Abstract Our previous studies have indicated that long noncoding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4‐IT1) was highly expressed in hepatocellular carcinoma (HCC). However, it still remained unclear how SPRY4‐IT1 worked in tumorgenesis in HCC. In this study, we tested the overexpression of SPRY4‐IT1 in HCC tissues and cells through a quantitative real‐time polymerase chain reaction. Statistical analyses showed that the upregulation had an association with the tumor node metastasis stage, thrombin time, and alkaline phosphatase. Furthermore, SPRY4‐IT1 could be involved in cell proliferation, metastasis, and the epithelial‐to‐mesenchymal transition (EMT) process in HCC in vitro and in vivo. RNA‐sequencing and transcriptome analysis were carried out to explore the mechanism of SPRY4‐IT1 in HCC. With SPRY4‐IT1 being knocked down or overexpressed, the level of proteins in the tumor necrosis factor (TNF) signaling pathway changed. We detected the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a SPRY4‐IT1 interacting protein through RNA pull‐down assay and liquid chromatography–mass spectrometry, then verified through RNA immunoprecipitation. Downregulation of HNRNPL induced the change of proteins observed on SPRY4‐IT1 downregulation revealing the SPRY4‐IT1: HNRNPL complex in the TNF signaling pathway and EMT process in HCC. In general, our experimental data and analysis demonstrated the role of SPRY4‐IT1 in promoting progress and metastasis of HCC by the TNF signaling pathway.
Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, accounting for over 700,000 deaths each year. The lack of predictive and prognostic biomarkers for HCC, with effective therapy, remains a significant challenge for HCC management. Long non-coding RNAs (lncRNAs) play a key role in tumorigenesis and have clinical value as potential biomarkers in the early diagnosis and prediction of HCC. Jun activation domain-binding protein 1 (Jab1, also known as COP9 signalosome subunit 5, CSN5) is a potential oncogene that plays a critical role in the occurrence of HCC. Here, we performed a comprehensive analysis for Jab1/CSN5-associated lncRNAs to predict the prognosis of HCC. The differentially expressed (DE) lncRNAs between in HCC were analyzed based on the TCGA RNA-seq data. We detected 1031 upregulated lncRNAs in 371 HCC tissues and identified a seven-lncRNA signature strongly correlated with Jab1/CSN5 (SNHG6, CTD3065J16.9, LINC01604, CTD3025N20.3, KB-1460A1.5, RP13-582O9.7, and RP11-29520.2). We further evaluated the prognostic significance of these lncRNAs by GEPIA ( http://gepia.cancer-pku.cn/ ). The expression data in 364 liver tumors indicated that this seven-lncRNA signature could better predict worse survival in HCC patients. Moreover, 35 clinical HCC samples were evaluated to assess the validity and reproducibility of the bioinformatic analysis. We found that the targeted lncRNAs were upregulated, with a strong association with Jab1/CSN5 and prognostic value in HCC. Functional enrichment analysis by Gene Ontology (GO) showed that these seven prognostic lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer. Overall, our findings demonstrate the clinical implication of Jab1/CSN5 with the seven‐lncRNAs in predicting survival for patients with HCC.
Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6‐adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real‐time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c‐Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ( ENO1 ), triosephosphate isomerase 1 ( TPI1 ), solute carrier family 2 member 1 ( SLC2A1 ), and pyruvate kinase M2 ( PKM2 ). The c‐Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c‐Myc protein and inhibited K48‐linked polyubiquitination of c‐Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c‐Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX‐bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300‐METTL5‐USP5‐c‐Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.
Abstract Background Aberrant lipid metabolism marks one of characteristic features of hepatocellular carcinoma (HCC). Here, we define the function and mechanism of CAND1 in lipid metabolism and progression of HCC in vitro and in vivo, and postulate CAND1/FBXO11/hnRNPA2B1 as a suitable therapeutic target for HCC. Methods We performed IHC staining, western blot analysis and prognostic analyses of CAND1 in HCC to define its prognostic value. The functions of CAND1 were evaluated through in vitro and in vivo experiments. RNA-Seq and lipidomic assays followed by serial biochemical experiments including mass spectrometry, immunoprecipitation, GST pulldown, and ubiquitination were performed to dissect the underlying mechanism. Results CAND1 was highly expressed in HCC tissues and cell lines and served as an independent prognostic risk factor for HCC. CAND1 promoted HCC cell proliferation, colony formation, migration, and invasion in vitro. CAND1 facilitated tumor growth and metastasis in vivo. Mechanism studies demonstrated that CAND1 promoted lipid synthesis through disrupting Skp1-Cul1-FBXO11 complex assembly. Furthermore, we identified hnRNPA2B1 as a novel FBXO11-binding partner mediating CAND1 function. FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 lysine 27 (K27)- and K48-linked ubiquitination and subsequent degradation. Interfering CAND1 by shRNA significantly reduced tumor burden in primary mouse liver cancer model and PDX model. Conclusions CAND1 promoted HCC and regulated lipid synthesis by upregulating hnRNPA2B1 through dissociating Skp1-Cul-FBXO11 complex, which caused hnRNPA2B1 ubiquitination and degradation. Targeting CAND1-SCF FBXO11 -hnRNPA2B1 axis may be a novel strategy against HCC.
Hepatocellular carcinoma (HCC) is leading cause of tumor-related deaths worldwide. The intracellular chloride channel protein (CLIC1) plays a role in the occurrence and progression of HCC, although the underlying mechanisms are still unclear. We evaluated the CLIC1 mRNA and protein levels in both patient tissues and HCC cell lines, and analyzed the correlation between CLIC1 expression and clinical features. The biological function of CLIC1 in HCC was examined in vivo and in vitro. The upstream regulatory factors were identified by bioinformatics programs, and downstream mechanisms affecting HCC behavior have also been explored and validated. CLIC1 was up-regulated in HCC tissues and cell lines, and promoted the proliferation, invasion and migration of HCC cells in vivo and in vitro. TP53 was identified as the upstream transcription factor of CLIC1. MiR-122-5p also regulated CLIC1 levels by degrading the transcripts. More importantly, we found that the increased CLIC1 was significantly related to the activation of MYC signaling. By binding with MYC, CLIC1 enhanced the transcription activity of MYC to downstream genes, rather than by altering its expression. Finally, a positive feedback regulatory loop between CLIC1 and MYC was established. CLIC1 is closely related to the occurrence, progression and prognosis of HCC, and a promising novel therapeutic target.
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide with limited therapeutic options. Accumulating evidences suggest that immunotherapy could be a promising option for treating HCC. T cell-associated immunotherapy lights up the hope for the improvement of complementary approach to conventional HCC treatments, which needs further research to consummate the clinical consequences. The present work reviewed several T cells associated cellular immunotherapies for HCC, including immune checkpoint blockade, gene–engineered T cells, bispecific T cell engagers, and so on. We also analyzed how these immunotherapies can mediate tumor cell eradication and evaluated their superiority or insufficiency.
Real time information retrieval enables stay in sync with the network devices' status. Solutions based on polling, are not optimal in network deployments, the devices have to interrupt their processes to send the information, which is received with some delay and may be critical for many applications. YANG push notifications define a mechanism to subscribe and to push for YANG datastore updates, improving the performance of previous technologies. This work demonstrates for the first time the implementation of YANG push notifications on an Open Terminal based on OpenConfig models.
Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data.
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