LINC00942 inhibits ferroptosis and induces the immunosuppression of regulatory T cells by recruiting IGF2BP3/SLC7A11 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high recurrence rate and a poor prognosis. Long intergenic nonprotein coding RNA 942 (LINC00942) is reported to be related to ferroptosis and the immune response in HCC and serves as an oncogene in various cancers. This research aimed to explore the contribution of LINC00942 in HCC progression. Functional assays were used to evaluate the functional role of LINC00942 in vitro and in vivo. Mechanistic assays were conducted to assess the association of LINC00942 with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and solute carrier family 7 member 11 (SLC7A11) and the regulatory pattern of LINC00942 in HCC cells. LINC00942 was found to exhibit upregulation in HCC tissue and cells. LINC00942 facilitated HCC cell proliferation, suppressed ferroptosis, and converted naive CD4+ T cells to inducible Treg (iTreg) cells by regulating SLC7A11. Furthermore, SLC7A11 expression was positively modulated by LINC00942 in HCC cells. IGF2BP3 was a shared RNA-binding protein (RBP) for LINC00942 and SLC7A11. The binding between the SLC7A11 3' untranslated region and IGF2BP3 was verified, and LINC00942 was found to recruit IGF2BP3 to promote SLC7A11 mRNA stability in an m6A-dependent manner. Moreover, mouse tumor growth and proliferation were inhibited, and the number of FOXP3+CD25+ T cells was increased, while ferroptosis was enhanced after LINC00942 knockdown in vivo. LINC00942 suppresses ferroptosis and induces Treg immunosuppression in HCC by recruiting IGF2BP3 to enhance SLC7A11 mRNA stability, which may provide novel therapeutic targets for HCC.

BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

Hsa_circ_0007059 sponges miR-421 to repress cell growth and stemness in hepatocellular carcinoma by the PTEN-AKT/mTOR pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a substantial health concern worldwide. Increasing studies have suggested that circle RNAs (circRNAs) function as new regulators in HCC progression. The present work explored the role of hsa_circ_0007059 (circ_0007059) in the developing process of hepatocarcinogenesis. METHODS: The circ_0007059 level in HCC was determined by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and northern blot. Its biological role in HCC cells was assessed using 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell, sphere formation and western blotting analyses. Bioinformatics analysis, luciferase reporter, and RNA immunoprecipitation (RIP) assays were used to test the regulatory mechanisms of circ_0007059. RESULTS: Our results revealed that circ_0007059 expression was downregulated in HCC samples and cells. Moreover, circ_0007059 overexpression inhibited HCC cell proliferation, migration, invasion, and stem cell-like property, and strengthened cell apoptosis. In mechanism, circ_0007059 suppressed AKT/mTOR pathway by positively regulating phosphatase and tensin homolog (PTEN) expression. Additionally, circ_0007059 acted as a positive regulator of PTEN through controlling the availability of miR-421. Rescue assays demonstrated that PTEN knockdown or SC79 (AKT agonist) eliminated the effect of circ_0007059 on HCC cell phenotypes. CONCLUSION: Circ_0007059 sponges miR-421 to inhibit oncogenic cellular process in HCC by mediating the PTEN-AKT/mTOR pathway.

A Cell Cycle Progression-Derived Gene Signature to Predict Prognosis and Therapeutic Response in Hepatocellular Carcinoma.

