ABSTRACT
Introduction: DEAD-box helicase 27 (DDX27) belongs to DEAD-Box nucleic acid helicase family. The function of DDX27 in hepatocellular carcinoma (HCC) remain enigmatic. In light of this, we tried to investigate the regulatory role and underlying mechanism of DDX27 in HCC. Materials and methods: DDX27 expression levels were detected by qRT-PCR, Western blot and immunohistochemistry assays in HCC tissues and cells. Colony formation, CCK-8, growth curve, wound healing and transwell assays were conducted to investigate the effect of DDX27 on the proliferation and metastasis of HCC cells. RNA-sequencing was performed to detect the effect of DDX27 on downstream signaling pathway. The effect of DDX27 on HCC progression was evaluated using in vivo murine xenograft model. Results: we found an increased expression of DDX27 in HCC tissues with comparison to its para-tumor tissues. The high expression levels of DDX27 were associated with poor prognosis in HCC patients. DDX27 upregulation promoted cell metastasis. Mechanistic studies suggested that DDX27 overexpression induces the major vault protein (MVP) expression and enhances the phosphorylation levels of ERK1/2. Inhibition of ERK pathway impaired the cellular metastastic abilities induced by DDX27. The induction of DDX27 in HCC progression was further confirmed from tumors in mouse model. Conclusion: our results disclose a novel mechanism by which DDX27 enhances ERK signaling during HCC progression. DDX27 might be used in targeted therapy for HCC patients.
Subject(s)
Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , DEAD-box RNA Helicases/genetics , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , MAP Kinase Signaling System , Adult , Aged , Animals , Biomarkers, Tumor , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , DEAD-box RNA Helicases/metabolism , Disease Models, Animal , Disease Progression , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Kaplan-Meier Estimate , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Mice , Middle Aged , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , PrognosisABSTRACT
COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1, anti-IL-6, anti-TNF, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNF, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.
