Chronic Lymphocytic Leukemia (CLL)

evaluation of AKT protein kinase and microRNA gene expression related to disease pathogenesis

Authors

  • Lorena Caixeta Gomes Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Rodrigo Ribeiro Resende Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Ricardo Cambraia Parreira Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Claúdia Natália Ferreira Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Edna Afonso Reis Department of Statistics, Institute of Exact Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Rita Carolina Figueiredo Duarte Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Luan Carlos Vieira Alves Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil https://orcid.org/0000-0002-9024-8872
  • Sergio Schusterschitz da Silva Araújo Hematology Unit of the Clinical Hospital, Federal University of Minas Gerais, Minas Gerais, Brazil
  • Maria das Graças Carvalho Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil https://orcid.org/0000-0002-1669-3302
  • Adriano Sabino Department of Clinical and Toxicological Analysis, School of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil https://orcid.org/0000-0001-8562-8689

DOI:

https://doi.org/10.1590/s2175-97902022e19946

Keywords:

Chronic Lymphocytic Leukemia, AKT protein kinase, microRNAs, Apoptosis

Abstract

The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.

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References

Admoni-Elisha L, Nakdimon I, Shteinfer A, Prezma T, Arif T, Arbel N, et al. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment. PLoS One. 2016;11(4):e0148500.

Balatti V, Pekarky Y, Croce CM. Role of microRNA in chronic lymphocytic leukemia onset and progression. J Hematol Oncol. 2015;8(12).

Carabia J, Carpio C, Abrisqueta P, Jimenez I, Purroy N, Calpe E, et al. Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia. Sci Rep. 2017;7(1):12262.

Chapman EA, Oates M, Mohammad IS, Davies BR, Stockman PK, Zhuang J, et al. Delineating the distinct role of AKT in mediating cell survival and proliferation induced by CD154 and IL-4/IL-21 in chronic lymphocytic leukemia. Oncotarget. 2017;8(61):102948-64.

Chen CY, Chang JT, Ho YF, Shyu AB. MiR-26 down-regulates TNF-alpha/NF-kappaB signalling and IL-6 expression by silencing HMGA1 and MALT1. Nucleic Acids Res. 2016;44(8):3772-87.

Chen X, Wang K, Xu Z, Li S, Liu Q, Fu D, et al. MiR-133b regulates bladder cancer cell proliferation and apoptosis by targeting Bcl-w and Akt1. Cancer Cell Int. 2014;14(70).

Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M, et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia. 2014;28(3):649-57.

Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.

Di Nicolantonio F, Mercer SJ, Knight LA, Gabriel FG, Whitehouse PA, Sharma S, et al. Cancer cell adaptation to chemotherapy. BMC Cancer. 2005;5:78.

Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259-69.

Ferracin M, Zagatti B, Rizzotto L, Cavazzini F, Veronese A, Ciccone M, et al. MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia. Mol Cancer. 2010;9:123.

Fu X, Han Y, Wu Y, Zhu X, Lu X, Mao F, et al. Prognostic role of microRNA-21 in various carcinomas: a systematic review and meta-analysis. Eur J Clin Invest. 2011;41(11):1245-53.

Gao J, Liu QG. The role of miR-26 in tumors and normal tissues (Review). Oncol Lett. 2011;2(6):1019-23.

Gonçalves RP, Maia DP, Custódio RKA, Machado RPG, Duarte FB, Silva LB. Evaluation of the hematologic profile of patients with chronic lymphocytic leukemia (CLL-B) at a state hemocenter. Rev Bras Hematol Hemoter. 2009;31(4):228-34.

Jayaraman M, Radhakrishnan R, Mathews CA, Yan M, Husain S, Moxley KM, et al. Identification of novel diagnostic and prognostic miRNA signatures in endometrial cancer. Genes Cancer. 2017;8(5-6):566-76.

Larsen JT, Shanafelt TD, Leis JF, LaPlant B, Call T, Pettinger A, et al. Akt inhibitor MK-2206 in combination with bendamustine and rituximab in relapsed or refractory chronic lymphocytic leukemia: Results from the N1087 alliance study. Am J Hematol. 2017;92(8):759-63.

Li J, Liang Y, Lv H, Meng H, Xiong G, Guan X, et al. miR-26a and miR-26b inhibit esophageal squamous cancer cell proliferation through suppression of c-MYC pathway. Gene. 2017;625:1-9.

Li Y, Li J, Sun X, Chen J, Zheng J, Chen R. MicroRNA-27a functions as a tumor suppressor in renal cell carcinoma by targeting epidermal growth factor receptor. Oncol Lett . 2016;11(6):4217-23.

Liu T, Tang H, Lang Y, Liu M, Li X. MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett. 2009;273(2):233-42.

Liu TM, Ling Y, Woyach JA, Beckwith K, Yeh YY, Hertlein E, et al. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells. Blood. 2015;125(2):284-95.

Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479-86.

Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res. 2007;67(22):11001-11.

Nair VS, Maeda LS, Ioannidis JP. Clinical outcome prediction by microRNAs in human cancer: a systematic review. J Natl Cancer Inst. 2012;104(7):528-40.

Palacios F, Abreu C, Prieto D, Morande P, Ruiz S, Fernandez-Calero T, et al. Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation. Leukemia . 2015;29(1):115-25.

Qiu X, Zhu H, Liu S, Tao G, Jin J, Chu H, et al. Expression and prognostic value of microRNA-26a and microRNA-148a in gastric cancer. J Gastroenterol Hepatol. 2017;32(4):819-27.

Rossi S, Shimizu M, Barbarotto E, Nicoloso MS, Dimitri F, Sampath D, et al. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival. Blood. 2010;116(6):945-52.

Salah Z, Arafeh R, Maximov V, Galasso M, Khawaled S, Abou-Sharieha S, et al. miR-27a and miR-27a* contribute to metastatic properties of osteosarcoma cells. Oncotarget . 2015;6(7):4920-35.

Saleh LM, Wang W, Herman SE, Saba NS, Anastas V, Barber E, et al. Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia. Leukemia . 2017;31(2):340-9.

Singh SP, Pillai SY, de Bruijn MJW, Stadhouders R, Corneth OBJ, van den Ham HJ, et al. Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive Btk and Akt signaling. Oncotarget . 2017;8(42):71981-95.

Wang H, Xu W, Shao Q, Ding Q. miR-21 silencing ameliorates experimental autoimmune encephalomyelitis by promoting the differentiation of IL-10-producing B cells. Oncotarget . 2017;8(55):94069-79.

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-4.

Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, et al. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology. 2013;58(1):158-70.

Zhang Y, Zhang B, Zhang A, Li X, Liu J, Zhao J, et al. IL-6 upregulation contributes to the reduction of miR-26a expression in hepatocellular carcinoma cells. Braz J Med Biol Res. 2013;46(1):32-8.

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Published

2022-11-23

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Original Article

How to Cite

Chronic Lymphocytic Leukemia (CLL): evaluation of AKT protein kinase and microRNA gene expression related to disease pathogenesis. (2022). Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-97902022e19946