Splicing factor hnRNPA2B1 contributes to tumorigenic potential of breast cancer cells through STAT3 and ERK1/2 signaling pathway

Abstract

Increasing evidence has indicated that the splicing factor hnRNPA2B1 plays a direct role in cancer development, progression, gene expression, and signal transduction. Previous studies have shown that knocking down hnRNPA2B1 in breast cancer cells induces apoptosis, but the mechanism and other functions of hnRNPA2B1 in breast cancer are unknown. The goal of this study was to investigate the biological function, clinical significance, and mechanism of hnRNPA2B1 in breast cancer. The expression of hnRNPA2B1 in 92 breast cancer and adjacent normal tissue pairs was analyzed by immunohistochemical staining. Stable clones exhibiting knockdown of hnRNPA2B1 via small hairpin RNA expression were generated using RNA interference technology in breast cancer cell lines. The effects of hnRNPA2B1 on cell proliferation were examined by MTT and EdU assay, and cellular apoptosis and the cell cycle were examined by flow cytometry. A nude mouse xenograft model was established to elucidate the function of hnRNPA2B1 in tumorigenesis in vivo. The role of hnRNPA2B1 in signaling pathways was investigated in vitro. Our data revealed that hnRNPA2B1 was overexpressed in breast cancer tissue specimens and cell lines. Knockdown of hnRNPA2B1 reduced breast cancer cell proliferation, induced apoptosis, and prolonged the S phase of the cell cycle in vitro. In addition, hnRNPA2B1 knockdown suppressed subcutaneous tumorigenicity in vivo. On a molecular level, hnRNPA2B1 knockdown decreased signal transducer and activator of transcription 3 and extracellular-signal-regulated kinase 1/2 phosphorylation. We concluded that hnRNPA2B1 promotes the tumorigenic potential of breast cancer cells, MCF-7 and MDA-MB-231, through the extracellular-signal-regulated kinase 1/2 or signal transducer and activator of transcription 3 pathway, which may serve as a target for future therapies.

β-Asarone Inhibits Invasion and EMT in Human Glioma U251 Cells by Suppressing Splicing Factor HnRNP A2/B1

“…To explore the molecular events downstream of hnRNP A2/B1, we first determined the expression of matrix metalloproteinases (MMPs) and STAT3, which are highly associated with the invasion and EMT of tumor cells and are modulated by hnRNP A2/B1 [ 10 , 17 , 18 , 19 ], after U251 cells were treated with β-asarone (60 µM) for different times. Our Western blotting results ( Figure 7 A) showed that β-asarone significantly reduced the MMP-9 protein expression in U251 cells at timepoints 12, 24 and 48 h. Moreover, β-asarone also significantly reduced the expression of p-STAT3 in U251 cells at timepoints 24 and 48 h. Furthermore, we determined the role of hnRNP A2/B1 in the down-regulation of MMP-9 and p-STAT3 by β-asarone.…”

hnRNPA2B1 inhibits the exosomal export of miR-503 in endothelial cells

“…Moreover, hnRNAP2B1 has been found to be a circulating biomarker of lung cancer [57] and a dual mediator of the development of breast cancer. First, hnRNPA2B1 is associated with the loss of breast cancer susceptibility gene 1 (brca1) [58] and, second, by being a regulator of the STAT3-ERK1/2-signaling pathway [59]. hnRNPA2B1 has also been linked to the efficiency of chemotherapy in vitro: Inhibition of hnRNPA2B1 expression improved chemosensitivity to gemcitabine, 5-fluorouracil (5-FU), and oxaliplatin in pancreatic cancer cell lines [60].…”

Quantitative SWATH-Based Proteomic Profiling for Identification of Mechanism-Driven Diagnostic Biomarkers Conferring in the Progression of Metastatic Prostate Cancer

“…The heterogeneous nuclear riboprotein A2/B1 is an oncogene that controls the sorting of miRNAs into exosomes through binding to specific motifs. Evidence has suggested HNRNPA2B1 playing a direct role in cancer initiation, development, gene expression, and signal transduction (35). HNRNPA2B1 affects the major hallmarks of cancer by promoting proliferative signaling, change of cellular energetics, and suppressing tumor-promoting inflammation and invasion and metastasis.…”

“…HNRNPA2B1 contributes in activating cyclo-oxygenase 2, which eventually leads to tumor growth, promoting EMT through ERK/SNAIL signaling reduced cell proliferation and prolonged S-phase and suppressed subcutaneous tumorigenicity. Knockdown of HNRNPA2B1 can lead to suppression in subcutaneous tumors in vivo models (35). Another study revealed that HNRNPA2B1 promotes EMT by downregualting E-cadherin and upregulated of mesenchymal markers such as N-cadherin and vimentin and also promotes invasion potential at in vitro and in vivo BALB/C-nu/nu mice (36).…”