miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling

  • Authors:
    • Ge Yang
    • Yang Fu
    • Xiaoyan Lu
    • Menghua Wang
    • Hongtao Dong
    • Qiuming Li
  • View Affiliations

  • Published online on: October 31, 2018     https://doi.org/10.3892/ijo.2018.4613
  • Pages: 177-187
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The present study aimed to explore the combined role of microRNA (miR)-34a, melanoma antigen-A (MAGE‑A) and p53 in altering the chemosensitivity of retinoblastoma (RB) cells. Human RB and adjacent tumor tissues, as well as human RB cell lines (HXO‑Rb44, SO‑Rb50, Y79 and WERI‑Rb-1) were used. In addition, four chemotherapeutic drugs, including carboplatin, etoposide, Adriamycin and vincristine, were used to treat the cell lines, in order to evaluate the sensitivity of RB cells. Furthermore, miR‑34a expression was detected by reverse transcription-quantitative polymerase chain reaction, and western blotting was implemented to quantify expression levels of MAGE‑A and p53. A luciferase reporter gene assay was used to validate the targeted association between miR‑34a and MAGE‑A. The results indicated that SO‑Rb50 cells exhibited the highest resistance to carboplatin, Adriamycin and vincristine (P<0.05), whereas HXO‑Rb44 cells revealed the highest inhibition rate in response to etoposide (P<0.05) out of the four cell lines. Furthermore, reduced miR‑34a expression and increased MAGE‑A expression significantly elevated the survival rate and viability of SO‑Rb50 cells following drug treatment (all P<0.05). miR‑34a was also demonstrated to directly target MAGE‑A, thereby significantly promoting the viability of RB cells and depressing apoptosis (P<0.05). p53, which was subjected to modulation by miR‑34a and MAGE‑A, also significantly reduced the proliferation rate of RB cells (P<0.05). In conclusion, the miR‑34a/MAGE‑A/p53 axis may be conducive to enhancing the efficacies of chemotherapeutic treatments for RB.

References

1 

Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F and Desjardins L: Retinoblastoma. Orphanet J Rare Dis. 1:312006. View Article : Google Scholar : PubMed/NCBI

2 

Kivelä T: The epidemiological challenge of the most frequent eye cancer: Retinoblastoma, an issue of birth and death. Br J Ophthalmol. 93:1129–1131. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Shields CL, Fulco EM, Arias JD, Alarcon C, Pellegrini M, Rishi P, Kaliki S, Bianciotto CG and Shields JA: Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intra-vitreal chemotherapy. Eye (Lond). 27:253–264. 2013. View Article : Google Scholar

4 

Abramson DH, Gerardi CM, Ellsworth RM, McCormick B, Sussman D and Turner L: Radiation regression patterns in treated retinoblastoma: 7 to 21 years later. J Pediatr Ophthalmol Strabismus. 28:108–112. 1991.PubMed/NCBI

5 

Fontanesi J, Pratt CB, Hustu HO, Coffey D, Kun LE and Meyer D; Jude Children’s Research Hospital Experience and Review of Literature: Use of irradiation for therapy of retinoblastoma in children more than 1 year old: The St Jude Children’s Research Hospital experience and review of literature. Med Pediatr Oncol. 24:321–326. 1995. View Article : Google Scholar : PubMed/NCBI

6 

Shields CL, Say EA, Pointdujour-Lim R, Cao C, Jabbour PM and Shields JA: Rescue intra-arterial chemotherapy following retinoblastoma recurrence after initial intra-arterial chemotherapy. J Fr Ophtalmol. 38:542–549. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Ruiz del Río N, Abelairas Gómez JM, Alonso García de la Rosa FJ, Peralta Calvo JM and de las Heras Martín A: Genetic analysis results of patients with a retinoblastoma refractory to systemic chemotherapy. Arch Soc Esp Oftalmol. 90:414–420. 2015.In Spanish. View Article : Google Scholar

