Downregulation of SMIM3 inhibits growth of leukemia via PI3K-AKT signaling pathway and correlates with prognosis of adult acute myeloid leukemia with normal karyotype

Journal of Translational Medicine

Research

Yafei Li¹  Luyao Shi¹  Yanfang Liu¹  Shujuan Wang¹  Mengya Li¹  Tao Li¹  Zhongxing Jiang¹  Yu Liu¹  Yu Zhang¹  Yufei Chen¹  Chong Wang¹  Lu Yang¹  Yajun Liu² 

[1] Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, 450052, Zhengzhou, China;Department of Orthopaedics, Warren Alpert Medical School/Rhode Island Hospital, Brown University, Providence, Rhode Island, USA;

关键词: Acute myeloid leukemia;    Prognosis;    SMIM3;    Cell proliferation;    Cell cycle;    PI3K-AKT;   

DOI  :  10.1186/s12967-022-03831-8

 received in 2022-10-27, accepted in 2022-12-12,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAcute myeloid leukemia (AML) patients with normal karyotype (NK-AML) have significant variabilities in outcomes. The European Leukemia Net stratification system and some prognostic models have been used to evaluate risk stratification. However, these common standards still have some limitations. The biological functions and mechanisms of Small Integral Membrane Protein 3 (SMIM3) have seldomly been investigated. To this date, the prognostic value of SMIM3 in AML has not been reported. This study aimed to explore the clinical significance, biological effects and molecular mechanisms of SMIM3 in AML.MethodsRT-qPCR was applied to detect the expression level of SMIM3 in bone marrow specimens from 236 newly diagnosed adult AML patients and 23 healthy volunteers. AML cell lines, Kasumi-1 and THP-1, were used for lentiviral transfection. CCK8 and colony formation assays were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to explore relevant signaling pathways. The biological functions of SMIM3 in vivo were validated by xenograft tumor mouse model. Survival rate was evaluated by Log-Rank test and Kaplan–Meier. Cox regression model was used to analyze multivariate analysis. The correlations between SMIM3 and drug resistance were also explored.ResultsThrough multiple datasets and our clinical group, SMIM3 was shown to be significantly upregulated in adult AML compared to healthy subjects. SMIM3 overexpression conferred a worse prognosis and was identified as an independent prognostic factor in 95 adult NK-AML patients. Knockdown of SMIM3 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. The reduced SMIM3 expression significantly suppressed tumor growth in the xenograft mouse model. Western blot analysis showed downregulation of p-PI3K and p-AKT in SMIM3-knockdown AML cell lines. SMIM3 may also be associated with some PI3K-AKT and first-line targeted drugs.ConclusionsSMIM3 was highly expressed in adult AML, and such high-level expression of SMIM3 was associated with a poor prognosis in adult AML. Knockdown of SMIM3 inhibited the proliferation of AML through regulation of the PI3K-AKT signaling pathway. SMIM3 may serve as a potential prognostic marker and a therapeutic target for AML in the future.

【 授权许可】

CC BY   
© The Author(s) 2022

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