Global research trends in the tumor microenvironment of hepatocellular carcinoma: insights based on bibliometric analysis.

Objective: This study aimed to use visual mapping and bibliometric analysis to summarize valuable information on the tumor microenvironment (TME)-related research on hepatocellular carcinoma (HCC) in the past 20 years and to identify the research hotspots and trends in this field. Methods: We screened all of the relevant literature on the TME of HCC in the Web of Science database from 2003 to 2023 and analysed the research hotspots and trends in this field via VOSviewer and CiteSpace. Results: A total of 2,157 English studies were collected. According to the prediction, the number of papers that were published in the past three years will be approximately 1,394, accounting for 64.63%. China published the most papers (n=1,525) and had the highest total number of citations (n=32,253). Frontiers In Immunology published the most articles on the TME of HCC (n=75), whereas, Hepatology was the journal with the highest total number of citations (n=4,104) and average number of citations (n=91). The four clusters containing keywords such as "cancer-associated fibroblasts", "hepatic stellate cells", "immune cells", "immunotherapy", "combination therapy", "landscape", "immune infiltration", and "heterogeneity" are currently hot research topics in this field. The keywords "cell death", "ferroptosis", "biomarkers", and "prognostic features" have emerged relatively recently, and these research directions are becoming increasingly popular. Conclusions: We identified four key areas of focus in the study of the TME in HCC: the main components and roles in the TME, immunotherapy, combination therapy, and the microenvironmental landscape. Moreover, the result of our study indicate that effect of ferroptosis on the TME in HCC may become a future research trend.

Effects of Dietary Supplementation of Quillaja Saponin or Phytase on the Growth Performance, Nutrient Digestibility, Faecal Gas Emissions, and Carcass Grade in Growing-Finishing Pigs.

This experiment aimed to evaluate the effects of low doses of Quillaja saponin (QS) or phytase (PHY) on growth performance, nutrient digestibility, faecal gas emissions, and carcass grade in growing-finishing pigs. A total of 72 pigs (Landrace × Yorkshire × Duroc), each weighing 25.82 ± 1.68 kg, were selected and randomly assigned to three treatment groups. Each group had six replicates, with four pigs per pen, and the allocation was based on the four initial body weight and sex of the pigs. They were randomly divided into the following three diet groups: the basal diet as a control (CON) group, the basal diet + 0.02% PHY; and the basal diet + 0.01% QS. The experiment period lasted for 110 days. The results of adding 0.01% QS to the basal diet of pigs show that it can significantly increase the body weight (BW) of growing-finishing pigs on the 110th day (p < 0.05). QS can significantly increase the average daily weight gain (ADG) on Days 80-110 of the experiment (p < 0.05). QS can significantly increase the total average daily weight gain (TADG) of growing-finishing pigs during the entire experimental period (p < 0.05) and has a tendency to improve the average daily feed intake and feed conversion rate during the entire experimental period. However, QS has no significant effect on pig nutrient digestibility and carcass grade. In addition, we also found that QS has a tendency to reduce carbon dioxide emissions. However, adding 0.02% PHY to the basal diet of growing-finishing pigs can only increase the TADG during the entire experimental period. Throughout the experiment, adding PHY to the diet had no significant impact on the nutrient digestibility, faecal gas emissions, and carcass grade of growing-finishing pigs. In summary, adding QS to feed can significantly improve the growth performance of growing-finishing pigs, and has a tendency to improve faecal gas emissions. PHY can only improve the growth performance of growing-finishing pigs.

Lactylation: An Innovative Approach to Disease Control.

Assessment of tissue microenvironment lactate levels has emerged as a crucial indicator of microcirculation and early organ dysfunction. Lactylation modification, closely associated with lactate concentration, represents a novel post-translational alteration targeting protein lysine residues. Post-translational modifications are chemical changes capable of modulating protein activity and functionality, serving as a rapid mechanism for enhancing proteomic diversity and influencing various life processes. While previous research primarily focused on histone lactylation, recent studies have revealed the occurrence of lactylation on non-histone proteins, exerting significant effects on gene expression and intercellular communication. Lactylation has been implicated in diverse diseases spanning embryonic development, neuronal excitability, inflammatory responses, cardiovascular conditions, tumor progression, invasion, and aging. Hence, lactylation emerges as a pivotal regulator in numerous pathological conditions. This review delves into the mechanisms underlying lactylation and disease pathogenesis, elucidates the multifaceted roles of lactylation in disease progression, and identifies novel therapeutic targets related to lactylation, offering potential avenues for future clinical interventions.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Exploring the biological diversity and source species of medicinal horseflies through metabarcoding.