8 

Nalini V, Segu R, Deepa PR, Khetan V, Vasudevan M and Krishnakumar S: Molecular insights on post-chemotherapy retinoblastoma by microarray gene expression analysis. Bioinform Biol Insights. 7:289–306. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Frankel LB and Lund AH: MicroRNA regulation of autophagy. Carcinogenesis. 33:2018–2025. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Tazawa H, Tsuchiya N, Izumiya M and Nakagama H: Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA. 104:15472–15477. 2007. View Article : Google Scholar : PubMed/NCBI

11 

Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G and Hermeking H: Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 6:1586–1593. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R, Sun Z and Zheng X: Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 582:1564–1568. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Yamakuchi M, Ferlito M and Lowenstein CJ: miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA. 105:13421–13426. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Ma ZB, Kong XL, Cui G, Ren CC, Zhang YJ, Fan SJ and Li YH: Expression and clinical significance of miRNA-34a in colorectal cancer. Asian Pac J Cancer Prev. 15:9265–9270. 2014. View Article : Google Scholar : PubMed/NCBI

15 

Liu G, Jiang C, Li D, Wang R and Wang W: miRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumour Biol. 35:9801–9806. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Dalgard CL, Gonzalez M, deNiro JE and O’Brien JM: Differential microRNA-34a expression and tumor suppressor function in reti-noblastoma cells. Invest Ophthalmol Vis Sci. 50:4542–4551. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Gao H, Zhao H and Xiang W: Expression level of human miR-34a correlates with glioma grade and prognosis. J Neurooncol. 113:221–228. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Li L, Yuan L, Luo J, Gao J, Guo J and Xie X: miR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin Exp Med. 13:109–117. 2013. View Article : Google Scholar

19 

Tang Y, Tang Y and Cheng YS: miR-34a inhibits pancreatic cancer progression through Snail1-mediated epithelial-mesenchymal transition and the Notch signaling pathway. Sci Rep. 7:382322017. View Article : Google Scholar : PubMed/NCBI

20 

Vinall RL, Ripoll AZ, Wang S, Pan CX and deVere White RW: miR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int J Cancer. 130:2526–2538. 2012. View Article : Google Scholar

21 

Kang L, Mao J, Tao Y, Song B, Ma W, Lu Y, Zhao L, Li J, Yang B and Li L: MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. Cancer Sci. 106:700–708. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Weeraratne SD, Amani V, Neiss A, Teider N, Scott DK, Pomeroy SL and Cho YJ: miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma. Neuro-oncol. 13:165–175. 2011. View Article : Google Scholar :

23 

Peche LY, Scolz M, Ladelfa MF, Monte M and Schneider C: MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs. Cell Death Differ. 19:926–936. 2012. View Article : Google Scholar :

24 

Nardiello T, Jungbluth AA, Mei A, Diliberto M, Huang X, Dabrowski A, Andrade VC, Wasserstrum R, Ely S, Niesvizky R, et al: MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin. Clin Cancer Res. 17:4309–4319. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Krauskopf J, de Kok TM, Hebels DG, Bergdahl IA, Johansson A, Spaeth F, Kiviranta H, Rantakokko P, Kyrtopoulos SA and Kleinjans JC: MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery. Sci Rep. 7:92622017. View Article : Google Scholar : PubMed/NCBI

26 

Jin Z, Zhan T, Tao J, Xu B, Zheng H, Cheng Y, Yan B, Wang H, Lu G, Lin Y, et al: MicroRNA-34a induces transdifferentiation of glioma stem cells into vascular endothelial cells by targeting Notch pathway. Biosci Biotechnol Biochem. 81:1899–1907. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Engkvist ME, Stratford EW, Lorenz S, Meza-Zepeda LA, Myklebost O and Munthe E: Analysis of the miR-34 family functions in breast cancer reveals annotation error of miR-34b. Sci Rep. 7:96552017. View Article : Google Scholar : PubMed/NCBI

28 

Huang X and Xie X, Wang H, Xiao X, Yang L, Tian Z, Guo X, Zhang L, Tang H and Xie X: PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a. J Exp Clin Cancer Res. 36:1292017. View Article : Google Scholar : PubMed/NCBI

