Differences between migrasome, a 'new organelle', and exosome.

The migrasome is a new organelle discovered by Professor Yu Li in 2015. When cells migrate, the membranous organelles that appear at the end of the retraction fibres are migrasomes. With the migration of cells, the retraction fibres which connect migrasomes and cells finally break. The migrasomes detach from the cell and are released into the extracellular space or directly absorbed by the recipient cell. The cytoplasmic contents are first transported to the migrasome and then released from the cell through the migrasome. This release mechanism, which depends on cell migration, is named 'migracytosis'. The main components of the migrasome are extracellular vesicles after they leave the cell, which are easy to remind people of the current hot topic of exosomes. Exosomes are extracellular vesicles wrapped by the lipid bimolecular layer. With extensive research, exosomes have solved many disease problems. This review summarizes the differences between migrasomes and exosomes in size, composition, property and function, extraction method and regulation mechanism for generation and release. At the same time, it also prospects for the current hotspot of migrasomes, hoping to provide literature support for further research on the generation and release mechanism of migrasomes and their clinical application in the future.

A Data Enhancement Algorithm for DDoS Attacks Using IoT.

With the rapid development of the Internet of Things (IoT), the frequency of attackers using botnets to control IoT devices in order to perform distributed denial-of-service attacks (DDoS) and other cyber attacks on the internet has significantly increased. In the actual attack process, the small percentage of attack packets in IoT leads to low accuracy of intrusion detection. Based on this problem, the paper proposes an oversampling algorithm, KG-SMOTE, based on Gaussian distribution and K-means clustering, which inserts synthetic samples through Gaussian probability distribution, extends the clustering nodes in minority class samples in the same proportion, increases the density of minority class samples, and improves the amount of minority class sample data in order to provide data support for IoT-based DDoS attack detection. Experiments show that the balanced dataset generated by this method effectively improves the intrusion detection accuracy in each category and effectively solves the data imbalance problem.

Controlled hypertension under hemostasis prevents post-gastric endoscopic submucosal dissection bleeding: a prospective randomized controlled trial.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a prominent minimally invasive operative technique for treating early gastrointestinal tumors but can result in postoperative bleeding. We conducted a randomized controlled trial to determine whether increasing blood pressure under hemostasis during gastric ESD to identify potential bleeding spots reduces the risk of post-ESD bleeding. METHODS: In this randomized, controlled, single-blinded clinical trial, 309 patients with early gastric cancer who were admitted to a hospital to undergo ESD were recruited from March 2017 to February 2018 and were randomized into intervention and control groups. In the control group, patients underwent normal ESD. In the intervention group, we increased patients' blood pressure to 150 mmHg for 5 min using a norepinephrine pump (0.05 µg/kg/min initial dose) after the specimen was extracted during the ESD operation to identify and coagulate potential bleeding spots with hot biopsy forceps. Our primary outcome was the incidence of postoperative bleeding over 60-day follow-up. RESULTS: The incidence of post-ESD bleeding was lower in the intervention group (1.3%, 2/151) than in the control group (10.1%, 16/158, p = 0.01). Deeper tumor invasion was associated with a higher risk of post-ESD bleeding (5.3% in mucosal/submucosal layer 1 group vs. 12.5% in submucosal layer 2/muscularis propria group, p < 0.001). Multi-factor but not univariate analysis showed that proton pump inhibitor administration three times per day may be a better choice than twice per day. CONCLUSION: Increasing blood pressure under hemostasis during ESD to identify and coagulate potential bleeding spots could reduce the risk of delayed bleeding after gastric ESD.

Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance.

BACKGROUND: Ubiquitin-specific protease 7 (USP7) is a de-ubiquitin enzyme that plays an essential role in multiple cancers and becomes a target for treatment. However, the role of USP7 and its therapeutic value for HCC remains unclear. METHODS: USP7 expression was examined in HCC tissues by western blot and immunohistochemistry. The correlation of USP7 and HCC prognosis was analyzed by Kaplan-Meier survival method. Mass spectrometry was determined and cell proliferation and tumorigenicity assays were conducted in vitro and in vivo treated by P22077 and sgRNA-USP7. RESULTS: USP7 expression was significantly increased in HCC and associated with its progression. Interestingly, many HCC cells are sensitive to USP7 inhibition by using P22077. P22077 treatment not only induced cell death but also inhibited cell proliferation and migration in Huh7 and SK-Hep1 cells. In a xenograft model, P22077 efficiently inhibited tumor growth. In chemo-resistant HCC cells, P22077 decreased cell sensitivity to chemotherapy. In addition, mass spectrometry reveals 224 of significantly changed proteins upon P22077 treatment. CONCLUSIONS: We demonstrate a critical role of USP7 in HCC devolvement and chemoresistance. Disruption of USP7 function results in dis-regulated several key biological processes and subsequently activates BAX. USP7 might be a novel and drug-able target in HCC.

