Open Access

miR‑338‑3p suppresses the malignancy of T‑cell lymphoblastic lymphoma by downregulating HOXA3

  • Authors:
    • Li Wang
    • Minghua Sui
    • Xiuli Wang
  • View Affiliations

  • Published online on: July 1, 2019     https://doi.org/10.3892/mmr.2019.10451
  • Pages: 2127-2134
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

T‑cell lymphoblastic lymphoma (T‑LBL) is an aggressive malignancy with poor prognosis due to frequent relapses. Previous studies have reported an association of the disease with abnormal chromosomal rearrangements, DNA copy number alterations and mutations in critical signaling factors, such as those in the Notch1 pathway; however, the molecular mechanisms underlying the development of the disease remain unclear, limiting the development of novel therapies. In the present study, gene expression was detected by qPCR and western blot analysis. Diagnostic analysis was performed by ROC curve. Cell proliferation, invasion and migration were analyzed by cell proliferation and Transwell assays. Gene interactions were analyzed using luciferase reporter assay. In the present study, it was observed that the expression levels of microRNA‑338‑3p (miR‑338‑3p) were reduced in patient lymphoma tissues and a T‑LBL cell line. Upregulation of its expression inhibited the migration and proliferation of cultured T‑LBL cells. Bioinformatics analysis of putative target mRNAs of miR‑338‑3p identified a direct binding site in the 3'‑untranslated of homeobox A3 (HOXA3). The levels of HOXA3 mRNA and protein were associated with those of miR‑338‑3p, and overexpression of HOXA3 promoted the malignant phenotype of T‑LBL cells. The results suggested that miR‑338‑3p may suppress the development of T‑LBL via the downregulation of oncogenic factors, such as HOXA3. The findings indicated that further investigation into miR‑338‑3p and the HOXA3 regulatory network may aid the development of novel therapeutic tools.

References

1 

Uckun FM, Gaynon PS, Sensel MG, Nachman J, Trigg ME, Steinherz PG, Hutchinson R, Bostrom BC, Sather HN and Reaman GH: Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: A children's cancer group study. J Clin Oncol. 15:2214–2221. 1997. View Article : Google Scholar : PubMed/NCBI

2 

Lepretre S, Graux C, Touzart A, Macintyre E and Boissel N: Adult T-type lymphoblastic lymphoma: Treatment advances and prognostic indicators. Exp Hematol. 51:7–16. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Portell CA and Sweetenham JW: Adult lymphoblastic lymphoma. Cancer J. 18:432–438. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Lee WJ, Moon HR, Won C, Chang SE, Choi JH, Moon KC and Lee MW: Precursor B- or T-lymphoblastic lymphoma presenting with cutaneous involvement: A series of 13 cases including 7 cases of cutaneous T-lymphoblastic lymphoma. J Am Acad Dermatol. 70:318–325. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Aifantis I, Raetz E and Buonamici S: Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol. 8:380–390. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Graux C, Cools J, Michaux L, Vandenberghe P and Hagemeijer A: Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: From thymocyte to lymphoblast. Leukemia. 20:1496–1510. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng AP, et al: NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA. 103:18261–18266. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, et al: c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20:2096–2109. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, et al: Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med. 13:70–77. 2007. View Article : Google Scholar : PubMed/NCBI

10 

Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, et al: Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 13:1203–1210. 2007. View Article : Google Scholar : PubMed/NCBI

11 

O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, Hardwick J, Welcker M, Meijerink JP, Pieters R, et al: FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 204:1813–1824. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Weng AP, Ferrando AA, Lee W, Morris JP IV, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT and Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 306:269–271. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Ye F: MicroRNA expression and activity in T-cell acute lymphoblastic leukemia. Oncotarget. 9:5445–5458. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Wallaert A, Van Loocke W, Hernandez L, Taghon T, Speleman F and Van Vlierberghe P: Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing. Sci Rep. 7:79012017. View Article : Google Scholar : PubMed/NCBI

15 

Saba R, Goodman CD, Huzarewich RL, Robertson C and Booth SA: A miRNA signature of prion induced neurodegeneration. PLoS One. 3:e36522008. View Article : Google Scholar : PubMed/NCBI

16 

Li Y, Chen P, Zu L, Liu B, Wang M and Zhou Q: MicroRNA-338-3p suppresses metastasis of lung cancer cells by targeting the EMT regulator Sox4. Am J Cancer Res. 6:127–140. 2016.PubMed/NCBI

17 

Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA and Tubiana M: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol. 7:1630–1636. 1989. View Article : Google Scholar : PubMed/NCBI

18 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Sweetenham JW: Treatment of lymphoblastic lymphoma in adults. Oncology (Williston Park). 23:1015–1020. 2009.PubMed/NCBI

20 

Guo B, Liu L, Yao J, Ma R, Chang D, Li Z, Song T and Huang C: miR-338-3p suppresses gastric cancer progression through a PTEN-AKT axis by targeting P-REX2a. Mol Cancer Res. 12:313–321. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Huang XH, Wang Q, Chen JS, Fu XH, Chen XL, Chen LZ, Li W, Bi J, Zhang LJ, Fu Q, et al: Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated. Hepatol Res. 39:786–794. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Caramuta S, Egyhazi S, Rodolfo M, Witten D, Hansson J, Larsson C and Lui WO: MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. J Invest Dermatol. 130:2062–2070. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Chojnowski JL, Masuda K, Trau HA, Thomas K, Capecchi M and Manley NR: Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse. Development. 141:3697–3708. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Manley NR and Capecchi MR: The role of Hoxa-3 in mouse thymus and thyroid development. Development. 121:1989–2003. 1995.PubMed/NCBI

25 

Zhang X, Liu G, Ding L, Jiang T, Shao S, Gao Y and Lu Y: HOXA3 promotes tumor growth of human colon cancer through activating EGFR/Ras/Raf/MEK/ERK signaling pathway. J Cell Biochem. 119:2864–2874. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Lee RC, Feinbaum RL and Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75:843–854. 1993. View Article : Google Scholar : PubMed/NCBI

27 

Wightman B, Ha I and Ruvkun G: Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 75:855–862. 1993. View Article : Google Scholar : PubMed/NCBI

28 

Guo H, Ingolia NT, Weissman JS and Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 466:835–840. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Bazzini AA, Lee MT and Giraldez AJ: Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science. 336:233–237. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Kohnken R, Porcu P and Mishra A: Overview of the use of murine models in leukemia and lymphoma research. Front Oncol. 7:222017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, L., Sui, M., & Wang, X. (2019). miR‑338‑3p suppresses the malignancy of T‑cell lymphoblastic lymphoma by downregulating HOXA3. Molecular Medicine Reports, 20, 2127-2134. https://doi.org/10.3892/mmr.2019.10451
MLA
Wang, L., Sui, M., Wang, X."miR‑338‑3p suppresses the malignancy of T‑cell lymphoblastic lymphoma by downregulating HOXA3". Molecular Medicine Reports 20.3 (2019): 2127-2134.
Chicago
Wang, L., Sui, M., Wang, X."miR‑338‑3p suppresses the malignancy of T‑cell lymphoblastic lymphoma by downregulating HOXA3". Molecular Medicine Reports 20, no. 3 (2019): 2127-2134. https://doi.org/10.3892/mmr.2019.10451