29 

Wang X, Xie Y and Wang J: Overexpression of microRNA-34a-5p inhibits proliferation and promotes apoptosis of human cervical cancer cells by downregulation of Bcl-2. Oncol Res. Aug 30–2017.Epub ahead of print. View Article : Google Scholar

30 

Kwon H, Song K, Han C, Zhang J, Lu L, Chen W and Wu T: Epigenetic silencing of miRNA-34a in human cholangiocarcinoma via EZH2 and DNA methylation: Impact on regulation of notch pathway. Am J Pathol. 187:2288–2299. 2017. View Article : Google Scholar : PubMed/NCBI

31 

Dai X, Li M and Geng F: Omega-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid enhance dexamethasone sensitivity in multiple myeloma cells by the p53/miR-34a/Bcl-2 axis. Biochemistry (Mosc). 82:826–833. 2017. View Article : Google Scholar

32 

Ritchie W, Rasko JE and Flamant S: MicroRNA target prediction and validation. Adv Exp Med Biol. 774:39–53. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Witkos TM, Koscianska E and Krzyzosiak WJ: Practical aspects of microRNA target prediction. Curr Mol Med. 11:93–109. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, Zhang C, Hong M, Wang S and Li X: miR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med. 13:2522015. View Article : Google Scholar : PubMed/NCBI

35 

Lian Y, Sang M, Gu L, Liu F, Yin D, Liu S, Huang W, Wu Y and Shan B: MAGE-A family is involved in gastric cancer progression and indicates poor prognosis of gastric cancer patients. Pathol Res Pract. 213:943–948. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Sang M, Wu X, Fan X, Lian Y and Sang M: MAGE-A family serves as poor prognostic markers and potential therapeutic targets for epithelial ovarian cancer patients: A retrospective clinical study. Gynecol Endocrinol. 33:480–484. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Sang M, Gu L, Yin D, Liu F, Lian Y, Zhang X, Liu S, Huang W, Wu Y and Shan B: MAGE-A family expression is correlated with poor survival of patients with lung adenocarcinoma: A retrospective clinical study based on tissue microarray. J Clin Pathol. 70:533–540. 2017. View Article : Google Scholar

38 

Marcar L, Maclaine NJ, Hupp TR and Meek DW: Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin. Cancer Res. 70:10362–10370. 2010. View Article : Google Scholar : PubMed/NCBI

39 

Zajac P, Schultz-Thater E, Tornillo L, Sadowski C, Trella E, Mengus C, Iezzi G and Spagnoli GC: MAGE-A antigens and cancer immunotherapy. Front Med (Lausanne). 4:182017.

40 

Sato F, Tsuchiya S, Meltzer SJ and Shimizu K: MicroRNAs and epigenetics. FEBS J. 278:1598–1609. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM and Zhang GZ: Biological functions of microRNAs: A review. J Physiol Biochem. 67:129–139. 2011. View Article : Google Scholar

42 

Kircelli F, Akay C and Gazitt Y: Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53. Int J Oncol. 30:993–1001. 2007.PubMed/NCBI

43 

Riley T, Sontag E, Chen P and Levine A: Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 9:402–412. 2008. View Article : Google Scholar : PubMed/NCBI

44 

Vousden KH and Prives C: Blinded by the light: The growing complexity of p53. Cell. 137:413–431. 2009. View Article : Google Scholar : PubMed/NCBI

45 

Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, Pierotti MA, Rodolfo M and Schneider C: MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc Natl Acad Sci USA. 103:11160–11165. 2006. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

January 2019
Volume 54 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yang, G., Fu, Y., Lu, X., Wang, M., Dong, H., & Li, Q. (2019). miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling. International Journal of Oncology, 54, 177-187. https://doi.org/10.3892/ijo.2018.4613
MLA
Yang, G., Fu, Y., Lu, X., Wang, M., Dong, H., Li, Q."miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling". International Journal of Oncology 54.1 (2019): 177-187.
Chicago
Yang, G., Fu, Y., Lu, X., Wang, M., Dong, H., Li, Q."miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling". International Journal of Oncology 54, no. 1 (2019): 177-187. https://doi.org/10.3892/ijo.2018.4613