Mesencephalic Astrocyte‐Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin‐Related Modifier (SUMO)ylation‐Related Suppression of NF‐κB/Snail Signaling Pathway and Epithelial‐Mesenchymal Transition

Abstract

Background and Aims Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an ER stress‐inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. Approach and Results Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse‐free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor‐node‐metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte‐specific deletion of MANF accelerated N‐nitrosodiethylamine (DEN)‐induced HCC by up‐regulating Snail1+2 levels and promoting epithelial‐mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF‐α)‐treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up‐regulated NF‐κB downstream target genes TNF‐α, interleukin (IL)‐6 and IL‐1α expression in vitro and in vivo. Finally, small ubiquitin‐related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. Conclusions MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF‐κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

“…The endogenous NO produced by tumor cells and tumor vascular endothelial cells plays an important role in promoting tumor angiogenesis and ensuring the maximum blood supply of tumors. Tumor angiogenesis is the basis of tumor growth and metastasis [88].…”

“…The transcription factors NF-κB and STAT3 are involved in inflammation and tumorigenesis and regulate cell survival, growth, and proliferation [97]. Many cytokines involved in the inflammatory response, such as TNF and IL-1, are involved in the activation of the NF-κB signaling pathway [88]. Activation of the STAT3 pathway also primarily depends on the corresponding inflammatory cytokines, such as IL-6, IL-10, and VEGF [98,99].…”

Pseudomonas Aeruginosa Secreted Protein PA3611 Promotes Bronchial Epithelial Cells Epithelial-Mesenchymal Transition Through TGF-β1 Inducing p38/miRNA/NF-κB Pathway

“…A lot of studies have revealed that NF-κB and p65 phosphorylation play a key role in the EMT process [17][18][19][20]. In order to clarify the effect of PA3611 on the expression of p65 p-p65 and EMT process, 16HBE and RTE cells were treated with PBS (negative control), TGF-β1 (2ng/ mL positive control), PA3611 (30ug/mL), and PA3611 (30ug/mL) + TGF-β1 neutralizing antibody (10μg/mL) for 24 hs, the results indicated that: TGF-β1 and PA3611 increased the expression of p-p65, α-SMA and Vimentin and decreased the expression of E-cadherin and Zo-1 obviously compared with PBS group, while PA3611 + TGF-β1 neutralizing antibody signi cantly decreased the expression of p-p65, α-SMA and Vimentin, and promoted the expression of E-cadherin and Zo-1, of which the change trend was similar to that in PBS group (Fig 2 B-H).…”

Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury

“…Recently, we reported that in comparison to liver cancer tissues in HCC patients, the MANF level was higher in the adjacent noncancer tissues of the same patient. MANF also acts as a cancer suppressor by inhibiting the NF- κ B/Snail signal pathway in HCC progression [ 16 ]. However, how hepatic MANF expression is affected by alcohol exposure and whether MANF can contribute to the hepatocyte survival in alcohol-induced liver injury remain unknown.…”