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Hepatocellular carcinoma is one of the most common gastrointestinal malignancies. Anti-angiogenesis therapies have recently demonstrated promise in the treatment of malignancies, although early treatment benefits may be accompanied by metastasis over time. Additional and more effective anti-angiogenic treatment modalities are therefore needed. We previously found that Yes-associated protein 1 (YAP1) expression is increased in hepatocellular carcinoma (HCC), particularly around tumor-associated blood vessels, suggesting a role in angiogenesis. The YAP1 inhibitor verteporfin is presently in anti-angiogenic clinical trials for the treatment of various cancers. Depleted YAP1 from vascular endothelial cells effectively reduced proliferation and tube formation, validating its utility as an anti-angiogenesis target. We also showed that YAP1 depletion or inhibition in vascular endothelial cells leads to increased release of exosomes containing the long non-coding RNA (lncRNA) MALAT1 into the tumor microenvironment. Direct exosomal transfer of MALAT1 to hepatic cells leads to increased hepatic cell invasion and migration via activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. These observations may explain the occurrence of distant tumor metastasis with YAP1-associated anti-angiogenic therapy over time. It provides insight into new pathways and treatment paradigms that may be targeted to increase the long-term success of anti-angiogenic therapies., Graphical Abstract, YAP1 deficiency effectively inhibits angiogenesis and promotes the release of exosomes. Released exosomes promote the distant migration of HCC cells by activating the ERK1/2 pathway; accordingly, ERK1/2 inhibitors can reverse the metastasis-promoting effect of YAP1-KD. The combination of VP and ERK1/2 inhibitor may be an effective new approach for anti-angiogenesis therapy.

Purpose Sorafenib has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy is limited by drug resistance. Autophagy is the process by which cellular components are transported to lysosomes for degradation, which promotes energy production and production of macromolecular precursors. Studies have suggested that the cytoprotective function of autophagy may contribute to chemoresistance or targeted drug resistance in cancer cells. We investigated the effects of miR-375 and autophagy-related protein 14, and their interrelationships, on sorafenib efficacy. Methods Cell viability was measured using the MTT assay, and apoptosis was evaluated using flow cytometry. Colony formation assay was performed to determine changes in cell number. Real-time PCR and Western blotting were performed to quantify the expression of key genes and proteins. Immunofluorescence and transmission electron microscopy were used to detect autophagy. Dual-luciferase reporter assays were used to verify a direct target. Results We characterized the relationship between sorafenib and autophagy. We showed that inhibition of autophagy enhanced sensitivity of HCC to sorafenib and showed that miR-375 was important in this process. Finally, we showed that miR-375 affected sensitivity of HCC cells to sorafenib through regulation of ATG14. Conclusion We showed that miR-375 sensitized HCC cells to sorafenib by blocking sorafenib-induced autophagy. We also showed that ATG14 was a direct autophagy-related target of miR-375. These findings indicated that miR-375-ATG14 was important in the development of sorafenib resistance in HCC.

In this investigation, to maximize the desired immunoenhancement effects of PsEUL and stimulate an efficient humoral and cellular immune response against an antigen, PsEUL and the model antigen ovalbumin (OVA) were coupled using the N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) reaction to yield a novel delivery system (PsEUL-OVA). The physicochemical characteristics and immune regulation effects of this new system were investigated. We found the yield of this EDC method to be 46.25%. In vitro, PsEUL-OVA (200 μg mL−1) could enhance macrophage proliferation and increase their phagocytic efficiency. In vivo, PsEUL-OVA could significantly increase the levels of OVA-specific antibody (IgG, IgG1, IgG2a, and IgG2b) titers and cytokine (IL-2, IL-4, IL-6, IFN-γ) levels. Additionally, it could activate T lymphocytes and facilitate the maturation of dendritic cells (DCs). These findings collectively suggested that PsEUL-OVA induced humoral and cellular immune responses by promoting the phagocytic activity of macrophages and DCs. Taken together, these results revealed that PsEUL-OVA had the potential to improve immune responses and provide a promising theoretical basis for the design of a novel delivery system.

Liver cancer is one of the most malignant cancer, with poor outcomes and a high incidence rate, and current treatment approaches to prevent tumor progression and development remain unsatisfactory. Therefore, it is urgent to explore novel methods to inhibit tumor growth and metastasis. Autophagy is a highly conserved process associated with metastasis and drug resistance. Lipids are selectively recognized and degraded via autophagy; thus, autophagy is a crucial process to maintain tumor self-protection. MicroRNA (miR)-425 is a tumor-associated gene involved in liver cancer development that can induce cell proliferation and drug resistance. Using Cell Counting Kit-8 assays, western blot analysis and immunofluorescence assays, the present study revealed that inhibition of miR-425 promoted lipophagy by mediating the autophagy process, which in turn helps to promote sorafenib resistance. Using a bioinformatics website, it was revealed that autophagy promoted lipophagy by targeting silent information regulator 2 homolog 1 (SIRT1). The results of luciferase reporter assays supported this finding, and rescue experiments provided additional evidence. Overall, the current results suggested that inhibition of miR-425 expression increased SIRT1 expression to promote lipophagy, leading to the inhibition of liver cancer cell proliferation.

PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance in different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel lncRNA and has been reported to promote multiple cancer progression. However, the biological roles of NEAT1 in hepatocellular carcinoma (HCC) is not cleared nowadays. In the present research, the level of NEAT1 was found to be upregulated in HCC by The Cancer Genome Atlas. In addition, NEAT1 expression is negatively correlated with the survival rate in HCC. Further investigation revealed that NEAT1 upregulation inhibited sorafenib efficacy and promoted autophagy. We found that NEAT1 could be a sponge for microRNA-204 (miR-204) and inhibits its level to upregulate ATG3 expression. In addition to the above, we demonstrated that miR-204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes HCC autophagy through modulating miR-204/ATG3 pathway. Collectively, this study first demonstrated that a novel NEAT1/miR-204/ATG3 signaling regulates HCC progression.