Horseflies from the Tabanidae family play a significant role in traditional Chinese medicine to treat various health conditions, including coronary heart disease, stroke, headaches, liver cirrhosis, psoriasis, and hepatic carcinoma. There are 27 species of Tabaninae (Tabanidae) used as medicine, and they showed high morphological similarities with those for which medicinal properties have not been reported. Nonetheless, there have been reports suggesting that medicinal crude drugs sometimes contain irrelevant or false species, impacting the drug's efficacy. In this current study, we collected 14 batches, totaling 13,528 individuals, from various provinces in China. Instead of "classic" DNA barcoding strategy, we employed a high-throughput metabarcoding approach to assess the biological composition of crude drug mixtures derived from horseflies. Our analysis identified 40 Amplicon Sequence Variants (ASVs) with similarity percentages ranging from 92% to 100% with 12 previously reported species. Species delimitation methods revealed the presence of 11 Molecular Operational Taxonomic Units (MOTUs), with ten belonging to the Tabanus genus and one to Hybomitra. Tabanus sp6 displayed the highest relative abundance, and its ASVs showed close resemblance to Tabanus pleski. Our investigations revealed that the medicinal batches were biologically composed of 6 to 12 species. Some batches contained ASVs that closely resembled species previously associated with false Tabanus species. In conclusion, our findings offer valuable insights into the biological composition of crude drugs derived from horseflies and have the potential to enhance the quality of these traditional medicines.

piRNA-823 is a novel potential therapeutic target in aortic dissection.

Aortic dissection (AD) presents a medical challenge for clinicians. Here, to determine the role of a novel small non-coding piRNA-823 (piR-823) in AD, murine and human aorta from patients with AD were used. A high expression levels of piR-823 were found in patients with AD. Using performed loss- and gain-of-function assays in vitro and in vivo, we explore the regulatory effect of piR-823 on vascular smooth muscle cells (VSMCs) and AD. piR-823 obviously facilitates the proliferation, migration, and phenotypic transformation of VSMCs with or without nicotine treatment. piR-823 directly binds and suppresses histone deacetylase 1 (HDAC1) expression, and regulates the acetylation of histone 3 (H3) via H3K9ac and H3K27ac, eventually, VSMC functions and AD. To consolidate our findings, AD murine model was performed, and we observed that piR-823 antagomir strongly inhibited the pathogenesis of AD through regulating vascular remodeling. Thus, our study finds a potential target for the prevention and treatment strategy for nicotine-induced AD.

Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases.

Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

A multidimensional model incorporating radiomics score and liquid biopsy for the prediction of malignant and benign pulmonary nodules.

Background: As the lesions in pulmonary nodules (PNs) are small and the clinical manifestations lack specificity, the etiology of PNs is complex, predisposing them to misdiagnoses missed diagnoses. Thus, the diagnosis and treatment of PNs remains challenging and an important clinical problem. Methods: This study prospectively enrolled 156 patients with computed tomography (CT)-diagnosed PNs who underwent circulating genetically abnormal cell (CAC) testing between January 2020 and December 2021. We collected data on clinical features closely related to the nature of PNs, such as age, smoking history, and type of nodule. All internal regions of interest (ROIs) of PNs in this study were segmented. Radiomic feature extraction was performed on the ROIs, and a radiomics model was constructed using least absolute shrinkage and selection operator (LASSO) regression to obtain a radiomics score (Rad-score). A comprehensive model combining clinical features, Rad-score, and liquid biopsy was constructed using logistic regression analysis. The diagnostic performance of the model was evaluated using receiver operating characteristic (ROC) curves. Results: In this study, 5 radiomics features were screened for model construction. The area under the ROC curve (AUC) of the radiomics model was 0.844 [95% confidence interval (CI): 0.766-0.915] in the training set. The Rad-score, clinical features, and CAC were further combined to construct a multidimensional analysis model. The AUC of the synthesized model was 0.943 (95% CI: 0.881-0.978) in the training set. Conclusions: A multidimensional model is an effective tool for the noninvasive diagnosis of malignant PNs. The validation and combination of multiple diagnostic methods is a productive avenue of research trend for the identification of malignant PNs.

