Abstract
Recent studies have shown that the microtubule disrupting protein Stathmin 1 (STMN1) is differentially expressed in AML patients and healthy control. The aim of this study was to explore the effects and molecular mechanism of STMN1 in AML. Here, the expression of STMN1 in peripheral blood cells (PBMCs) and bone marrow of AML patients and healthy volunteers was detected by RT-PCR and Western blot. STMN1 expression was regulated by transfected with STMN1 overexpressed plasmid or shRNA in two human leukemia cell lines K562 and HL60. Cell proliferation was examined by CCK8 and Edu staining. Annexin V and TUNEL assays were applied to test cell apoptosis. Flow cytometry was used to test the cell cycle distribution. The activation of the PI3K signaling pathway and the expression levels of cell cycle and cell apoptosis-related protein were determined by Western blot. In this study, we found that STMN1 was overexpressed in PBMCs and bone marrow of AML patients. STMN1 expression was closely related to FAB subtypes, risk stratification, disease-free survival, and overall survival of AML. Functional assays showed that overexpression of STMN1 in HL60 and K562 cells enhanced cell proliferation, decreased cell apoptosis, and caused G1 phase arrest. In contrast, suppression of STMN1reduced cell proliferation and enhanced cell apoptosis in both HL60 and K562 cells. Moreover, the PI3K/Akt pathway was activated by STMN1, while suppression of STMN1 dysregulated the PI3K/Akt pathway and upregulating the levels of caspases3 and Bax expression. In conclusion, STMN1 was confirmed to promote the proliferation and inhibit the apoptosis of HL60 and K562 cells by modulating the PI3K/Akt pathway. STMN1 might be a novel molecular target for treating AML.
Highlights
As the most common type of acute leukemia, the pathophysiology of acute myeloid leukemia (AML) involves the maturational arrest of bone marrow cells and the activation or inactivation of genes that contribute to genomic instability (Ghiaur et al, 2015)
Stathmin 1 (STMN1) expression is induced in AML patients The expression of STMN1 in the PBMCs and bone marrow from 30 patients with AML and 10 healthy control was detected, and our analysis showed that the levels of STMN1 mRNA expression were significantly elevated in the PBMCs and bone marrow of AML patients when compared with their levels in healthy control subjects (Figs. 1A and 1B)
STMN1 expression was closely related to the disease-free survival time and overall survival time of AML patients We found that STMN1 expression was not related to patient age, sex, or white blood cell (WBC) (p > 0.05)
Summary
As the most common type of acute leukemia, the pathophysiology of acute myeloid leukemia (AML) involves the maturational arrest of bone marrow cells and the activation or inactivation of genes that contribute to genomic instability (Ghiaur et al, 2015). Cytogenetic markers are considered as the most important factors for risk classification and selecting a treatment for AML patients (De Kouchkovsky and Abdul-Hay, 2016). The identification of new biomarkers has increased our understanding of the molecular mechanism of AML, and those markers can be used to predict the results of therapy (De Kouchkovsky and Abdul-Hay, 2016). Recent findings show that STMN1 is highly expressed in various types of human cancers and plays critical roles in regulating tumor progression (Rana et al, 2008; Belletti and Baldassarre, 2011). STMN1 induces cell proliferation, migration, and differentiation in several types of solid tumors, andSTMN1 expression is related to the prognosis of tumor patients (Hsieh et al, 2010; Zheng et al, 2010; Zhang et al, 2019).
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