Background Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Abnormally expressed long noncoding RNAs (lncRNAs) have been confirmed to regulate multiple processes associated with tumor progression. However, the mechanism by which lncRNAs affect exosome secretion remains unclear. Methods The underlying mechanisms of long noncoding RNA LINC00511 (LINC00511) regulation of multivesicular body (MVB) trafficking, exosome secretion, invadopodia formation, and tumor invasion were determined through gene set enrichment analysis (GSEA), immunoblotting, nanoparticle tracking analysis, confocal colocalization analysis, electron microscopy, and invasion experiments. Results We revealed that the tumorigenesis process is associated with a significant increase in vesicle secretion in hepatocellular carcinoma (HCC). Additionally, LINC00511 was significantly more highly expressed in HCC tissues and is related to vesicle trafficking and MVB distribution. We also found that in addition to the formation of invadopodia in HCC progression, abnormal LINC00511 induces invadopodia formation in HCC cells by regulating the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23) to induce the invadopodia formation, which are key secretion sites for MVBs and control exosome secretion. Finally, we revealed that LINC0051-induced invadopodia and exosome secretion were involved in tumor progression. Conclusions Our experiments revealed novel findings on the relationship between LINC00511 dysregulation in HCC and invadopodia production and exosome secretion. This is a novel mechanism by which LINC00511 regulates invadopodia biogenesis and exosome secretion to further promote cancer progression.

Background Qigong has a long-term application as an initiative therapy for prevent and cure diseases, as a mindful exercise, it’s unique function of integrate mind, breath and body gets a lot of attention, researches show that qigong practice could adjust brain and heart function. Currently we have limitations on study qigong’s coordinate mechanism between mind and body, existing studies lack of evidence on electrophysiology research.Our object here is to propose a method to evaluate the effects of qigong on mind body adjustment, and to analyse the coordinate function of Electroencephalogram (EEG) and Heart rate variability (HRV) by complex signal process.MethodsA two-arm randomized clinical trial with eighty-four qigong naïve subjects without cerebral or cardiovascular diseases or other severe syndromes will be allocate to either intervention group(n=42) or wait in list control group(n=42). Participants in the intervention group will conduct Three-circle post standing qigong exercise 5 times per week for 8 weeks, while wait in list group will maintain their current lifestyle during 8 weeks period. The outcome will be complexity-based measures of heart rate and EEG signals assessed at baseline and 8 weeks. Multiscale entropy analysis will be used as measures of complexity.ConclusionThis study will be investigate the effects of qigong exercise by EEG and HRV analyse before and after Three-circle post standing practice, and to measure their synergies by complex signal process method. Results of this study may lead to novel biomarkers that help us monitor and understand the physiological processes of brain and heart function and explore the potential benefits of Qigong and will provide a research evidence for qigong’s mind and body synergy function and to direct future clinical treatment.Ethics and disseminationThe protocol has been approved by the institutional review boards of Beijing University of Chinese Medicine, where the study will take place(approval number: 2018BZHYLL0109).Trail registrationThis study has been registered with the“Chinese Clinical Trail Registry”, Republic of China, which is a registry in the WHO Registry Network. Register number: ChiCTR-Bon-17010840.

The tumor microenvironment represents a dynamically composed matrix into which cancer cells and many other cell types are embedded to form organ-like structures. The tumor immune microenvironment (TIME), composed of immune cells, is an inseparable part of the tumor microenvironment. Extracellular vesicles (EVs) participate in the occurrence and development of tumors by delivering various biologically active molecules between cells; their role in cancer immune escape in particular has been widely proven. EVs can carry a wide array of cargo, such as non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, which are selectively loaded by EVs, secreted, and transported to participate in the proliferation of immune cells. Hence, strategies to specifically target EV-ncRNAs could be attractive therapeutic options. In this review, we summarize the current research on the role of EV-ncRNAs in cancer immune escape, and discuss the latest research on the function and regulation mechanism of EV-ncRNAs in cancer immune escape, highlighting and elucidating the potential clinical applications of EV-ncRNAs, including in diagnosis and immunotherapy.

This study aimed to investigate the function of OCT3/4 on tumor immune escape in bladder cancer. Initially, the expression of OCT3/4, TET1, NRF2 and MDM2 was quantified in tumor tissues and cells, followed by gain- or loss-of-function studies to define their roles in cell migration, invasion and apoptosis and tumorigenicity in nude mice. Bladder cancer presented with abundant expression levels of OCT3/4, TET1, NRF2 and MDM2. We found that OCT3/4 promoted TET1 expression via binding to its promoter and that TET1 recruited MLL protein to NRF2 promoter and upregulated its expression, while NRF2 enhanced MDM2 expression. Upregulated MDM2 accelerated tumor immune escape in bladder cancer in mice. OCT3/4 knockdown suppressed the cell migration and invasion while inducing apoptosis, and consequently prevented tumor growth and immune escape in mice. Collectively, OCT3/4 may promote the progression of tumor immune escape in bladder cancer through acting as a promoter of the TET1/NRF2/MDM2 axis.