BP5 alleviates endotoxemia-induced acute lung injury by activating Nrf2 via dual regulation of the Keap1-Nrf2 interaction and the Akt (Ser473)/GSK3ß (Ser9)/Fyn pathway.

Oxidative stress and inflammation play a crucial role in the pathogenesis of acute lung injury (ALI). Previously, pentapeptide bursopentin (BP5, Cys-Lys-Arg-Val-Tyr) was reported to possess significant antioxidant activity and inhibit lipopolysaccharides (LPS)-induced NF-κB activation in vitro, whereas little is known about its effects in vivo. In this study, we explored the effects of BP5 on endotoxemia-induced ALI in mice and the underlying molecular mechanisms. Our studies revealed that BP5 markedly improved survival and effectively alleviated lung injury by reducing overoxidation and excessive inflammatory response in endotoxemia mice. In LPS-stimulated mouse primary macrophages and RAW 264.7 cells, BP5 also exhibited antioxidant and anti-inflammatory properties by enhancing Nrf2 activation. Importantly, these beneficial effects were abolished by Nrf2 knockdown. To further elucidate the underlying mechanisms, we performed localized surface plasmon resonance (LSPR) assays, molecular docking, together with cell-based studies, and found that BP5 inhibited the Keap1-Nrf2 interaction to promote Nrf2 nuclear translocation and activation. Moreover, BP5-induced Nrf2 activation was shown to be accompanied by an increase in the phosphorylation of Akt (at Ser473) and GSK3ß (at Ser9), and a decrease in Fyn nuclear accumulation both in vitro and in vivo. Pharmacologically inhibiting phosphorylation of Akt and GSK3ß obviously enhanced Fyn nuclear accumulation in RAW 264.7 cells, which partially attenuated the promoting effect of BP5 on Nrf2 nuclear accumulation and activation. Furthermore, In Nrf2-/- mice, the protective effects of BP5 on the endotoxemia-induced ALI in WT mice were largely vanished. Our findings indicated that BP5 effectively protected endotoxemia-induced ALI against oxidative stress and inflammatory response, which are largely dependent on activation of the Nrf2 pathway. Underlying mechanisms include dual regulation of the Keap-Nrf2 interaction and the Akt (Ser473)/GSK3ß (Ser9)/Fyn pathway.

The Phenomenon of Gene Rearrangement is Frequently Associated with TP53 Mutations and Poor Disease-Free Survival in Hepatocellular Carcinoma.

PURPOSE: Gene rearrangements (GRs) have been reported to be related to adverse prognosis in some tumours, but the relationship in hepatocellular carcinoma (HCC) remains less studied. The objective of our study was to explore the clinicopathological characteristics and prognosis of HCC patients (HCCs) with GRs (GR-HCCs). PATIENTS AND METHODS: This retrospective study included 297 HCCs who underwent hepatectomy and had their tumours sequenced by next-generation sequencing. Categorical variables between groups were compared by the chi-square test. The impact of variables on disease-free survival (DFS) and survival after relapse (SAR) was analysed by the Kaplan-Meier method and Cox regression. RESULTS: We observed four repetitive GR events in 297 HCCs: BRD9/TERT, ARID2/intergenic, CDKN2A/intergenic and OBSCN truncation. GR-HCCs frequently presented with low tumour differentiation, tumour necrosis, microvascular invasion, elevated AFP and gene mutations (TP53, NTRK3 and BRD9). The 1-, 2-, and 3-year cumulative DFS rates in GR-HCCs were 45.1%, 31.9%, 31.9%, respectively, which were significantly lower than those of GR-negative HCCs (NGR-HCCs) (72.5%, 57.9%, and 49.0%, respectively; P = 0.001). GR was identified as an independent risk factor for inferior DFS in HCCs (HR = 1.980, 95% CI = 1.246-3.147; P = 0.004). However, there was no significant difference in SAR between GR-HCCs and NGR-HCCs receiving targeted therapy or immunotherapy. CONCLUSION: GR is frequently associated with TP53 mutations and significantly affects DFS following radical resection for HCC. We recommend that GR-HCCs should be closely followed up as a high-risk group for postoperative recurrence.

Severe Fatigue is an Important Factor in the Prognosis of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib.