Coupling function of cyclin-dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with a poorly defined molecular mechanism. Cyclin-dependent kinase 2 (CDK2) and Septin2 (SEPT2) are 2 known oncogenic molecules but the mechanism of functional interactions remains unclear. Here, we interestingly found that CDK2 and SEPT2 show very similar dynamic expression during the cell cycle. Both CDK2 and SEPT2 show the highest protein levels in the G2/M phase, resulting in CDK2 interacting with SEPT2 and stabilizing SEPT2 in HCC. In a panel of 8 pairs of fresh HCC tissues and corresponding adjacent tissues, both western blot and immunohistochemistry (IHC) assays demonstrate that CDK2 expression is highly correlated with SEPT2. HCC with high expression of both CDK2 and SEPT2 are more likely to relapse. This observation is further demonstrated by a large panel of 100 HCC patients. In this large panel, high expression of both CDK2 and SEPT2 significantly correlates with tumor differentiation and microvascular invasion, which is an independent prognostic factor in HCC patients. In summary, our results reveal a cooperative function between CDK2 and SEPT2. HCC with high expression of CDK2 and SEPT2 might be more aggressive and respond poorly to current therapy.

Progress in the application of exosomes as therapeutic vectors in tumor-targeted therapy.

Cancer is the second leading cause of death in the world with a high annual incidence level. Researchers have been working on developing treatments for cancer. Targeted therapy is an emerging treatment modality that is more novel than surgery, radiotherapy and chemotherapy. In targeted therapy, exogenous nanoscale microparticles are applied as carriers for drugs or genes. However, conventional particles have certain limitations attributed to non-specific cytotoxicity, biocompatibility and low delivery efficacy in individual therapeutic vector systems. Exosomes are small vesicles secreted by various cells that consist of lipid bilayer membranes without organelles. Due to their excellent biocompatibility, exosomes have received increased attention in recent years for targeted therapy applications. This review briefly introduces the current status of targeted therapy, and exosomes are introduced by their structural characteristics, physiological effects and separation methods. This review also discusses the applications of engineered exosomes derived from different cells in the field of targeted therapies and compares the two-way regulation of mesenchymal stromal cell-derived exosomes in tumor therapy.

Correlation between S100A11 and the TGF-ß1/SMAD4 pathway and its effects on the proliferation and apoptosis of pancreatic cancer cell line PANC-1.

S100A11 as a S100 protein family member has been documented to play dual-direction regulation over cancer cell proliferation. We explored the role of S100A11 in the proliferation and apoptosis of pancreatic cancer cell line PANC-1 and the potential mechanisms involving the TGF-ß1/SMAD4/p21 pathway. S100A11 and TGF-ß1 protein expressions in 30 paraffin-embedded specimens were evaluated by immunohistochemistry. S100A11 and TGF-ß1 expression in PANC-1 cell line was suppressed using small interfering RNA (siRNA), respectively. Subsequently, pancreatic cancer cell apoptosis was measured by Cell Counting Kit-8 and flow cytometry, and S100A11 and TGF-ß1/SMAD4/p21 pathway proteins and genes were detected with Western blotting and quantitative polymerase chain reaction (qPCR). S100A11 cytoplasmic/nuclear protein translocation was examined using NE-PER® cytoplasm/nuclear protein extraction in cells interfered with TGF-ß1 siRNA. Our results showed that S100A11 expression was positively correlated with TGF-ß1 expression in pancreatic cancerous tissue. Silencing TGF-ß1 down-regulated intracellular P21WAF1 expression by 90%, blocked S100A11 from cytoplasm entering nucleus, and enhanced cell proliferation. Silencing S100A11 down-regulated intracellular P21 expression and promoted cell apoptosis without significantly changing TGF-ß1 and SMAD4 expression. Our findings revealed that S100A11 and TGF-ß1/SMAD4 signaling pathway were related but mutually independent in regulating PANC-1 cells proliferation and apoptosis. Other independent mechanisms might be involved in S100A11's regulation of pancreatic cell growth. S100A11 could be a potential gene therapy target for pancreatic cancer.