Molecular oxygen (O2) is a universal electron acceptor that is eventually synthesized into ATP in the mitochondrial respiratory chain of all metazoans. Therefore, hypoxia biology has become an organizational principle of cell evolution, metabolism and pathology. Hypoxia-inducible factor (HIF) mediates tumour cells to produce a series of glucose metabolism adaptations including the regulation of glucose catabolism, glycogen metabolism and the biological oxidation of glucose to hypoxia. Since HIF can regulate the energy metabolism of cancer cells and promote the survival of cancer cells, targeting HIF or HIF mediated metabolic enzymes may become one of the potential treatment methods for cancer. In this review, we summarize the established and recently discovered autonomous molecular mechanisms that can induce cell reprogramming of hypoxic glucose metabolism in tumors and explore opportunities for targeted therapy.

Background Surgical management of patients with ventral abdominal wall defects, especially complex abdominal wall defects, remains a challenging problem for abdominal wall reconstructive surgeons. Effective surgical treatment requires appropriate preoperative assessment, surgical planning, and correct operative procedure in order to improve postoperative clinical outcomes and minimize complications. Although substantial advances have been made in surgical techniques and prosthetic technologies, there is still insufficient high-level evidence favoring a specific technique. Broad variability in existing practice patterns, including clinical pre-operative evaluation, surgical techniques and surgical procedure selection, are still common. Data sources With the purpose of providing a best practice algorithm, a comprehensive search was conducted in Medline and PubMed. Sixty-four surgeons considered as experts on abdominal wall defect repair and reconstruction in China were solicited to develop a Chinese consensus and give recommendations to help surgeons standardize their techniques and improve clinical results. Conclusions This consensus serves as a starting point to provide recommendations for adult ventral abdominal wall repair and reconstruction in China and may help build opportunities for international cooperation to refine AWR practice.

In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.

Timber folded-plate structures built with cross-laminated timber (CLT) panels can be applied to gymnasiums and conference halls. The design of the joints is crucial to facilitate the development of timber folded-plate structures. Considering that the compressive performance of CLT panels should be fully utilized and the failure of the joints was induced by the self-tapping screws, 45° miter-connected (MCJR) and mortise-tenon (MTJR) joints reinforced with self-tapping screws were designed. Eight CLT specimen groups with varying connection type, loading direction, and self-tapping screw spacing and diameter were designed and subjected to tests. Typical characteristics of the failure modes and moment–rotation curves were evaluated, and the corresponding rotational stiffness, yield rotation, yield moment, ultimate rotation, and ultimate moment of the specimens were calculated. The results showed that the failure mode of the MCJR and MTJR in push was the pull-out of self-tapping screws, and those in pull included the shear-off and pull-out of self-tapping screws. The loading direction significantly influenced the rotational stiffness and ultimate moment of both types of joints. The mechanical behavior of the MTJR in pull was better than that of the MCJR in pull; however, the rotational stiffness and ultimate moment of the MTJR in push were relatively lower than those of the MCJR in push. Moreover, increased self-tapping screw diameter and decreased self-tapping screw spacing significantly improved the mechanical behavior of MCJR. Finally, an analytical model was established to determine the rotational stiffness of the MCJR and MTJR in different loading directions. A comparison of the analytical and experimental results demonstrates that the proposed analytical method can conservatively estimate the rotational stiffness of the MCJR and MTJR.

The long non-coding RNA HOX transcript antisense RNA (HOTAIR) plays a key role in the progression of various carcinomas. However, whether or not HOTAIR influences glucose metabolism and the specific underlying mechanism in hepatocellular carcinoma (HCC) cells remain unclear. In the present study, we found markedly increased HOTAIR expression in 84 HCC tissues and demonstrated that HOTAIR overexpression promoted cell proliferation using Cell Counting Kit-8. The effect on glucose metabolism regulated by HOTAIR in HCC cells was determined by detecting lactate and glucose levels: HOTAIR promoted glycolysis by upregulating glucose transporter isoform 1 (GLUT1) and activating mammalian target of rapamycin (mTOR) signaling, whereas knockdown of HOTAIR suppressed this effect. Our research reveals a novel relationship between HOTAIR and glucose metabolism in HCC cells, and it may be a therapeutic target for diagnosing and treating HCC.

The success of targeted drug therapy for cancer patients has attracted extensive attention from academia and society. However, the rapid development of acquired drug resistance is becoming a major challenge. Autophagy, as an essential homeostatic and catabolic process, is crucial for the degradation or recycling of proteins and cellular components. Autophagy has a crucial role in several cellular functions and its dysregulation is associated with tumorigenesis, tumor–stroma interactions, and resistance to cancer therapy. A growing body of evidence shows that in multiple types of cancer, autophagy is also a key regulator in the tumor microenvironment and the cellular drug response. However, our understanding of the process of autophagy remains incompletely. In this review, we identify the role of autophagy and describe recent advances in the identification of the mechanism by which autophagy is implicated in drug resistance, with a focus on the mode of action, and validation as potential therapeutics.

Supplemental Digital Content is available in the text, Backgrounds: There is no consensus concerning whether surgery or non-surgical treatment is preferred for displaced midshaft clavicle fracture. We performed a meta-analysis of randomized controlled trials (RCTs) to compare healing effects and cosmetic results between surgery and non-surgery. Methods: We retrieved RCTs regarding open reduction and plate fixation (ORPF) and non-surgical method for the treatment of displaced midshaft clavicle fracture published before June 2018 from PubMed, EMBASE and Cochrane Library. The difference between the two treatments was comparatively discussed in aspects of nonunion, malunion, functional outcome, cosmetic results, and complications. Results: Nine RCTs were included. The results showed that ORPF is advantageous over the non-surgical treatment in terms of nonunion rate (RR, 0.11[95%CI, 0.06–0.23]), malunion rate (RR, 0.16[95%CI, 0.08–0.35]), appearance dissatisfaction rate (RR, 0.35[95%CI 0.23–0.55]), and shoulder appearance defect rate (RR, 0.06[95%CI, 0.02–0.17]). The non-surgical treatment showed lower rate of complication (RR, 1.60[95%CI, 1.02–2.53]) and no significant differences were found between the 2 treatment groups with respect to functional outcome (disabilities of the arm, shoulder and hand (DASH) questionnaire score) (MD, −4.17[95%CI, −9.35 to 1.01]). Conclusions: This meta-analysis updated previous results. The current findings suggested that ORPF yielded better efficacy than conservation treatment for displaced midshaft clavicle fracture from perspectives of fracture healing and appearance.

