HnRNPA2B1 promotes the proliferation of breast cancer MCF-7 cells via the STAT3 pathway.

HnRNPA2/B1 is highly expressed in many tumors. However, the role of hnRNPA2/B1 in breast cancer is not clear. In this study, we found the proliferation rate was decreased after knockout of hnRNPA2/B1 by CRISPR-CAS9 in MCF-7 cells, as demonstrated by the reduced expression of CDK4 and p-AKT, and the increased expression of P27. Besides this, the western blot results showed that knockout of hnRNPA2/B1 increased the rate of apoptosis and declined autophagy. By in vivo assay, we found that knockout of hnRNPA2/B1 suppressed tumor growth in a xenograft mouse model. Immunohistochemical staining results confirmed knockout of hnRNPA2/B1 impaired tumor angiogenesis, as illustrated by downregulated expression of VEGF-A. Besides this, interacting proteins with hnRNPA2/B1 were identified by mass spectrometry and the PPI network was constructed. GO analysis suggests that the Interacting proteins are mainly enriched in the Wnt signaling pathway, tumor necrosis factor-mediated signaling pathway, translation, and so on. We then identified hnRNPA2/B1 interacted with signal transducer and activator of transcription 3 (STAT3), as supported by the colocalization of hnRNPA2/B1 and STAT3. Meanwhile, knockout of hnRNPA2/B1 inhibited the phosphorylation of STAT3. Collectively, our results demonstrate that hnRNPA2/B1 promotes tumor cell growth in vitro and in vivo by activating the STAT3 pathway, regulating apoptosis and autophagy.

NPM promotes hepatotoxin-induced fibrosis by inhibiting ROS-induced apoptosis of hepatic stellate cells and upregulating lncMIAT-induced TGF-ß2.

Liver fibrosis is caused by a variety of chronic liver injuries and has caused significant morbidity and mortality in the world with increasing tendency. Elucidation of the molecular mechanism of liver fibrosis is the basis for intervention of this pathological process and drug development. Nucleophosmin (NPM) is a widely expressed nucleolar phosphorylated protein, which is particularly important for cell proliferation, differentiation and survival. The biological role of NPM in liver fibrosis remains unknown. Here we show that NPM promotes liver fibrosis through multiple pathways. Our study found that NPM was up-regulated in cirrhosis tissues and activated in hepatic stellate cells (HSCs). NPM inhibition reduced liver fibrosis markers expression in HSCs and inhibited the HSCs proliferation and migration. In mice model, NPM knockdown in HSCs or application of specific NPM inhibitor can remarkably attenuate hepatic fibrosis. Mechanistic analysis showed that NPM promotes hepatic fibrosis by inhibiting HSCs apoptosis through Akt/ROS pathway and by upregulating TGF-ß2 through Akt-induced lncMIAT. LncMIAT up-regulated TGF-ß2 mRNA by competitively sponging miR-16-5p. In response to liver injury, hepatocytes, Kupffer cells and HSCs up-regulated NPM to increase TGF-ß2 secretion to activate HSCs in a paracrine or autocrine manner, leading to increased liver fibrosis. Our study demonstrated that NPM regulated hepatotoxin-induced fibrosis through Akt/ROS-induced apoptosis of HSCs and via the Akt/lncMIAT-up-regulated TGF-ß2. Inhibition of NPM or application of NPM inhibitor CIGB300 remarkably attenuated liver fibrosis. NPM serves a potential new drug target for liver fibrosis.