed/NCBI

6 

Chen Y, Liu W, Chao T, Zhang Y, Yan X, Gong Y, Qiang B, Yuan J, Sun M and Peng X: MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G. Cancer Lett. 272:197–205. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Papagiannakopoulos T, Shapiro A and Kosik KS: MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 68:8164–8172. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Hu J, Sun T, Wang H, Chen Z, Wang S, Yuan L, Liu T, Li HR, Wang P, Feng Y, et al: miR-215 Is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell. 29:49–60. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Shi Y, Chen C, Zhang X, Liu Q, Xu JL, Zhang HR, Yao XH, Jiang T, He ZC, Ren Y, et al: Primate-specific miR-663 functions as a tumor suppressor by targeting PIK3CD and predicts the prognosis of human glioblastoma. Clin Cancer Res. 20:1803–1813. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Hong Y, Liang H, Uzair-Ur-Rehman, Wang Y, Zhang W, Zhou Y, Chen S, Yu M, Cui S, Liu M, et al: miR-96 promotes cell proliferation, migration and invasion by targeting PTPN9 in breast cancer. Sci Rep. 6:374212016. View Article : Google Scholar : PubMed/NCBI

11 

Xu L, Zhong J, Guo B, Zhu Q, Liang H, Wen N, Yun W and Zhang L: miR-96 promotes the growth of prostate carcinoma cells by suppressing MTSS1. Tumour Biol. 37:12023–12032. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Wang TH, Yeh CT, Ho JY, Ng KF and Chen TC: OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma. Mol Carcinog. 55:366–375. 2016. View Article : Google Scholar

13 

Ma Y, Yang HZ, Dong BJ, Zou HB, Zhou Y, Kong XM and Huang YR: Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. Oncotarget. 5:9169–9182. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, Liu J, Yu J and Chen J: miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 70:6015–6025. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Tanaka M, Suzuki HI, Shibahara J, Kunita A, Isagawa T, Yoshimi A, Kurokawa M, Miyazono K, Aburatani H, Ishikawa S, et al: EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. Oncogene. 33:2454–2463. 2014. View Article : Google Scholar

16 

Ress AL, Stiegelbauer V, Winter E, Schwarzenbacher D, Kiesslich T, Lax S, Jahn S, Deutsch A, Bauernhofer T, Ling H, et al: miR-96–5p influences cellular growth and is associated with poor survival in colorectal cancer patients. Mol Carcinog. 54:1442–1450. 2015. View Article : Google Scholar

17 

Leung WK, He M, Chan AW, Law PT and Wong N: Wnt/β-Catenin activates miR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion. Cancer Lett. 362:97–105. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Wu L, Pu X, Wang Q, Cao J, Xu F, Xu LI and Li K: miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9. Oncol Lett. 11:945–952. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Xia H, Chen S, Chen K, Huang H and Ma H: miR-96 promotes proliferation and chemo- or radioresistance by down-regulating RECK in esophageal cancer. Biomed Pharmacother. 68:951–958. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Liao J, Liu R, Shi YJ, Yin LH and Pu YP: Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer. Int J Oncol. 48:2567–2579. 2016. View Article : Google Scholar : PubMed/NCBI

21 

Zhang X, Gee H, Rose B, Lee CS, Clark J, Elliott M, Gamble JR, Cairns MJ, Harris A, Khoury S, et al: Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers. BMC Cancer. 16:862016. View Article : Google Scholar : PubMed/NCBI

22 

Hwang SK, Baker AR, Young MR and Colburn NH: Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65. Carcinogenesis. 35:1469–1480. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Wang L, Zhao M, Guo C, Wang G, Zhu F, Wang J, Wang X, Wang Q, Zhao W, Shi Y, et al: PDCD4 deficiency aggravated colitis and colitis-associated colorectal cancer via promoting IL-6/STAT3 pathway in mice. Inflamm Bowel Dis. 22:1107–1118. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Zhen Y, Li D, Li W, Yao W, Wu A, Huang J, Gu H, Huang Y, Wang Y, Wu J, et al: Reduced PDCD4 expression promotes sell growth through PI3K/Akt signaling in non-small cell lung cancer. Oncol Res. 23:61–68. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Chen Z, Yuan YC, Wang Y, Liu Z, Chan HJ and Chen S: Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer. Breast Cancer Res Treat. 152:29–39. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Supiot S, Gouraud W, Campion L, Jezéquel P, Buecher B, Charrier J, Heymann MF, Mahé MA, Rio E and Chérel M: Early dynamic transcriptomic changes during preoperative radiotherapy in patients with rectal cancer: A feasibility study. World J Gastroenterol. 19:3249–3254. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Bredel M, Scholtens DM, Harsh GR, Bredel C, Chandler JP, Renfrow JJ, Yadav AK, Vogel H, Scheck AC, Tibshirani R, et al: A network model of a cooperative genetic landscape in brain tumors. JAMA. 302:261–275. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Gao F, Wang X, Zhu F, Wang Q, Zhang X, Guo C, Zhou C, Ma C, Sun W, Zhang Y, et al: PDCD4 gene silencing in gliomas is associated with 5′CpG island methylation and unfavourable prognosis. J Cell Mol Med. 13:4257–4267. 2009. View Article : Google Scholar