Background: Qigong has a long-term application by integration of mind, breath and body to prevent and cure diseases. Researches show that qigong practice could adjust anxiety, the mechanism may found on brain and heart functions. Currently there are limitations on qigong's anxiety-release mechanism study between mind and body, and existing studies lack of evidence on electrophysiology research. Our objective to analyse qigong's anxiety-release effect and mechanism. Methods: A two-arm randomized clinical trial with 144 qigong naïve anxiety subjects without cerebral or cardiovascular diseases or other severe syndromes will be allocated to either a body and breath regulation group (n = 72) or a body regulation group (n = 72). Participants will conduct three-circle post standing qigong exercise 5 times per week for 8 weeks, while the three-circle post standing qigong combined with abdominal breath regulation (TCPSQ-BR) group will combined with abdominal breath regulation. The primary outcome will be the Self-Rating Anxiety Scale (SAS), and the secondary outcome will be complexity-based measures of heart rate and electroencephalogram (EEG) signals assessed at baseline and 8 weeks. Multiscale entropy analysis will be used as measure of complexity. Conclusion: This study will be investigate the effects of qigong's anxiety-release by SAS, and will analyze the coordinates of EEG and heart rate variability (HRV) signals before and after three-circle post standing qigong (TCPSQ) practice, and to analyse their synergies by complex signal process method. Ethics and trail registration: The protocol was approved by the institutional review boards of Beijing University of Chinese Medicine (2018BZHYLL0109). This study was registered with the “Chinese Clinical Trail Registry” in the WHO Registry Network (ChiCTR-Bon-17010840).

This paper presents a full-scale experimental investigation to study the nonlinear dynamic stiffness of high-modulus polyethylene (HMPE) fibre rope under long-term cyclic loading. Three kinds of ropes with different constructions and diameters were selected as test samples. The influences of mean load and load amplitude on axial stiffness and the corresponding evolution process were respectively studied. The experimental results showed that various braided ropes' dynamic stiffness was slightly different, which was mainly caused by the different twist angles. Furthermore, the non-dimensional stiffness of small-scale rope was lower than the large samples to some extent. This should be related to the small-scale ropes without an outer jacket were much softer and thus had more distinct deformation. The validations against two existing empirical expressions have also been performed. The results pointed out that these equations had some errors predicting the evolution procedure of the dynamic stiffness and the magnitude of small-scale sample's stiffness. On these accounts, a set of empirical expressions, taking into account braid constructions, diameter and input load conditions, has been newly derived. The comparison against the present experimental results proved its good reliability.

The effects of heat shock protein 70 (HSP70)/HSP70-peptide complexes (HSP70-PCs) on the invasion and metastasis ability of hepatocellular carcinoma (HCC) Huh-7 cells were investigated. Wound healing assay revealed that cells treated with HSP70/HSP70-PCs healed faster than negative control cells. HSP70/HSP70-PCs-treated cells also exhibited better migration ability and higher invasion ability than control cells. HSP70/HSP70-PCs treatment did not alter the messenger RNA (mRNA) or protein levels of matrix metalloproteinase-9; the opposite was true for Ras homolog family member A (RhoA) mRNA and protein levels. RNA interference of RhoA attenuated the migration of HSP70/HSP70-PCs-treated cells. The present findings indicate that regulation of HCC cell migration by HSP70/HSP70-PCs occurs via regulation of RhoA expression.

The development of chemotherapy drugs has promoted anticancer treatment, but the effect on tumours is not clear because of treatment resistance; thus, it is necessary to further understand the mechanism of cell death to explore new therapeutic targets. As a new type of programmed cell death, ferroptosis is increasingly being targeted in the treatment of many cancers with clinical drugs and experimental compounds. Ferroptosis is stimulated in tumours with inherently high levels of ferrous ions by a reaction with abundant polyunsaturated fatty acids and the inhibition of antioxidant enzymes, which can overcome treatment resistance in cancers mainly through GPX4. In this review, we focus on the intrinsic cellular regulators against ferroptosis in cancer resistance, such as GPX4, NRF2 and the thioredoxin system. We summarize the application of novel compounds and drugs to circumvent treatment resistance. We also introduce the application of nanoparticles for the treatment of resistant cancers. In conclusion, targeting ferroptosis represents a considerable strategy for resistant cancer treatment.