ß2-AR regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway.

Psychological stress has been recognized as a well-documented risk factor associated with ß2-adrenergic receptor (ß2-AR) in the development of pancreatic cancer. Aldo-keto reductase 1 member B1 (AKR1B1) is a potential interacting partner of ß2-AR, but the effect of their interaction on pancreatic cancer cells is not known at present. We found a positive correlation between AKR1B1 and ß2-AR expression in pancreatic cancer tissue samples, and co-localization of these proteins in the human pancreatic cancer BXPC-3 cell line. Compared to the controls, the CFPAC-1 and PANC-1 pancreatic cancer cells overexpressing ß2-AR and AKR1B1 respectively showed significantly higher proliferation rates, which is attributed to higher proportion of cells in the S phase and decreased percentage of early apoptotic cells. Furthermore, overexpression of ß2-AR led to a significant increase in the expression of AKR1B1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2). Overexpression of AKR1B1 significantly decreased ß2-AR levels and increased that of p-ERK1/2. Taken together, ß2-AR directly interacted with and up-regulated AKR1B1 in pancreatic cancer cells, and promoted their proliferation and inhibited apoptosis via the ERK1/2 pathway. Our findings also highlight the ß2-AR-AKR1B1 axis as a potential therapeutic target for pancreatic cancer.

Expression pattern of BCCIP in hepatocellular carcinoma is correlated with poor prognosis and enhanced cell proliferation.

BCCIP was originally identified as a BRCA2- and CDKN1A- (Cip1/waf1/p21) interacting protein, also known as BCCIP. It has been reported to express in various types of cancers, including colorectal cancer (CRC), astrocytic brain tumors, and glioblastomas. However, the relationship between BCCIP expression and clinicopathological features of hepatocellular carcinoma (HCC) remains to be determined. Herein, we demonstrated that BCCIP was downregulated in clinical HCC tissues; its level was inversely correlated with multiple clinicopathological factors, such as tumor grade, tumor size, and Ki67 expression. Cox regression analysis of tumor samples revealed that BCCIP expression status was an independent prognostic factor for HCC patients' poor survival. Our study also indicated that BCCIP shutdown reduces p21 expression and accelerates G1 to S progression of LO2 hepatocytes significantly. Moreover, there is an interaction between BCCIP and p53 in hepatic L02 cells, and the downregulation of p21 expression by BCCIP is in a p53-dependent way. These findings revealed that BCCIP may play a significant role for the determination of HCC progression through its role in regulating cell growth. Thus, our results suggest that BCCIP is of potential interest for prognostic marker and therapeutic target of HCC.

Upregulated TRIM32 correlates with enhanced cell proliferation and poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and the sixth most prevalent human malignancies worldwide. However, the molecular mechanisms underlying hepatocarcinogenesis remain unclear. For HCC patients, there is not only a lack of effective therapeutic targets but also a lack of predictive or prognostic biomarkers. In this article, we reported that TRIM32 was obviously upregulated in HCC tumor tissues and HCC cell lines. Its expression patterns were positively correlated with histological grade, tumor sizes, and HBsAg of HCC patients. TRIM32 expression was a significant predictor for the overall survival time of HCC patients. Moreover, the overexpression of TRIM32 in cells accelerated the G1-S phase transition, promoted cell proliferation rates, and induced the resistance of HCC patients to oxaliplatin. All these findings suggest that TRIM32 might play important roles in the hepatocarcinogenesis. TRIM32 could be a novel direction to explore the mechanism underlying HCC pathogenesis.

Expression and Clinical Role of Cdc5L as a Novel Cell Cycle Protein in Hepatocellular Carcinoma.