29 

Xiao J, Pan Y, Li XH, Yang XY, Feng YL, Tan HH, Jiang L, Feng J and Yu XY: Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis. 7:e22772016. View Article : Google Scholar : PubMed/NCBI

30 

Jiang LP, He CY and Zhu ZT: Role of microRNA-21 in radiosensitivity in non-small cell lung cancer cells by targeting PDCD4 gene. Oncotarget. 8:23675–23689. 2017.PubMed/NCBI

31 

Allen M, Bjerke M, Edlund H, Nelander S and Westermark B: Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med. 8:54re32016. View Article : Google Scholar

32 

Lee DH, Ryu HW, Won HR and Kwon SH: Advances in epigenetic glioblastoma therapy. Oncotarget. 8:18577–18589. 2017.PubMed/NCBI

33 

Shen Y, Wang Y, Sheng K, Fei X, Guo Q, Larner J, Kong X, Qiu Y and Mi J: Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma. Cell Death Dis. 2:e2412011. View Article : Google Scholar : PubMed/NCBI

34 

Jalbert LE, Elkhaled A, Phillips JJ, Neill E, Williams A, Crane JC, Olson MP, Molinaro AM, Berger MS, Kurhanewicz J, et al: Metabolic profiling of IDH mutation and malignant progression in infiltrating glioma. Sci Rep. 7:447922017. View Article : Google Scholar : PubMed/NCBI

35 

Wang J, Su HK, Zhao HF, Chen ZP and To SS: Progress in the application of molecular biomarkers in gliomas. Biochem Biophys Res Commun. 465:1–4. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Binabaj MM, Bahrami A, ShahidSales S, Joodi M, Joudi Mashhad M, Hassanian SM, Anvari K and Avan A: The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials. J Cell Physiol. 233:378–386. 2018. View Article : Google Scholar

37 

Figueroa JM, Skog J, Akers J, Li H, Komotar R, Jensen R, Ringel F, Yang I, Kalkanis S, Thompson R, et al: Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro Oncol. 19:1494–1502. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI

39 

Guo Q, Guo P, Mao Q, Lan J, Lin Y, Jiang J and Qiu Y: ID1 affects the efficacy of radiotherapy in glioblastoma through inhibition of DNA repair pathways. Med Oncol. 30:3252013. View Article : Google Scholar : PubMed/NCBI

40 

Costa PM, Cardoso AL, Nóbrega C, Pereira de Almeida LF, Bruce JN, Canoll P and Pedroso de Lima MC: MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma. Hum Mol Genet. 22:904–918. 2013. View Article : Google Scholar :

41 

Cheng Y, Xiang G, Meng Y and Dong R: MiRNA-183-5p promotes cell proliferation and inhibits apoptosis in human breast cancer by targeting the PDCD4. Reprod Biol. 16:225–233. 2016. View Article : Google Scholar : PubMed/NCBI

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APA
Guo, P., Yu, Y., Tian, Z., Lin, Y., Qiu, Y., Yao, W., & Zhang, L. (2018). Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4. International Journal of Oncology, 53, 1591-1600. https://doi.org/10.3892/ijo.2018.4498
MLA
Guo, P., Yu, Y., Tian, Z., Lin, Y., Qiu, Y., Yao, W., Zhang, L."Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4". International Journal of Oncology 53.4 (2018): 1591-1600.
Chicago
Guo, P., Yu, Y., Tian, Z., Lin, Y., Qiu, Y., Yao, W., Zhang, L."Upregulation of miR-96 promotes radioresistance in glioblastoma cells via targeting PDCD4". International Journal of Oncology 53, no. 4 (2018): 1591-1600. https://doi.org/10.3892/ijo.2018.4498