Background: Liver cancer is one of the most common gastrointestinal malignancies. Anti-angiogenesis therapies have recently demonstrated promise in the treatment of liver cancer and other malignancies, although early treatment benefits may be accompanied by metastasis over time. Additional and more effective anti-angiogenic treatment modalities are therefore needed. We previously found that YAP1 expression is increased in hepatocellular carcinoma, particularly around tumor-associated blood vessels, suggesting a role in angiogenesis. The YAP1 inhibitor verteporfin (VP) is presently in anti-angiogenic clinical trials for the treatment of various cancers. Further elucidating the role of YAP1 in tumor angiogenesis may offer novel therapeutic targets. Methods and Results: We depleted YAP1 from vascular endothelial cells effectively reduces proliferation and tube formation, validating its utility as an anti-angiogenesis target. We also show that YAP1 depletion or inhibition in vascular endothelial cells leads to increased release of exosomes containing the lncRNA MALAT1 into the tumor microenvironment. Direct exosomal transfer of MALAT1 to hepatic cells leads to increased hepatic cell invasion and migration via activation of ERK1/2 signaling. Depletion of endothelial MALAT1 or inhibition of hepatocyte ERK1/2 signaling can suppress VP treatment-associated hepatocyte invasion and migration. Furthermore, we find that MALAT1 expression in patients with hepatocellular carcinoma is associated with decreased disease-free survival and increased lymph node metastasis. Conclusions: These observations may explain the occurrence of distant tumor metastasis with YAP1-associated anti-angiogenic therapy over time, and provide insight into new pathways and treatment paradigms that may be targeted to increase the long-term success of anti-angiogenic therapies. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (No.81472302/No.81572425/No.81871983/No.81572831). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The Institutional Review Board of the Fourth Affiliated Hospital of China Medical University approved the use of human tissue samples for this project. All patients gave their informed written consent for the use of clinical specimens for research.

Background Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown. Methods We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O2) and hypoxic (1% O2) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression. Results In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis. Conclusions Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0892-2) contains supplementary material, which is available to authorized users.

Cancer susceptibility candidate 2 (CASC2), a long non-coding RNA (lncRNA), has been demonstrated to be a tumor suppressor in several types of cancer. However, the role and mechanism of CASC2 in breast cancer (BC) have not been investigated. In the present study, the expression and functions of CASC2 in BC were investigated. The expression of CASC2 was significantly decreased in BC tissues and cells compared with adjacent normal tissues and mammary epithelial cells, respectively. CASC2 overexpression inhibited the viability, migration and invasion, and elevated apoptosis of BC cells. In addition, CASC2 acted as a competing endogenous RNA for hsa-microRNA (miR)-96-5p and regulated the expression of its target gene, synoviolin (SYVN1). In miR-96-5p-overexpressed MDA-MB-231 cells, cell viability, migration and invasion was increased, and cell apoptosis was decreased, which was reversed by the upregulation of SYVN1. Taken together, the present study data indicated that decreased SYVN1 expression was a tumor suppressor, which inhibited the growth and metastasis of BC through the miR-96-5p/SYVN1 axis.

The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been reported to be an oncogene that influences tumor cell development and that correlates with prognosis in hepatocellular carcinoma (HCC). Accumulating evidence indicates that autophagy plays a significant role in tumorigenesis and cancer cell survival, but whether HOTAIR modulates autophagy in HCC cells remains unknown. In this study, HOTAIR expression was measured in 54 matched paired HCC tissues and the adjacent non-tumor tissues. HOTAIR was overexpressed in the HCC tissues as compared with the adjacent non-tumor tissues and was associated with tumor size. In vitro assays revealed that the overexpression of HOTAIR promoted the activation of autophagy in HCC cell lines, whereas HOTAIR knockdown suppressed it. Further investigation revealed that overexpressed HOTAIR upregulated autophagy-related 3 (ATG3) and ATG7 expression in HCC cells. In conclusion, HOTAIR, overexpressed in HCC and associated with tumor size, could activate autophagy by increasing ATG3 and ATG7 expression, promoting HCC cell proliferation.

Intrahepatic cholangiocarcinoma is the second most common primary malignant tumor of the liver, and it originates from the intrahepatic biliary duct epithelium. Prognosis is poor due to lack of effective comprehensive treatments. In this study, we assessed the expression of Gab1, VEGFR-2, and MMP-9 in intrahepatic cholangiocarcinoma solid tumors by immunohistochemistry and determined whether their expression was associated with clinical and pathological features. We found that expression of Gab1, VEGFR-2, and MMP-9 was highly and positively correlated with each other and with lymph node metastasis and TNM stage in intrahepatic cholangiocarcinoma tissues. Interference of Gab1 and VEGFR-2 expression via siRNA in the intrahepatic cholangiocarcinoma cell line RBE resulted in decreased PI3K/Akt pathway activity. Inhibition of Gab1 and VEGFR-2 expression also caused decreased cell proliferation, cell cycle arrested in G1 phase, increased apoptosis, and decreased invasion in RBE cells. These results suggest that Gab1, VEGFR-2, and MMP-9 contribute significantly to the highly malignant behavior of intrahepatic cholangiocarcinoma. The regulation of growth, apoptosis, and invasion by Gab1 through the VEGFR-2/Gab1/PI3K/Akt signaling pathway may represent potential targets for improving the treatment of intrahepatic cholangiocarcinoma.

Background Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H+ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation. Methods Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription–PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues. Results Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3). Conclusion Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-018-0673-y) contains supplementary material, which is available to authorized users.

IntroductionMany surgical techniques have been used to repair abdominal wall defects in the inguinal region based on the anatomic characteristics of this region and can be categorised as ‘tension’ repair or ‘tension-free’ repair. Tension-free repair is the preferred technique for inguinal hernia repair. Tension-free repair of inguinal hernia can be performed through either the anterior transversalis fascia approach or the preperitoneal space approach. There are few large sample, randomised controlled trials investigating the curative effects of the anterior transversalis fascia approach versus the preperitoneal space approach for inguinal hernia repair in patients in northern China.Methods and analysisThis will be a prospective, large sample, multicentre, randomised, controlled trial. Registration date is 1 December 2016. Actual study start date is 6 February 2017. Estimated study completion date is June 2020. A cohort of over 720 patients with inguinal hernias will be recruited from nine institutions in Liaoning Province, China. Patient randomisation will be stratified by centre to undergo inguinal hernia repair via the anterior transversalis fascia approach or the preperitoneal approach. Primary and secondary outcome assessments will be performed at baseline (prior to surgery), predischarge and at postoperative 1 week, 1 month, 3 months, 1 year and 2 years. The primary outcome is the incidence of postoperative chronic inguinal pain. The secondary outcome is postoperative complications (including rates of wound infection, haematoma, seroma and hernia recurrence).Ethics and disseminationThis trial will be conducted in accordance with the Declaration of Helsinki and supervised by the institutional review board of the Fourth Affiliated Hospital of China Medical University (approval number 2015–027). All patients will receive information about the trial in verbal and written forms and will give informed consent before enrolment. The results will be published in peer-reviewed journals or disseminated through conference presentations.Trial registration numberNCT02984917; preresults.

