Download PDF
CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2019; 40(03): 381-385
DOI: 10.4103/ijmpo.ijmpo_203_17
Original Article

FoxO3a Gene Down-regulation in Pathogenesis of Pediatric Acute Lymphoblastic Leukemia

Malihe Mirzaie
Department of Biology, Islamic Azad University, Arsanjan, India
,
Mahboobeh Nasiri
Department of Biology, Islamic Azad University, Arsanjan, India
,
Mehran Karimi
Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, India
,
Majid Yavarian
Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, India
,
Arghavan Kavosi
Department of Cellular and Molecular Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University, Tehran, India
› Author Affiliations Financial support and sponsorship This study was financially supported by Islamic Azad University, Arsanjan Branch, Arsanjan, Iran.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignancy found in the pediatrics with the peak prevalence between the ages of 2 and 5 years. The constitutive activation of PI3K/AKT pathway inhibits the tumor-suppressor role of FoxO3a (a member of the forkhead class O [FoxO] transcription factor family) in a variety of cancers and leads to tumorigenesis. This study aims to investigate the expression of FoxO3a in three different stages of pediatric ALL in mRNA level. Subjects and Methods: In this case-control study, 70 patients with childhood ALL and 70 healthy age- and gender-matched as the control group were enrolled. Real-time quantitative RT-polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression level of FoxO3a in children with different stages of ALL and healthy children as a control group. Results: Data showed that the expression of FoxO3a mRNA was lower in newly diagnosed ALL patients compared to controls (P < 0.0001), maintenance (P = 0.0342), and relapse (P = 0.0006) groups, while no difference was observed between other groups. In addition, T-ALL patients showed decreased expression of FoxO3a compared to Pre-B ALL ones (P < 0.0001). Conclusion: The study results suggest that FoxO3a plays a tumor-suppressor role in ALL. Thus, its up-regulation seems to be a plausible therapeutic strategy for this type of tumor.

Keywords

FoxO3a - gene expression - pediatric acute lymphoblastic leukemia - PI3K/AKT pathway


