ABSTRACT
Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.
Subject(s)
Carcinoma, Hepatocellular/genetics , Gene Expression Regulation, Neoplastic/genetics , Mitochondrial Dynamics/genetics , RNA, Long Noncoding/genetics , Animals , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice, Nude , Proto-Oncogene Mas , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
OBJECTIVE: To investigate the levels of FasL mRNA in peripheral blood mononualear cells (PBMCs), serum soluble Fas ligand (sFasL) and their regulatory effect on T lymphocyte subsets in patients with severe acute pancreatitis (SAP). METHODS: Forty-eight patients with pancreatitis were randomly divided into two groups: 20 cases with SAP and 28 cases with mild acute pancreatitis (MAP). Twenty-eight healthy volunteers were selected as control group. The expression of FasL mRNA in PBMCs was detected by real-time quantitative PCR(qRT-PCR), and serum sFasL was measured by ELISA. T lymphocyte subsets in peripheral blood were detected by flow cytometry. RESULTS: Compared with control group and MAP group, FasL mRNA of PBMCs and serum sFasL increased significantly in SAP group (P<0.05), a little increase in MAP group, and there was no significant difference between MAP group and control group (P>0.05). The CD4(+) T cell ratio, CD4(+)/CD8(+) ratio decreased significantly in SAP group (P<0.05) vs control group and MAP group), and they were found negatively related to FasL mRNA, serum sFasL level. CONCLUSION: The SAP patients showed the significantly increased FasL mRNA of PBMCs and serum sFasL and decreased CD4(+) T-cell ratio, CD4(+)/CD8(+) ratio. FasL may mediate the apoptosis of T lymphocytes.
Subject(s)
Fas Ligand Protein/blood , Fas Ligand Protein/genetics , Pancreatitis/genetics , Pancreatitis/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Acute Disease , Adult , Case-Control Studies , Fas Ligand Protein/chemistry , Fas Ligand Protein/metabolism , Humans , Middle Aged , Pancreatitis/blood , RNA, Messenger/genetics , RNA, Messenger/metabolism , SolubilityABSTRACT
BACKGROUND: Severe acute pancreatitis (SAP) is a dangerous illness with high mortality where most patients do not die of excessive inflammation, but die of immunosuppression and multiple infections at a later stage. The mechanism of immunosuppression in SAP is unknown. AIM: The purpose of this study was to analyze the role of Fas expression on the occurrence of immunosuppression in patients with SAP. METHODS: Forty-eight patients with pancreatitis were divided into two groups: 20 cases with SAP (7 cases with sepsis, 13 cases without sepsis) and 28 cases with mild acute pancreatitis (MAP). Twenty-eight healthy volunteers were selected as controls. Fas mRNA expression in peripheral blood was detected by qPCR and Fas protein of lymphocyte membranes; T lymphocyte subsets and expression of monocyte Human leukocyte antigen DR (HLA-DR) in peripheral blood were detected by flow cytometry. RESULTS: Compared with MAP and control groups, expression level of Fas mRNA and lymphocyte Fas protein in peripheral blood were significantly increased in the SAP group (all P < 0.01). There was a further significant increase in the SAP group with sepsis compared to those without sepsis (all P < 0.01). The CD4(+) T cell ratio, CD4(+)/CD8(+) ratio and monocyte HLA-DR expression in the SAP group were decreased significantly compared with MAP and control groups (all P < 0.01). Significant negative relationships were observed between Fas mRNA expression and CD4(+) T-cell ratio, CD4(+)/CD8(+) ratio, and monocyte HLA-DR expression in SAP patients with sepsis (all P < 0.05). CONCLUSIONS: The results suggest that expression level of Fas is related to severity and immune status of pancreatitis. Overexpression of Fas may lead to the occurrence of immunosuppression and sepsis.