Exosomes are a new means of intercellular information exchange that have aroused great research interest. Long neglected in research, exosomes were deemed nonfunctional cellular components to be discarded. However, it has been gradually revealed that exosomes are an important tool for the exchange of intercellular information and material. Exosomes contain specific repertoires of non-coding RNAs (ncRNAs, including microRNA and lncRNA), indicating that a specific RNA sorting mechanism may exist. Correspondingly, intracellular multivesicular bodies (MVBs) are produced after fusion with the cell membrane to release exosomes rather than inducing autophagy, which reveals that there may be a specific regulatory mechanism for MVB secretion. Cells can trigger cancer-related disorders after the recognition and uptake of circulating exosomal ncRNAs, providing indications for early tumor biopsy and treatment. The use of exosomes as a biological carrier in targeted therapy has been demonstrated. However, there may be a specific, unknown switch for loading drugs. This review focuses on the mechanisms of exosome biogenesis, release, and uptake. We also review the promotion of tumor development by exosomal ncRNAs including chemotherapy resistance, metastasis and the prospective use of exosomes in cancer diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality. Tumor neovascularization is necessarily required for tumor progression and metastasis. CD105 and vascular endothelial growth factor (VEGF) have separately been identified as important contributors to angiogenesis; however, it is unclear if these factors interact to promote the progression of HCC. The goal of this study was to determine the interaction between CD105 and VEGF in HCC, using HCC tissue samples and the human HCC cell line SMMC-7721. In a survey of 89 HCC tumor samples, we determined that CD105 and VEGF expressions were positively correlated with each other and expressed at a higher level in tumor cells. Furthermore, the expression of CD105 was closely related to the tumor-node-metastasis (TNM) staging of HCC, degree of tumor differentiation, portal vein invasion, and lymph node metastasis (P

The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced Toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and the molecular mechanism was investigated. The HCC cells were used to study the invasion ability of LPS-induced HCC cells and the epithelial-mesenchymal transition (EMT) in vitro. The in vitro experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate JNK/MAPK signaling through TLR4 in HCC cells. Interestingly, blocking JNK/MAPK signaling significantly inhibited EMT occurrence. Our results indicate that TLR4/JNK/MAPK signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.

Background Many types of regional nerve blocks have been used during anesthesia for modified radical mastectomy. In recent years, the use of pectoral nerve (PECS) block has gained importance in postoperative analgesia, but there are still controversies regarding its efficacy. There is especially no consensus on the optimal type of PECS block to be used. Herein, we attempt to evaluate the analgesic efficacy of the PECS block after radical mastectomy. Methods We searched PubMed, EMBASE, and the Cochrane library for randomized controlled trials (RCTs) for studies regarding PECS versus general anesthesia (GA) that were published prior to May 31, 2018. Outcome measures such as intra- and postoperative consumption of opioids, postoperative nausea and vomiting (PONV), need for postoperative rescue analgesia, and pain scores were analyzed. After quality evaluation and data extraction, a meta-analysis was performed using Review Manager 5.3 software, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used for rating the quality of evidence. Results A total of 8 RCTs and 2 cohort studies involving 993 patients were eligible. Compared with the GA group, the PECS block group effectively reduced the intraoperative and postoperative use of opioid drugs, incidence of PONV, need for postoperative rescue analgesia, and pain scores within 0 to 6 hours after surgery. However, subgroup analysis showed that PECS I block did not have a significant advantage in reducing the intra- and postoperative consumption of opioids. Results for each outcome indicator were confirmed as having a high or moderate level of evidence. Conclusions Even considering the limitations (evaluations of efficacy in different age groups and for chronic pain were not carried out) of this meta-analysis, it can be concluded that the PECS II block is an effective anesthetic regimen in modified radical mastectomy that can effectively reduce the intra- and postoperative consumption of opioids, postoperative PONV, and the need for postoperative rescue analgesia and can alleviate early pain (0-6 hours) after surgery.

// Xiaodong Zhang 1, * , Qing Fan 1, * , Yan Li 1, 2, * , Zhaoguo Yang 1 , Liang Yang 1 , Zhihong Zong 3 , Biao Wang 3 , Xin Meng 3 , Qin Li 1 , Jingang Liu 1 and Hangyu Li 1 1 Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, P. R. China 2 Department of Oncology, Tumour Angiogenesis and Microenvironment Laboratory (TAML), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, P. R. China 3 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University, Shenyang, P. R. China * These authors have contributed equally to this work Correspondence to: Hangyu Li, email: sj_li_hangyu@sina.com Keywords: transforming growth factor-beta, hepatocellular carcinoma, Hippo signaling, proliferation Received: August 10, 2016 Accepted: December 27, 2016 Published: January 05, 2017 ABSTRACT In this study, we examined the expression of core proteins of the Hippo signaling pathway in hepatocellular carcinoma (HCC) cells treated with transforming growth factor-β 1(TGF-β1) and investigated the relationship between TGF-β1 and the Hippo signaling pathway, in order to better understand their roles in HCC and their potential implications for cancer therapy. We prove that the Hippo signaling pathway is involved in the TGF-β1-induced inhibition of the growth of HCC cells. Large tumor suppressor expression (LATS1) was overexpression and yes association protein 1(YAP1) translocated from the nucleus to the cytoplasm in HCC cells treated with TGF-β1. Overexpression of LATS1 and the nucleocytoplasmic translocation of YAP1 play an anti-oncogenetic role in the occurrence and development of liver cancer. Our findings provide new insight into strategies for liver cancer therapy.

