EXT1, Regulated by MiR-665, Promotes Cell Apoptosis via ERK1/2 Signaling Pathway in Acute Lymphoblastic Leukemia

Abstract

BackgroundEXT1 is an endoplasmic reticulum-resident glycosyl transferase whose intracellular expression alters the biosynthesis and distribution of heparan sulfate. EXT1 is regarded as a classic tumor suppressor. MiR-665 can act as either an oncogene or tumor-suppressing gene in different tumors. The aim of the current study was to determine the function and molecular mechanisms of EXT1 and miR-665 in acute lymphoblastic leukemia (ALL).Material/MethodsEXT1 expression in ALL was evaluated by real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of EXT1 in ALL were explored by Cell Counting Kit-8 (CCK-8)/EdU assays, western blotting, flow cytometry, and in vivo tumorigenesis assays. Label-free quantification was used to detect differentially expressed proteins in EXT1-overexpressing Reh cells.ResultsEXT1 expression is downregulated in ALL and negatively correlated with miR-665 expression. Moreover, low EXT1 and high miR-665 expression levels in adult ALL bone marrow tissues are correlated with poor patient survival. Our study showed that EXT1 modulates the proliferation and apoptosis of ALL cells in vitro and in vivo and that miR-665 promotes cell growth and inhibits apoptosis by suppressing EXT1. EXT1 promotes cell apoptosis via deactivating the ERK1/2 pathway.ConclusionsIn conclusion, this study is the first to confirm the association between low EXT1 levels and several clinical features of ALL. Low bone marrow EXT1 levels independently predict poor prognoses in adult ALL patients. Thus, our study suggests that EXT1- or miR-665-targeted strategies can confer the therapeutic effect of promoting apoptosis by deactivating the ERK1/2 pathway.

microRNA‐665 is down‐regulated in gastric cancer and inhibits proliferation, invasion, and EMT by targeting PPP2R2A

“…Zhang et al indicated that up‐regulation of miR‐1297 inhibited GC cell proliferation and induced GC cell apoptosis by directly regulating the CDC6 expression . Numerous studies have found that miR‐665 not only affected cell proliferation but also was closely associated with prognosis in cancers including breast cancer, hepatocellular carcinoma, acute lymphoblastic leukaemia, colorectal cancer, cervical cancer, and ovarian cancer …”

“…Many human miRNAs have been confirmed to be dysregulated in GC, including miR‐32‐5p, miR‐544a, miR‐1297, miR‐625, and miR‐383‐5p . Up to now, miR‐665 has been reported to function as an oncogene in breast cancer, hepatocellular carcinoma, acute lymphoblastic leukaemia, or function as a tumour suppressor in colorectal cancer, cervical cancer, and ovarian cancer; the functions of miR‐665 in GC were rare unexplored previously. Therefore, we investigated the functional roles and its mechanisms of miR‐665 in GC.…”

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

“…Furthermore, mutations in EXT2 have been detected in breast tumor patients, and thyroid cancer [54][55][56]. Epigenetic inactivation of EXT1 by promoter hyper-methylation preventing HS chain synthesis is observed in leukemia and non-melanoma skin cancer [57,58]. An antiproliferative effect of D-glucuronyl C5-epimerase (GLCE) has been ascertained in breast and small lung cancer cells [59][60][61], whereas increased GLCE expression has been associated with advanced stages of prostate tumors [62,63].…”

Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity

“…In addition, EXT1 can be regulated by microRNAs. High miR-655 expression levels, as found in acute lymphoblastic leukemia, were correlated to low EXT1 expression and thus reduced apoptosis and increased cell growth [ 145 ]. Whether cells modulate EXT1 and EXT2 gene expression levels under physiological conditions to generate specific HS structures has not been investigated yet.…”