OBJECTIVE: To investigate the effects of fatigue on the survival of patients with advanced hepatocellular carcinoma treated with sorafenib. PATIENTS AND METHODS: A retrospective analysis of 182 cases of patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2017, showed clinical and pathological data and follow-up results. The clinical and pathological data as well as follow-up results of 182 patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2018, were retrospectively analyzed. All patients were treated for at least 3 months. Patients were divided into three groups: fatigue grade I (n=74), fatigue grade II (n=62), and fatigue grade III (n=46), according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 5.0. Survival analysis between groups was performed by the Kaplan-Meier method (Log rank test), continuous variables were analyzed by t-test, and categorical variables were analyzed by chi-square test. RESULTS: The overall survival (OS) of patients who were relieved of fatigue was 33.0±9.3 months, whereas the OS of patients who were not relieved of fatigue was 15.0±1.8 months (P<0.000). Furthermore, the time to progress (TTP) of patients who were relieved of fatigue by resting was 20.3 ± 10.9 months compared to a TTP of 7.7 ± 1.0 months in patients who were not relieved of fatigue (P<0.000). CONCLUSION: Patients, especially the elderly and infirm, were more susceptible to toxicity.

Anti-inflammatory effects of Rhodiola rosea L.: A review.

Rhodiola rosea L., a worldwide botanical adaptogen, has been confirmed to possess protective effects of inflammatory injury for many diseases, including cardiovascular diseases, neurodegenerative diseases, diabetes, sepsis, and cancer. This paper is to review the recent clinical and experimental researches about the anti-inflammatory effects and the related mechanisms of Rhodiola rosea L. extracts, preparations, and the active compounds. From the collected information reviewed, this paper will provide the theoretical basis for its clinical application, and provide the evidences or guidance for future studies and medicinal exploitations of Rhodiola rosea L.

Effect of Nitrogen-Doped Graphene Oxide on the Aging Behavior of Nitrile-Butadiene Rubber.

Nitrogen-doped graphene oxide (GO), namely, NG, was prepared by o-phenylenediamine (OPD) grafting onto GO. The structure and morphology of NG were characterized by FITR, XRD, SEM, EDS, Raman spectroscopy, and TGA. OPD was linked to the GO surface by covalent bonds, and the absorption peak of the C=N bond in the phenazine structure was identified in the FITR spectra. The aging resistance properties of nitrile-butadiene rubber (NBR)-NG composites was investigated by mechanical testing, before and after aging. The resistance of the NBR/NG composites with the addition of 3 phr NG fillers was the highest. The aging mechanism was investigated by TGA-DSC, DMA, equilibrium swelling testing, and ATR-FTIR. The results showed that NG could effectively inhibit chain cross-linking in NBR.

Bursopentin (BP5) induces G1 phase cell cycle arrest and endoplasmic reticulum stress/mitochondria-mediated caspase-dependent apoptosis in human colon cancer HCT116 cells.

BACKGROUND: Bursopentin (BP5) is a multifunctional pentapeptide found in the chicken bursa of Fabricius. Recent study indicated that BP5 significantly stimulates expression of p53 protein in colon cancer HCT116 cells. However, the effects and underlying mechanisms of BP5 on HCT116 cell proliferation remain largely unclear. METHODS: Analyses of cell viability, cell cycle arrest as well as apoptosis were performed to study the actions of BP5 on HCT116 cells. Western blot analyse was assayed to measure the cell cycle-related and apoptosis-related proteins. Specific siRNAs targeting IRE1, ATF-6, and PERK were used for IRE1, ATF-6, and PERK knockdown, respectively. Cellular reactive oxygen species (ROS) were detected using a H2DCF-DA green fluorescence probe. Cytosolic free Ca2+ concentrations and mitochondrial membrane potential (ΔΨm) were measured using Fluo-3 AM and JC-1 stains, respectively. RESULTS: BP5 possessed strong inhibitory effects on the cell growth and induced apoptosis in HCT116 cells. Mechanistically, BP5 arrested the cell cycle at G1 phase by increasing p53 and p21 expression and decreasing cyclin E1-CDK2 complex expression. BP5 treatment dramatically activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway, as revealed by the significantly enhanced expression of unfolded protein response (UPR) sensors (IRE1α, ATF6, PERK) as well as downstream signaling molecules (XBP-1s, eIF2α, ATF4 and CHOP), and by the significantly altered the BP5-induced phenotypic changes in IRE1, ATF6, and PERK knockdown cells. Additionally, BP5-induced ER stress was accompanied by the accumulation of cytosolic free Ca2+ and intracellular ROS. Furthermore, BP5 treatment resulted in the increase of Bax expression, the decrease of Bcl-2 expression and the reduction of ΔΨm, subsequently causing a release of cytochrome c from the mitochondria into the cytoplasm and finally enhancing the activities of caspase-9 and -3. In addition, z-VAD-fmk, a pan-caspase inhibitor, markedly rescued BP5-induced cell viability reduction and reduced BP5-induced apoptosis. CONCLUSIONS: Our present results suggest that BP5 has an anticancer capacity to arrest cell cycle at G1 phase and to trigger ER stress/mitochondria-mediated caspase-dependent apoptosis in HCT116 cells. Therefore, our findings provide insight into further investigations of the anticancer activities of BP5.