Heat shock protein 70 (HSP70) and HSP70-peptide complexes (HSP70-PCs) have been implicated in the pathogenesis of multiple tumors in humans and have been experimentally shown to increase the proliferation of cell lines derived from hepatocellular carcinoma. The goal of this study was to elucidate the molecular mechanisms through which extracellular HSP70/HSP70-PCs stimulate the proliferation of hepatocellular carcinoma (HCC). The molecular mechanisms of HSP70/HSP70-PC action were studied in the human hepatocellular carcinoma cell lines HepG2 and Huh-7, as well as tumor tissue collected from patients with HCC (n = 95). We found that HSP70/HSP70-PCs can stimulate the proliferation of HepG2 cells and that this effect is blocked by knocking down TLR2 and TLR4 expression by RNA interference. A physical interaction between HSP70/HSP70-PCs and TLR2/4 was established using co-immunoprecipitation and pull-down assays. Pharmacological inhibition of different branches of the MAPK intracellular signaling pathway indicated that the extracellular HSP70/HSP70-PC effect was mediated by the JNK1/2 signaling pathway within the cell. We also studied TLR2 and TLR expression at the protein and messenger RNA (mRNA) level in tumor and non-tumor tissue in patients with HCC (n = 95), finding that TLR2 and 4 are increased in HCC tumor tissue and that the expression of TLR2 correlates with clinicopathologic features of HCC. Our data conclusively demonstrates that extracellular HSP70/HSP70-PCs can promote the proliferation of HCC cells through activation of TLR2 and TLR4 and subsequent activation of the intracellular JNK1/2/MAPK signaling pathway.

Part of the patients with incisional hernia (IH) suffered from constipation or even circulatory impairment, which is called large IH with loss of domain (LOD) or giant IH. For now, there is still controversy about the definition and pathomechanism of the LOD; meanwhile, there is no clear criterion for evaluating and treating patients with LOD. A systematic search of the literature was implemented in PubMed and the Cochrane database by using the keywords “IH, abdominal wall function(AWF), LOD” and got 60 publications finally. First, there is still no unified definition for LOD, but we found that it was translated into a situation that abdominal content can hardly be reduced with AWF deficiency in 2018th Chinese Guidelines. Second, we concluded that poor abdominal wall contraction caused by muscular atrophy or fibrillation after large area aponeurosis released shall be important pathomechanism of LOD. Third, we found that there are different methods for evaluating LOD, while the activity evaluation may be most useful. Finally, component separation technique (CST), bridge repair or utotransplantation have been recommended in many publications for variable condition. The definition of LOD is better to be divided into the functional deficiency and the anatomical defect just like Chinese guidelines. The pathomechanism of LOD was actually based on anatomical destruction of abdominal wall contraction system. The activity evaluation may be the most convenient method mentioned in the publications. CST was strongly recommended to be used in giant hernia, the defect of which can be hardly closed. Patients who have IH with LOD are proposed to receive hernioplasty as early as possible because of the impendency to reconstruct the large defect on the abdominal wall as well as restoration of the AWF. Surgeons may select appropriate CST to repair IH according to the length of the defect.

To study the anti-tumor effect of arsenic trioxide on the HepG2 human hepatocellular carcinoma cell line, and to explore its mechanism of action. The MTT assay was used to determine the inhibitory effect of As2O3 on HepG2 cells at various As2O3 concentrations. The expression of p-JNK, caspase-3 and PARP was detected by Western blots. As2O3 markedly inhibited the growth of the HepG2 cells and induced apoptosis. The results of Western blot analysis showed that the As2O3-induced apoptosis was accompanied by caspase-3 and PARP activation. p-JNK was detected at 10 min following As2O3 treatment, and preceded to peak at 20 min, and decreased by 30 min. The total protein content did not obviously change. The activation of JNK occurred prior to cell apoptosis. SP600125, a JNK inhibitor, suppressed the As2O3-induced activation of caspase-3 and PARP cleavage. As2O3 inhibits the proliferation of human HepG2 hepatocellular carcinoma cells by inducing apoptosis in vitro. As2O3-induced apoptosis is accessed through the caspase-3 pathway. The JNK signal-transduction pathway and caspase-3 are involved upstream in the As2O3-induced HepG2 apoptotic response.

Activation of stress-activated protein kinase/c-Jun N-terminal kinase was inhibited in cells, in which heat shock protein70 was induced to a high level, indicating that heat shock protein70 might be anti-apoptosis protein.We examined the expression of heat shock protein70 and c-Jun N-terminal kinase signal transduction pathway in human liver carcinoma to explore their relationship and clinical parameters.The expression of heat shock protein70, c-Jun N-terminal kinase1, c-Jun N-terminal kinase2 and c-Jun were detected immunohistochemically in 62 samples of liver cancer. Western blot was used to confirm immunostaining results.Heat shock protein70 expression showed a positive correlation with the malignant differentiation in liver carcinoma (r=0.449, P0.0005). The expression of c-Jun N-terminal kinase1, c-Jun N-terminal kinase2, and c-Jun showed a negative correlation with the malignant differentiation in liver carcinoma (r=-0.351, P=0.005; r=-0.303, P=0.017; r=-0.302, P=0.017). Heat shock protein70 expression was correlated with c-Jun N-terminal kinase1 (r=-0.385, P=0.002), c-Jun N-terminal kinase2 (r=-0.309, P=0.015) and c-Jun (r=-0.302, P=0.017). Expression of heat shock protein70, as well as c-Jun N-terminal kinase1, was correlated with recurrence-free survival after the resection. Heat shock protein70 was associated with prognosis (P=0.004).Expression of heat shock protein70 and c-Jun N-terminal kinase-related proteins might be an indicator of malignant potential in liver carcinoma. The balance between heat shock protein70 and c-Jun N-terminal kinase-related protein may increase the stability of liver cancer cells in stress. Negative expression of heat shock protein70 might be a protective factor of recurrence of liver carcinoma.

