Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Abstract

Hypoxia inducible factor-1α (HIF-1α) is an important transcription factor, which plays a critical role in the formation of solid tumor and its microenvironment. The objective of the present study was to evaluate the expression and function of HIF-1α in human leukemia bone marrow stromal cells (BMSCs) and to identify the downstream targets of HIF-1α. HIF-1α expression was detected at both the RNA and protein levels using real-time PCR and immunohistochemistry, respectively. Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) were detected in stromal cells by enzyme-linked immunosorbent assay. HIF-1α was blocked by constructing the lentiviral RNAi vector system and infecting the BMSCs. The Jurkat cell/BMSC co-cultured system was constructed by putting the two cells into the same suitable cultured media and conditions. Cell adhesion and secretion functions of stromal cells were evaluated after transfection with the lentiviral RNAi vector of HIF-1α. Increased HIF-1α mRNA and protein was detected in the nucleus of the acute myeloblastic and acute lymphoblastic leukemia compared with normal BMSCs. The lentiviral RANi vector for HIF-1α was successfully constructed and was applied to block the expression of HIF-1α. When HIF-1α of BMSCs was blocked, the expression of VEGF and SDF-1α secreted by stromal cells was decreased. When HIF-1α was blocked, the co-cultured Jurkat cell's adhesion and migration functions were also decreased. Taken together, these results suggest that HIF-1α acts as an important transcription factor and can significantly affect the secretion and adhesion functions of leukemia BMSCs.

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

“…34 It has been shown that silencing HIF-1 α in Jurkat cells significantly decreased their migration and infiltration capacity. 35 In this study, TPL combined with IDA reduced both protein and mRNA levels of HIF-1 α in LSC-like cells (Figures 5b and c). In addition, the expression levels of HIF-1 α downstream genes, such as BNIP3, VEGF and CAIX, were also reduced (Figure 5b).…”

Bioinformatics-based Prediction of the mechanism and targets for BushenjieduDecoction in preventing relapse of acute leukemia

“…For example, HIF-1αhigh-expression-mediated microenvironment hypoxia in MSC is one of the important triggers of the niches tumorous process (37). Hypoxia can not only enhance the adhesion and chemotaxis between LSC and MSC, but also reduce the sensitivity of LSC to chemotherapy drugs (39,40).…”

High Throughput Bioinformatics-based Prediction of the targets for BushenjieduDecoction in preventing relapse of acute leukemia

“…For example, HIF-1αhigh-expression-mediated microenvironment hypoxia in MSC is one of the important triggers of the niches tumorous process (37). Hypoxia can not only enhance the adhesion and chemotaxis between LSC and MSC, but also reduce the sensitivity of LSC to chemotherapy drugs (39,40). Down regulated expression of HIF-1αin MSC can improve hypoxia in niches and suppress the activity and invasion of LSC (41).…”