Roles of Non-Coding RNAs in Normal Human Brain Development, Brain Tumor, and Neuropsychiatric Disorders.

One of modern biology's great surprises is that the human genome encodes only ~20,000 protein-coding genes, which represents less than 2% of the total genome sequence, and the majority of them are transcribed into non-coding RNAs (ncRNAs). Increasing evidence has shown that ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating a wide range of biological processes of the human brain. They not only regulate the pathogenesis of brain tumors, but also the development of neuropsychiatric diseases. This review provides an integrated overview of the roles of ncRNAs in normal human brain function, brain tumor development, and neuropsychiatric disease. We discussed the functions and molecular mechanisms of miRNAs, lncRNAs, and circRNAs in normal brain function and glioma, respectively, including those in exosome vesicles that can act as a molecular information carrier. We also discussed the regulatory roles of ncRNAs in the development of neuropsychiatric diseases. Lastly, we summarized the currently available platforms and tools that can be used for ncRNA identification and functional exploration in human diseases. This study will provide comprehensive insights for the roles of ncRNAs in human brain function and disease.

SETD3 negatively regulates VEGF expression during hypoxic pulmonary hypertension in rats.

Angiogenesis and activation of vascular endothelial growth factor (VEGF) signaling are tightly regulated under the condition of hypoxic pulmonary hypertension (HPH); therefore, deciphering the regulatory mechanisms associated with VEGF is important. SET domain-containing 3 (SETD3) and VEGF expression in lung tissue during hypoxia exposure and lentivirus. SETD3 treatments were detected by real-time PCR and Western blot analysis. Remodeling of pulmonary vasculature and hypertrophy of the RV were evaluated. The effects of SETD3 over-expression on the interaction between SETD3 and forkhead box protein M1 (FoxM1) at the VEGF promoter and downstream of the VEGF signal pathway during chronic hypoxia were detected. SETD3 lentiviral vector treatment not only inhibited the increase in VEGF expression but also significantly relieved pulmonary vasculature remodeling and hypertrophy of the RV during HPH. The functional interplay between SETD3 and FoxM1 on chromatin may negatively regulate VEGF expression under HPH through the VEGF receptor-extracellular signal-regulated kinase-hypoxia-induced factor-1 signal pathway. SETD3-mediated transcriptional modification of VEGF may be a potential target to inhibit the development of HPH.

Aging-Resistant Functionalized LDH⁻SAS/Nitrile-Butadiene Rubber Composites: Preparation and Study of Aging Kinetics/Anti-Aging Mechanism.

With the aim of improving the anti-aging properties of nitrile-butadiene rubber (NBR), a functional organic filler, namely LDH⁻SAS, prepared by intercalating 4-amino-benzenesulfonic acid monosodium salt (SAS) into layered double hydroxides (LDHs) through anion exchange, was added to nitrile-butadiene rubber (NBR), giving the NBR/LDH⁻SAS composites. Successful preparation of LDH⁻SAS was confirmed by XRD, TGA and FTIR. LDH⁻SAS was well dispersed in the NBR matrix, owing to its strong interaction with the nitrile group of NBR. The obtained NBR/LDH⁻SAS composites exhibited excellent thermo-oxidative aging resistance as shown by TGA-DSC. Further investigation by ATR-FTIR indicated that SAS can capture the radical groups, even during the aging process, which largely accounts for the improved aging resistance.

Prognostic effect of IL-6/JAK2/STAT3 signal-induced microRNA-21-5p expression on short term recurrence of hepatocellular carcinoma after hepatectomy.