BACKGROUND: Cell division cycle 5-like (Cdc5L), as a pre-mRNA splicing factor, is a regulator of mitotic progression. Previous study found that deletion of endogenous Cdc5L decreases the cell viability via dramatic mitotic arrest, while the role of Cdc5L in cancer biology remains under debate. AIMS: To investigate the involvement of Cdc5L in the progression of hepatocellular carcinoma (HCC). METHODS: In this study, the expression of Cdc5L was evaluated by Western blot in 8 paired fresh HCC tissues and immunohistochemistry on 116 paraffin-embedded slices. We treated HCC cells by nocodazole to analyze the role of Cdc5L in mitotic progress. To determine whether Cdc5L could regulate the proliferation of HCC cells, we increased endogenous Cdc5L and analyzed the proliferation of HCC cells using Western blot, CCK8, flow cytometry assays, and colony formation analyses. Furthermore, Cdc5L-siRNA oligos were used to confirm that Cdc5L plays an essential role in HCC development. RESULTS: Cdc5L was highly expressed in HCC and significantly associated with multiple clinicopathological factors, including AJCC stage, tumor size, and Ki-67. Besides, univariate and multivariate survival analyses demonstrated that high Cdc5L expression was an independent prognostic factor for HCC patients' poor survival. Overexpression of Cdc5L favors cell cycle progress of HCC cells, while downregulation of Cdc5L results in cell cycle arrest at G2/M phase and reduced cell proliferation of HCC cells. CONCLUSIONS: Our findings suggested that Cdc5L could play an important role in the tumorigenesis of HCC and thus be a potential therapeutical target to prevent HCC progression.

Decreased Expression of EHD2 Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Metastasis remains the most common cause of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Understanding molecular mechanisms that regulate metastasis process is crucial for improving treatment of hepatocellular carcinoma. AIMS: In this article, we examined whether Eps15 homology domain-containing 2 (EHD2) played a critical role in hepatocellular carcinoma metastasis and explored the possible mechanism. METHODS: EHD2 and E-cadherin expression levels in hepatocellular carcinoma patients were examined using Western blotting and immunohistochemistry. The cell migration and invasion were evaluated by wound-healing assay and trans-well assay. Epithelial-mesenchymal transition was analyzed by immunofluorescence, and the vital markers were detected by Western blotting. The correlation of EHD2 and E-cadherin was confirmed by co-immunoprecipitation. RESULTS: EHD2 expression, along with the epithelial marker E-cadherin, was markedly reduced in tumor tissues than in adjacent noncancerous tissues. Moreover, EHD2 was positively correlated with E-cadherin, histological grade, tumor metastasis, and microvascular invasion. Kaplan-Meier survival analysis showed that hepatocellular carcinoma patients with decreased EHD2 expression had shorter overall survival times than those with higher EHD2 expression. Knockdown of EHD2 induced an increase in cell invasion and changes characteristic of epithelial-mesenchymal transition, while overexpression of EHD2 inhibited these processes. CONCLUSIONS: Molecular data indicated that EHD2 inhibited migration and invasion of hepatocellular carcinoma probably by interacting with E-cadherin and it might be an independent, significant risk factor for survival after curative resection.

Upregulated HOXC8 Expression Is Associated with Poor Prognosis and Oxaliplatin Resistance in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. It is indispensable to understanding molecular mechanisms of HCC progression and to developing clinically useful biomarkers for this disease. AIM: In this article, we examined whether HOXC8 was associated with the poor prognosis of hepatocellular carcinoma and explored the possible underlying mechanism. METHODS: The HOXC8 and Ki67 expression levels in 86 patients with hepatocellular carcinoma were examined using immunohistochemistry. HOXC8 levels in HCC cells were downregulated by siRNA transfection. The cycle progression and cell proliferation status of HCC cells and the oxaliplatin effectiveness were evaluated by flow cytometry and CCK-8 assay. HOXC8, CyclinD1, PCNA, Nkd2, and cleaved caspase-3 levels were detected by western blot. RESULTS: HOXC8 was upregulated in HCC tissues, compared with adjacent non-tumor ones. HOXC8 expression levels in 86 patients with hepatocellular carcinoma were positively correlated with histological grade. Univariate and multivariate survival analysis revealed that HOXC8 was a significant predictor for overall survival of HCC patients. HOXC8 siRNA knockdown delayed the G1-S phase transition, inhibited cell proliferation, and attenuated resistance to oxaliplatin. CONCLUSIONS: HOXC8 promoted HCC proliferation and predicted poor prognosis. Furthermore, upregulated HOXC8 expression was associated with oxaliplatin resistance in hepatocellular carcinoma.

Overexpressed nuclear BAG-1 in human hepatocellular carcinoma is associated with poor prognosis and resistance to doxorubicin.