OBJECTIVE: Dysregulation of cell cycle progression (CCP) is one of the hallmarks of cancer. Here, our study is aimed at developing a CCP-derived gene signature for predicting high-risk population of hepatocellular carcinoma (HCC). METHODS: Our study retrospectively analyzed the transcriptome profiling and clinical information of HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. Uni- and multivariate cox regression models were conducted for identifying which hallmarks of cancer were risk factors of HCC. CCP-derived gene signature was developed with LASSO method. The predictive efficacy was verified by ROC curves and subgroup analyses. A nomogram was then generated and validated by ROC, calibration, and decisive curves. Immune cell infiltration was estimated with ssGSEA method. Potential small molecular compounds were predicted via CTRP and CMap analyses. The response to chemotherapeutic agents was evaluated based on the GDSC project. RESULTS: Among hallmarks of cancer, CCP was identified as a dominant risk factor for HCC prognosis. CCP-derived gene signature displayed the favorable predictive efficacy in HCC prognosis independent of other clinicopathological parameters. A nomogram was generated for optimizing risk stratification and quantifying risk evaluation. CCP-derived signature was in relation to immune cell infiltration, HLA, and immune checkpoint expression. Combining CTRP and CMap analyses, fluvastatin was identified as a promising therapeutic agent against HCC. Furthermore, CCP-derived signature might be applied for predicting the response to doxorubicin and gemcitabine. CONCLUSION: Collectively, CCP-derived gene signature was a promising marker in prediction of survival outcomes and therapeutic responses for HCC patients.

Down-Regulation of C3aR/C5aR Inhibits Cell Proliferation and EMT in Hepatocellular Carcinoma.

Complement 3a (C3a) and complement 5a (C5a), small cleavage fragments generated by complement activation, has been previously shown to be obviously up-regulated in highly metastatic hepatocellular carcinoma (HCC) cells. However, their functional roles in HCC cells remains unclear. Here, we investigated the biological function of G protein-coupled receptor C3aR/C5aR using small interference RNA in HCC cells. Our data showed that C3aR and C5aR knockdown significantly inhibited the proliferation, migration and invasion of HCC cells using CCK-8, colony formation and transwell assays. Flow cytometry assay showed C3aR and C5aR knockdown induced cell cycle G0/G1 phase arrest and apoptosis in HCC cells. Moreover, we found down-regulation of C3aR/C5aR obviously down-regulated the expression of PCNA, Ki-67 and suppressed the epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) in HCC cells. Collectively, our data demonstrated that targeting C3aR/C5aR may hold promise for the treatment of HCC.

Treatment of severe acute pancreatitis via endoscopic pancreatic stenting and nasopancreatic drainage: Case reports.

Severe acute pancreatitis (SAP) is associated with high mortality. SAP is generally treated by conservative management at the early phase, and removal of the pancreatic and peripancreatic necrotic tissue at the late phase. However, studies have suggested that the surgical treatment of SAP should focus on pressure reduction and drainage. In this case report, 3 SAP patients of 44, 30 and 60 years of age were treated at the General Hospital of Ningxia Medical University. They underwent emergency endoscopic pancreatic stenting at the early phase and nasopancreatic drainage at the late phase when peripancreatic encapsulated effusion was observed. All patients were successfully treated and discharged from the hospital. The disease duration of the patients was 71, 58, and 88 days, respectively. Our cases suggested that the surgical strategy of endoscopic pancreatic stenting at the early phase and nasopancreatic drainage at the late phase is promising for the treatment of SAP.

Oxaliplatin reverses the GLP-1R-mediated promotion of intrahepatic cholangiocarcinoma by altering FoxO1 signaling.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, with a 5-year survival rate of <10%; effective drug treatment for ICC is currently lacking. Glucagon-like peptide-1 receptor (GLP-1R) is upregulated in ICC; however, the functions of GLP-1R in ICC remain unknown. In this study, the upregulation of GLP-1R was confirmed in ICC cells using reverse transcription-quantitative polymerase chain reaction and western blot analysis, and GLP-1R was determined to promote the migration and invasion of ICC cells using Transwell assays. This tumor-promoting effect depended on the upregulation of epithelial-mesenchymal transformation-associated proteins, which was mediated by the FoxO1 signaling pathway. It was also indicated that following oxaliplatin treatment, the effects of GLP-1R on EMT and invasion were reversed. This functional reversion was associated with the reduced phosphorylation of S256 in forkhead box O1 (FoxO1) and an increase in the levels of unphosphorylated FoxO1. These findings suggest that incretin-based therapies may increase the risk of ICC metastasis and should not be used solely for the treatment of patients with ICC.