AIM: To investigate the putative role of interleukin (IL)-6/Janus Kinase (JAK) 2/Signal transducers and activators of transcription (STAT) 3 signaling pathway in hepatocellular carcinoma (HCC) short term recurrence (STR), and whether the pathway promotes HCC progression through microRNA-21-5p (miRNA-21). METHODS: Immunohistochemistry was performed to evaluate the protein expression of IL-6, JAK2 and STAT3. Real-time PCR was used to evaluate the miRNA-21 expression. We also analyzed the correlation of IL-6, JAK2 and STAT3 protein expression with miRNA-21. Clinicopathological variables, including prognosis, were compared between low and high-expressing groups of miRNA-21. RESULTS: miRNA-21 expression was significantly increased in the HCC tumor tissue compared to the non-tumor tissue. IL-6 and STAT3 high expression was significantly correlated to high miRNA-21 expression in HCC tumor tissues. Patients with high miRNA-21 expression have more frequent early recurrence. The 6 month overall survival and disease-free survival rate of the miRNA-21 high groups were 72.1% and 30.8%, respectively. Moreover, high miRNA-21 expression was correlated with disease-free survival (DFS) (P < 0.05) and overall survival (OS) (P < 0.05). Multivariate analysis revealed that miRNA-21 and STAT3 high expression were independent prognostic factors of DFS and OS. The area under the ROC curve (AUC) of miRNA-21 and STR, DFS, OS was 0.951 (P < 0.001), 0.847 (P < 0.001), 0.844 (P < 0.001), respectively. CONCLUSIONS: miRNA-21 expression, induced by IL-6/JAK2/STAT3 signaling pathway, was increased in the early recurrence of HCC patients and indicated poor prognosis. Expression analysis of miRNA-21 revealed that it may be a valuable prognostic biomarker for HCC.

USP10 inhibits lung cancer cell growth and invasion by upregulating PTEN.

To determine the potential tumor suppressor functions of ubiquitin-specific protease 10 (USP10) in lung cancer and elucidate underlying molecular mechanism. The relative expression of USP10 was determined by real-time PCR and immunoblotting. The inhibitory effect of USP10 on tumor growth was demonstrated on allograft mice with Lewis carcinoma cell inoculation. The relative cell proliferation was measured with Cell Counting Kit-8 (CCK-8). The invasive capacity was evaluated by transwell assay. The interaction between USP10 and Phosphatase And Tensin Homolog (PTEN) was examined by co-immunoprecipitation. Ubiquitination/deubiquitination was analyzed by immunoprecipitation followed by immunoblotting. USP10 was down-regulated in lung cancer. Knockdown of USP10 promotes tumor growth and invasion both in vitro and in vivo. We further demonstrated that USP10 directly interacted with and stabilized PTEN via deubiquitination. The pro-cancerous effect of USP10 deficiency was abolished by re-introduction of PTEN. We suggested a tumor suppressor function of USP10 in lung cancer via deubiquitinating and stabilizing PTEN.

IL-1ß-stimulated ß-catenin up-regulation promotes angiogenesis in human lung-derived mesenchymal stromal cells through a NF-κB-dependent microRNA-433 induction.

Considerable attentions have been focused on the treatment of lung injury using mesenchymal stem cells that can replenish damaged tissues including the blood vessels. In human lung-derived mesenchymal stem cells (hL-MSC), we investigated the potential role of an IL-1ß-stimulated miR-433 pathway in angiogenesis in vitro. The expressions of miR-433 and its target genes were examined in cells treated with IL-1ß. The angiogenic activity of hL-MSC was studied by cell migration and tube formation assays in which miR-433 levels were manipulated. The reporter assay and chromatin immunoprecipitation (ChIP) were also performed to analyze the underlying regulations. We found that the expression of miR-433 was enhanced in hL-MSC by IL-1ß in a NF-κB dependent manner via a NF-κB binding site at its promoter region. The effects of IL-1ß on promoting angiogenic activities in hL-MSC can be mimicked by the overexpression of miR-433 and were blocked by anti-miR-433. Mechanistically, our data suggested that miR-433 directly targets the 3'-UTR of Dickkopf Wnt signaling pathway inhibitor 1 (DKK1) mRNA and decreases its expression. Consistently, the expression of ß-catenin, the major mediator of canonical Wnt pathway that is capable of inducing endothelial differentiation and angiogenesis, was upregulated by IL-1ß through miR-433. Thus, increasing miR-433 expression by IL-1ß in mesenchymal stem cells could stimulate their capacity of vascular remodeling for efficient repair processes, which may be utilized as a therapeutic target in patients suffering from severe lung injury.