Bcl-2-associated athanogene-1 (BAG-1) is a multifunctional anti-apoptotic protein which regulates an array of cellular processes, including apoptosis, signaling, proliferation, transcription, and cell motility and has been reported to be over-expressed in a number of human malignancies. To investigate the possible involvement of BAG-1 in tumorigenesis of hepatocellular carcinoma (HCC), we performed Western blot analysis in eight paired samples of HCC and adjacent peritumoral tissues and immunohistochemistry in 65 paraffin sections of HCC, which both showed an enhanced expression of nuclear BAG-1 isoform in HCC tissues. Statistical analysis confirmed that overexpression of nuclear BAG-1 in HCC tissues was significantly associated with histological grading (P < 0.001), poor prognosis (P = 0.004), and was found to be an independent prognostic indicator for HCC (P = 0.023). We also noted that BAG-1 was overexpressed in four HCC cell lines compared with a normal hepatocyte cell line, and BAG-1 overexpression increased resistance of HCC cells to doxorubicin, a common chemotherapeutic agent for HCC. Furthermore, we observed that knock down of BAG-1 with siRNA in HepG2 cells increased the chemosensitivity of cells, a process mediated through inhibition of doxorubicin-triggered NF-κB activation; and knock down of BAG-1 suppressed proliferation and cell cycle transition of HepG2 cells. In consequence, our results for the first time indicated that BAG-1 was dysregulated in HCC and suppression of BAG-1 expression which resulted in inhibiting of NF-κB signaling might be developed into a new strategy in HCC therapy.

CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A.

C-terminal binding protein-2 (CtBP2), as a transcriptional co-repressor, has been shown to mediate the repression of p16(INK4A) , a tumor suppressor gene product, in primary human cells. Here we aimed to investigate how the correlation between CtBP2 and p16(INK4A) influenced the development of esophageal squamous cell carcinoma (ESCC). Immunohistochemistry of ESCC tissue sections indicated that the CtBP2 and p16(INK4A) expressions were inversely correlated to each other with a linear regression coefficient of -0.747 (P < 0.05), and Western blot analysis revealed that CtBP2 was higher expressed in tumorous tissues than in adjacent non-tumorous tissues. Either CtBP2 or p16(INK4A) expression was significantly related to histological differentiation (P = 0.016 or 0.001) and to the expression of Ki-67, a proliferating marker (P = 0.006 or 0.02), and patients with higher CtBP2 and lower p16(INK4A) expressions had shorter overall survival. We also observed that CtBP2 modulated the cell proliferation and cell cycle in ECA109 cells, an ESCC cell line, by inhibiting p16(INK4A) . Overexpression or knockdown of CtBP2 in ECA109 cells was found to inhibit or activate the mRNA or protein expression of p16(INK4A) , which in turn altered the cell proliferation and cell cycle in ECA109 cells, as measured by flow cytometry and cell count assay. Additionally, after ECA109 cells silenced for CtBP2 were treated with cisplatin (an anti-ESCC agent), the p16(INK4A) expression was up-regulated, and the cell apoptosis was promoted, thus confirming the repression of p16(INK4A) by CtBP2. Collectively, all results suggested that CtBP2 might contribute to the progression of ESCC through a negative transcriptional regulation of p16(INK4A).

Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion.

Although the transcriptional regulation of the programmed death ligand 1 (PD-L1) promoter has been extensively studied, the transcription factor residing in the PD-L1 super-enhancer has not been comprehensively explored. Through saturated CRISPR-Cas9 screening of the core region of the PD-L1 super-enhancer, we have identified a crucial genetic locus, referred to as locus 22, which is essential for PD-L1 expression. Locus 22 is a potential binding site for NFE2:MAF transcription factors. Although genetic silencing of NRF2 (NFE2L2) did not result in a reduction of PD-L1 expression, further analysis reveals that MAFG and NFE2L1 (NRF1) play a critical role in the expression of PD-L1. Importantly, lipopolysaccharides (LPS) as the major component of intratumoral bacteria could greatly induce PD-L1 expression, which is dependent on the PD-L1 super-enhancer, locus 22, and NFE2L1/MAFG. Mechanistically, genetic modification of locus 22 and silencing of MAFG greatly reduce BRD4 binding and loop formation but have minimal effects on H3K27Ac modification. Unlike control cells, cells with genetic modification of locus 22 and silencing of NFE2L1/MAFG failed to escape T cell-mediated killing. In breast cancer, the expression of MAFG is positively correlated with the expression of PD-L1. Taken together, our findings demonstrate the critical role of locus 22 and its associated transcription factor NFE2L1/MAFG in super-enhancer- and LPS-induced PD-L1 expression. Our findings provide new insight into understanding the regulation of PD-L1 transcription and intratumoral bacteria-mediated immune evasion.

Flap endonuclease 1 Facilitated Hepatocellular Carcinoma Progression by Enhancing USP7/MDM2-mediated P53 Inactivation.

