NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells
Acute lymphoblastic leukemia (ALL) is the most prevalent of pediatric cancers. Neuroepithelial cell-transforming 1 (NET1) has been associated with malignancy in a number of cancers, but the role of NET1 in ALL development is unclear. In the present study, we investigated the effect
of NET1 gene in ALL cell proliferation and chemoresistance. We analyzed GEO microarray data comparing bone marrow expression profiles of pediatric B-cell ALL samples and those of age-matched controls. MTT and colony formation assays were performed to analyze cell proliferation. ELISA assays,
Western blot analyses, and TUNEL staining were used to detect chemoresistance. We confirmed that NET1 was targeted by miR-206 using Western blot and luciferase reporter assays. We identified NET1 gene as one of the most significantly elevated genes in pediatric B-ALL. MTT and colony formation
assays demonstrated that NET1 overexpression increases B-ALL cell proliferation in Nalm-6 cells. ELISA assays, Western blot analyses, and TUNEL staining showed that NET1 contributes to ALL cell doxorubicin resistance, whereas NET1 inhibition reduces resistance. Using the TargetScan database,
we found that several microRNAs (miRNAs) were predicted to target NET1, including microRNA-206 (miR-206), which has been shown to regulate cancer development. To determine whether miR-206 targets NET1 in vitro, we transfected Nalm-6 cells with miR-206 or its inhibitor miR-206-in. Western blot
assays showed that miR-206 inhibits NET1 expression and miR-206-in increases NET1 expression. Luciferase assays using wild-type or mutant 3′-untranslated region (3′-UTR) of NET1 confirmed these findings. We ultimately found that miR-206 inhibits B-ALL cell proliferation and chemoresistance
induced by NET1. Taken together, our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1. This study therefore not only contributes to a greater understanding of the molecular mechanisms
underlying B-ALL progression but also opens the possibility for developing curative interventions.
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Acute lymphoblastic leukemia (ALL);
Neuroepithelial cell-transforming 1 (NET1);
Document Type: Research Article
Department of Hematology, Shenzhen Longhua People’s Hospital, Shenzhen, P.R. China
Department of Hematology, Daqing Oilfield General Hospital, Daqing, P.R. China
Department of Neurology, Shenzhen Longhua People’s Hospital, Shenzhen, P.R. China
August 8, 2019
This article was made available online on April 17, 2019 as a Fast Track article with title: "NET1 enhances proliferation and chemoresistance in Acute Lymphoblastic Leukemia cells".
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