// Yue-Mei Xu 1, * , Hong-Jiang Wang 2, * , Fang Chen 3, * , Wan-Hua Guo 4, * , Yan-Yang Wang 4, * , Hang-Yu Li 5, * , Jin-Hai Tang 6, * , Ying Ding 1 , Ya-Chen Shen 7 , Min Li 1, 7 , Wen-Ying Xuan 1 , Lin-Hui Liu 1 , Jia Wang 2 , Xue-Rong Wang 1 , Ze-Jun Gao 1 , Xiu-Bin Liang 7 , Dong-Ming Su 1, 7, 8 1 State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China 2 Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China 3 Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China 4 Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China 5 Department of General Surgery, 4th Affiliated Hospital, China Medical University, Shenyang, China 6 Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China 7 Center of Metabolic Research, Nanjing Medical University, Nanjing, China 8 Center of Cellular therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Dong-Ming Su, e-mail: sudongming@njmu.edu.cn Keywords: HRD1, breast cancer, metastasis, IGF-1R, degradation Received: May 02, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-κB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo . Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer.

Background Ganoderma lucidum polysaccharides (GLPS) have been used as traditional Chinese medicine for their properties of cancer prevention and immunomodulation. However, it is unclear whether GLPS has therapeutic effect on anti-hepatocellular carcinoma (HCC) in vivo. In this study, the effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) was measured in a model of hepatoma-bearing mice. Methods The effect of GLPS and their impact on the balance of regulatory T cell (Treg) and effector T cell (Teff) were measured in a model of hepatoma-bearing mice. Real-time PCR detected the levels of MicroRNAs (miRNAs) and mRNA. The effects of Tregs on Teff proliferation were determined via suppression assay. The mircroRNA-125b (miR-125b) inhibitor was used to down-regulate miR-125b expression. Results GLPS significantly suppressed tumor growth in hepatoma-bearing mice associated with an increase of the ratio of Teffs to Tregs. Moreover, GLPS eliminate Treg suppression of Teff proliferation with an increase in IL-2 secretion. Addition of GLPS to treat T cells inhibited Notch1 and FoxP3 expression through increase of miR-125b expression. In hepatoma-bearing mice, miR-125b inhibitor obviously abolished the effect of GLPS on tumor growth. Conclusions This finding provides the novel evidence for GLPS on inhibition of HCC through miR-125b inhibiting Tregs accumulation and function.

Background/Aims: The molecular mechanisms of celastrol on hepatocellular carcinoma (HCC) cells migration and invasion ability is the major problem that prompted the study. Methods: We first evaluated the effect of celastrol on migration and invasion ability of HepG2 cells using transwell migration and matrigel invasion assays. Next, we assessed the effect of celastrol on NF-κB transcriptional activity in hepatocellular carcinoma cells using western blot and luciferase reporter assay. We also performed real-time PCR to measure miR-224, MMP-2 and MMP-9 expression. Western blot was used to measure protein expression of MMP-2 and MMP-9. Furthermore, we used miR-224 inhibitor to evaluate whether down-regulation of miR-224 expression can affect MMP-2 and MMP-9 expression. The binding ability of p65/NF-κB on the miR-224 promote has been assessed by chromatin immunoprecipitation and quantitative real-time PCR (ChIP-qPCR). Finally, we evaluated the effect of miR-224 on celastrol-induced anti-tumor activity using miR-224 precursor. Results: Celastrol significantly impaired migration and invasion of HepG2 cells and inhibited the activation of NF-κB and Akt in dose-dependent manner. IGF (the strong stimulator of Akt) inhibited the transcriptional activity of NF-κB in cells treated with celastrol. Besides, celastrol efficiently decreased the expression of miR-224 and protein expression of MMP-2 and MMP-9. ChIP-qPCR showed that p65/NF-κB binding to the miR-224 promoter sharply decreased after exposure to celastrol in time-dependent manner. Furthermore, inhibition of miR-224 expression can decrease MMP-9 protein level. Most importantly, miR-224 precursor can reverse the effect of celastrol on impairment of migration and invasion in HepG2 and Huh7 cells. Conclusion: Celastrol treatment inhibits migration and invasion of HCC cell and that the effect is partly due to NF-κB regulating miR-224 expression.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic small- and medium-sized-vessel vasculitis. The literature contains only a few reports of gastrointestinal perforation with this condition. We report a patient with EPGA treated with high-dose steroid who underwent emergency surgery for intestinal perforations. We performed a simple repair of the 11 perforations. Intestinal fistulas developed 8 d postoperatively; they healed well after 60 d of continuous washing and negative pressure suction. The clinical data of 14 additional patients with EGPA or Churg-Strauss syndrome complicated with gastrointestinal perforation, which were reported from 1996 to 2014, were also collected and compared. The formation of multiple perforations and fistulas following high dosage steroid administration can have a good outcome with appropriate management. Meticulous attention to abdominal symptoms and appropriate interventions can result in timely management. Corticosteroid administration remains a very important perioperative procedure for EPGA.