Overexpression of Flap endonuclease 1 (FEN1) has been previously implicated in hepatocellular carcinoma (HCC), while its expression features and mechanisms remain unclear. In the current study, differential expression genes (DEGs) were screened in HCC tissues and normal liver tissues in 4 Gene Expression Omnibus (GEO) datasets. FEN1, one of the hub co-overexpressed genes, was further determined overexpressed in HCC tissues in TCGA, local HCC cohorts, and hepatocarcinogenesis model. In addition, high expression of FEN1 indicated poor prognosis of HCC patients. Loss-of-function and gain-of-function assays demonstrated that FEN1 enhanced the proliferation, cell cycle phage transition, migration/ invasion, therapy resistance, xenograft growth, and epithelial-mesenchymal transition (EMT) process of HCC cells. Mechanically, FEN1 could inactivate P53 signaling by preventing the ubiquitination and degradation of mouse double minute 2 (MDM2) via recruiting ubiquitin-specific protease 7 (USP7). Interfering USP7 with P22077 significantly reversed the malignant phenotypes activated by FEN1. In conclusion, this study suggests FEN1 as a robust prognostic biomarker and potential target for HCC.

The lncRNA B3GALT5-AS1 Functions as an HCC Suppressor by Regulating the miR-934/UFM1 Axis.

Accumulating evidence has demonstrated that long noncoding RNA (lncRNA) is importantly related to the occurrence and development of cancer. According to reports, the expression of B3GALT5-AS1 in hepatocellular carcinoma (HCC) is downregulated; however, the role of B3GALT5-AS1 in HCC is not yet clear. In this study, our purpose is to explore the biological function of B3GALT5-AS1 in HCC and its coupling mechanism with miR-934 and ubiquitin-fold modifier 1 (UFM1). We found that the B3GALT5-AS1 expression level was of significant reduction in both HCC tissues and cell lines; B3GALT5-AS1 overexpression (ov) may inhibit the malignant features of HCC. In addition, we demonstrated that miR-934 mimics could reverse the effect of B3GALT5-AS1 ov, which proved miR-934 was the downstream regulator of B3GALT5-AS1. Furthermore, si-UFM1 could reverse the effect of miR-934 inhibitor, which revealed the connection between them. Moreover, we found that B3GALT5-AS1 could keep down the PI3K/AKT pathway through UFM1. Our results demonstrated that B3GALT5-AS1 was an excellent HCC suppressant by regulating miR-934 and UFM1 to achieve negative regulation of HCC cell proliferation, invasion, and metastasis, indicating that B3GALT5-AS1 is a promising potential therapeutic target for HCC treatment.

Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma.

PURPOSE: Ubiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC). METHODS: Genomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate/multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE89377. In addition, the expression feature of USP39 was further explored in HCC tissues by performing western blotting and immunohistochemistry. RESULTS: Genomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by eight USPs for HCC prognosis. High-risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. Furthermore, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE89377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. The overexpression of USP39 was further determined in a local HCC cohort and correlated with poor prognosis. The co-concurrence analysis suggested that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes. CONCLUSION: The current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.

Biological testing of chitosan-collagen-based porous scaffolds loaded with PLGA/Triamcinolone microspheres for ameliorating endoscopic dissection-related stenosis in oesophagus.

OBJECTIVES: Endoscopic submucosal dissection (ESD), a preferential approach for early oesophageal neoplasms, inevitably results in oesophageal strictures in patients. Clinical use of glucocorticoids through submucosal injection is beneficial for inhibiting oesophageal stricture following injury; however, it also has limitations, such as dose loss and perforation. Hence, alternatives to glucocorticoid therapy should be developed. METHODS: A novel porous composite scaffold, ChCo-TAMS, composed of chitosan, collagen-I and triamcinolone acetonide (TA) loaded into poly (lactic-co-glycolic) acid (PLGA) microspheres (TAMS), was successfully constructed and subjected to biological testing to ameliorate oesophageal ESD-related stenosis. RESULTS: The synthesized biomaterials displayed unique properties in inhibiting the activation of macrophages, chemokine-mediated cell recruitment and fibrogenesis of fibroblasts. Further application of the scaffolds in the rat dermal defect and porcine oesophageal ESD model showed that these novel scaffolds played a robust role in inhibiting wound contracture and oesophageal ESD strictures. CONCLUSIONS: The developed composite scaffolds provide a promising clinical medical device for the prevention of post-operative oesophageal stricture.