NEAT1 paraspeckle promotes human hepatocellular carcinoma progression by strengthening IL-6/STAT3 signaling

Abstract

The formation of paraspeckle, a stress-induced nuclear body, increases in response to viral infection or proinflammatory stimuli. Paraspeckle consists of lncRNA (nuclear paraspeckle assembly transcript 1, NEAT1) and protein components including NONO, SFPQ, PSPC1, etc., which are shown to be involved in viral infection and cancer. Both NEAT1 and NONO expression increase in human hepatocellular carcinoma (HCC) samples according to TCGA data. However, the role of paraspeckle in HCC progression needs further identification. IL-6 signaling is well known to contribute to HCC progression. Here we reported that IL-6 signaling increased paraspeckle formation in HCC cells. Destruction of paraspeckle formation by silencing the paraspeckle essential components NEAT1_2 or NONO could suppress IL-6induced STAT3 phosphorylation in HCC cells, and consequently repressed IL-6-promoted in vitro HCC cell invasion, cell cycle progression and survival. Mechanistically, paraspeckle promotes IL-6-induced STAT3 phosphorylation by binding and trapping peroxiredoxin-5 (PRDX5) mRNA in nucleus, decreasing protein level of PRDX5 which can directly interact with STAT3 and inhibit STAT3 phosphorylation. Besides, glutathione S-transferase P (GSTP1) protein, which inhibits DNA damage and apoptosis through its detoxification and anti-oxidation function, was also trapped within paraspeckles under IL-6 stimulation. Paraspeckle-trapping of both PRDX5 mRNA and GSTP1 protein contributes to IL-6-increased DNA damage in HCC cells. Our results demonstrate that paraspeckle can nuclear entrap the inhibitors of IL-6/ STAT3 signaling as well as DNA damage, and then strengthen the promoting effect on HCC progression by IL-6. Therefore, paraspeckle contributes to the inflammation-related HCC progression and might be a potential therapeutic target for HCC.

Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

“…Mechanistically, upregulation of NEAT1 in GSCs under ADV infection could be attributed to TLR9 activation, and knockdown of NEAT1 was accompanied by an inhibition of STAT3 expression and phosphorylation. This is consistent with several reports showing that NEAT1 promotes cancer progression by enhancing STAT3 signaling [48][49][50] .…”

“…These results, in combination with literatures, suggested that NEAT1 is downstream to TLR9-MYD88 and regulates STAT3 46,[48][49][50] .…”

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…Accelerated loss of white adipose tissue is a salient characteristic of cachexia. IL-6 signaling through STAT3 has been shown to control this process, as evidenced by inhibition of white adipose tissue lipolysis in mice treated with anti-IL-6R antibody (Babaei et al, 2018;Wang et al, 2018a). Additionally, STAT3 is thought to be involved in cachexia-related adipose tissue breakdown by modulating enzymes involved in lipolysis.…”

Long non‐coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen‐activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma

“…In HCC, lncRNA‐ATB, a mediator of transforming growth factor‐β signaling, could predispose HCC patients to metastases and could serve as a potential target for antimetastatic therapies . NEAT1 paraspeckle promotes human HCC progression by strengthening interleukin‐6/signal transducer and activator of transcription 3 signaling . DSCR8 activates the Wnt/β‐catenin pathway to promote HCC progression by the DSCR8/microRNA (miR)‐485‐5p/FZD7 axis .…”

“…8 NEAT1 paraspeckle promotes human HCC progression by strengthening interleukin-6/signal transducer and activator of transcription 3 signaling. 9 DSCR8 activates the Wnt/β-catenin pathway to promote HCC progression by the DSCR8/microRNA (miR)-485-5p/FZD7 axis. 10 The findings provide promising and valuable strategies for targeted therapy of HCC.…”