Publication History

Received: 29 September 2017

Accepted: 18 April 2018

Article published online:
03 June 2021

© 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Wang Y, Zhou L, Chen J, Li J, He L, Wu P. et al. Association of the 3'UTR FOXO3a polymorphism rs4946936 with an increased risk of childhood acute lymphoblastic leukemia in a Chinese population. Cell Physiol Biochem 2014; 34: 325-32
    CrossrefPubMedGoogle Scholar
  • 2 Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013; 381: 1943-55
    CrossrefPubMedGoogle Scholar
  • 3 Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM. et al. The 2016 Revised to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391-405
    CrossrefPubMedGoogle Scholar
  • 4 Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: A review. Environ Health Perspect 2007; 115: 138-45
    CrossrefPubMedGoogle Scholar
  • 5 Pui CH. Acute lymphoblastic leukemia: Introduction. Semin Hematol 2009; 46: 1-2
    CrossrefPubMedGoogle Scholar
  • 6 Hui RC, Francis RE, Guest SK, Costa JR, Gomes AR, Myatt SS. et al. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther 2008; 7: 670-8
    CrossrefPubMedGoogle Scholar
  • 7 Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: An updated review. Ann Med 2014; 46: 372-83
    CrossrefPubMedGoogle Scholar
  • 8 Tsai WB, Chung YM, Takahashi Y, Xu Z, Hu MC. Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 2008; 10: 460-7
    CrossrefPubMedGoogle Scholar
  • 9 Ferber EC, Peck B, Delpuech O, Bell GP, East P, Schulze A. et al. FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ 2012; 19: 968-79
    CrossrefPubMedGoogle Scholar
  • 10 Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW. et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 2002; 22: 7842-52
    CrossrefPubMedGoogle Scholar
  • 11 Yang JY, Xia W, Hu MC. Ionizing radiation activates expression of FOXO3a, fas ligand, and bim, and induces cell apoptosis. Int J Oncol 2006; 29: 643-8
    PubMedGoogle Scholar
  • 12 Tran H, Brunet A, Grenier JM, Datta SR, Fornace Jr. AJ, DiStefano PS. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the gadd45 protein. Science 2002; 296: 530-4
    CrossrefPubMedGoogle Scholar
  • 13 Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128: 325-39
    CrossrefPubMedGoogle Scholar
  • 14 Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410-25
    CrossrefPubMedGoogle Scholar
  • 15 Ausserlechner MJ, Salvador C, Deutschmann A, Bodner M, Viola G, Bortolozzi R. et al. Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL and Noxa. Oncotarget 2013; 4: 995-1007
    CrossrefPubMedGoogle Scholar
  • 16 Komatsu N, Watanabe T, Uchida M, Mori M, Kirito K, Kikuchi S. et al. Amember of forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J Biol Chem 2003; 278: 6411-9
    CrossrefPubMedGoogle Scholar
  • 17 Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 2009; 10: 176-84
    CrossrefPubMedGoogle Scholar
  • 18 Wang W, Lv L, Pan K, Zhang Y, Zhao JJ, Chen JG. et al. Reduced expression of transcription factor AP-2α is associated with gastric adenocarcinoma prognosis. PLoS One 2011; 6: e24897
    CrossrefPubMedGoogle Scholar
  • 19 Prasad SB, Yadav SS, Das M, Govardhan HB, Pandey LK, Singh S. et al. Down regulation of FOXO1 promotes cell proliferation in cervical cancer. J Cancer 2014; 5: 655-62
    CrossrefPubMedGoogle Scholar
  • 20 Webb AE, Kundaje A, Brunet A. Characterization of the direct targets of FOXO transcription factors throughout evolution. Aging Cell 2016; 15: 673-85
    CrossrefPubMedGoogle Scholar
  • 21 Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: Implications for therapeutic strategies in leukemia. Blood 2012; 119: 911-23
    CrossrefPubMedGoogle Scholar
  • 22 Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1: 101-12
    CrossrefPubMedGoogle Scholar
  • 23 Engström M, Karlsson R, Jönsson JI. Inactivation of the forkhead transcription factor foxO3 is essential for PKB-mediated survival of hematopoietic progenitor cells by kit ligand. Exp Hematol 2003; 31: 316-23
    CrossrefPubMedGoogle Scholar
  • 24 Kubota Y, Ohnishi H, Kitanaka A, Ishida T, Tanaka T. Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: Direct evidence of PI3K activation. Leukemia 2004; 18: 1438-40
    CrossrefPubMedGoogle Scholar
  • 25 Chapuis N, Park S, Leotoing L, Tamburini J, Verdier F, Bardet V. et al. IκB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia. Blood 2010; 116: 4240-50
    CrossrefPubMedGoogle Scholar
  • 26 Ticchioni M, Essafi M, Jeandel PY, Davi F, Cassuto JP, Deckert M. et al. Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene 2007; 26: 7081-91
    CrossrefPubMedGoogle Scholar
  • 27 Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J. et al. Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. Endocrinology 2004; 145: 2014-22
    CrossrefPubMedGoogle Scholar
  • 28 Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y. et al. Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 2007; 26: 7647-55
    CrossrefPubMedGoogle Scholar
  • 29 Lin H, Dai T, Xiong H, Zhao X, Chen X, Yu C. et al. Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One 2010; 5: e15797
    CrossrefPubMedGoogle Scholar
  • 30 Yang XB, Zhao JJ, Huang CY, Wang QJ, Pan K, Wang DD. et al. Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients. PLoS One 2013; 8: e78158
    CrossrefPubMedGoogle Scholar
  • 31 Gomes AM, Soares MV, Ribeiro P, Caldas J, Póvoa V, Martins LR. et al. Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels. Haematologica 2014; 99: 1062-8
    CrossrefPubMedGoogle Scholar
  • 32 Dewar R, Chen ST, Yeckes-Rodin H, Miller K, Khosravi-Far R. Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker. Cancer Biol Ther 2011; 11: 552-8
    CrossrefPubMedGoogle Scholar
  • 33 Tang YL, Huang LB, Lin WH, Wang LN, Tian Y, Shi D. et al. Butein inhibits cell proliferation and induces cell cycle arrest in acute lymphoblastic leukemia via FOXO3a/p27kip1 pathway. Oncotarget 2016; 7: 18651-64
    CrossrefPubMedGoogle Scholar