Effect In Liver Cancer Research Articles

Integration of network pharmacology, metabolomics and lipidomics for clarifying the role of sphingolipid metabolism in the treatment of liver cancer by regorafenib

AimsRegorafenib, an FDA-approved drug for advanced primary liver cancer (PLC), could provide survival benefits for patients. However, markers for its therapeutic sensitivity are lacking. This study seeks to identify sensitive targets of regorafenib in PLC from the perspective of small molecular metabolites. Materials and methodsInitiated with network pharmacology (NP) to map regorafenib's target landscape and metabolic regulatory network in liver cancer. Subsequently, regorafenib's impact on hepatoma cells was evaluated by flow cytometry, western blotting (WB) and cell viability assay. Advanced metabolomics and lipidomics were employed to elucidate regorafenib's metabolic reprogramming effects in liver cancer. Metabolic enzyme expression was assessed by WB, immunohistochemical and immunofluorescence assays. Ultimately, mendelian randomization (MR) analysis was utilized to investigate the potential causality of sphingolipid metabolism in hepatic cancer. Key findingsRegorafenib was observed to inhibit hepatoma cell proliferation and cell cycle progression at G0/G1 phase, resulting in significant alterations in sphingolipid levels. It promoted the significant accumulation of 16:0 dihydroceramide (16:0 dhCer) by upregulating ceramide synthase 6 (CERS6) expression and inhibiting dihydroceramide desaturase 1 (DEGS1) activity. The MR analysis revealed that DEGS1 was a risk factor for the development and progression of liver cancer, while cumulative 16:0 dhCer was a protective factor. SignificanceSphingolipids, particularly dhCer and regulatory enzymes, may be potential sensitive markers of regorafenib in the treatment of liver cancer, providing new insights for enhancing the treated efficacy of regorafenib in liver cancer.

Weighted gene co-expression network analysis identified GBP2 connected to PPARα activity and liver cancer

Liver cancer is the fourth leading cause of cancer-related deaths with a steadily increasing rate worldwide, as a well-known hallmark of liver cancer, metabolic alterations are related to liposomal changes, a common characteristic of primary liver cancers based on recent lipidomics studies. Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor with important lipid homeostasis function, therefore we aimed to understand the molecular mechanisms and pathways that activate PPARα after using PPAR-α agonist WY-14643 and identify candidate biomarkers related to PPARα activity and evaluate their effects in liver cancer. The data from differently expressed genes (DEGs) between liver cancer tissue from obese subjects alone and liver tissue after treatment were evaluated by DESeq2 and module genes were analyzed using weighted gene co-expression network analysis (WGCNA). Final candidate genes were identified by intersecting genes among highly ranked DEGs and the brown module, which demonstrated a significant negative correlation with drug treatments. We conducted a protein–protein interaction network, and KEGG enrichment analysis, and core hub genes (CD40, CXCL9, CXCL10, TNFSF14, GBP2, GBP3, APOL3, CLDN1) were identified using the cyto-hubba plugin, among them we focused on GBP2 that plays key roles in oncogenesis and evaluate its expressional with clinical outcomes. In conclusion, the WGCNA-based co-expression network identified GBP2 as one of the hub genes with a negative relation with PPARα agonist treatments. higher expression of GBP2 was closely associated with HCC progression. Therefore, GBP2 might be a potential candidate for the study of PPARα activity in HCC.

Jaranol Loaded in Ferroferric Oxide Nanoparticles Inhibits the Activities of Liver Cancer Cell Through Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathway

Liver cancer is highly aggressive and the MEK/ERK signaling regulates tumor cell proliferation and metastasis. Jaranol is a natural product with anti-proliferative and anti-metastatic effects in several tumors. However, its interaction with the MEK/ERK pathway in liver cancer is unclear. This study explores whether ferroferric oxide nanoparticles-loaded Jaranol inhibits proliferation and metastasis in liver cancer cell Hep3B by regulating MEK/ERK signaling, and its underlying mechanism. Fe3O4-Jaranol nanoparticles were prepared and used in Hep3B experiments to observe the biological efficacy of Fe3O4-Jaranol, and further explore its effect and mechanism on the MEK/ERK pathway using PCR, WB, etc. Fe3O4-Jaranol were successfully prepared with a certain tumor suppressor effect in liver cancer. The expression of MEK/ERK was increased in liver cancer. Inhibiting its pathway activity suppressed the development of liver cancer. Trametinib and C16-PAF were used to inhibit Hep3B respectively. MEK expression in cells treated with Trametinib was reduced accompanied by a low expression of ERK, while the expression of MEK and ERK levels in the C16-PAF group showed an opposite trend, indicating that Trametinib, C16-PAF successfully intervened on MEK and ERK. Further analysis of the activity of Hep3B cells found that the proliferation ability of the Trametinib group was significantly inhibited. Fe3O4-Jaranol significantly inhibited liver cancer cell Hep3B and this effect was accomplished by inhibiting MEK/ERK signaling, causing tumor cell proliferation to be restricted and reducing the ability to metastasize. This research result provides strong evidence for a deep understanding of the mechanism of Jaranol in treating liver cancer, so as to better guide clinical practice.

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer.

Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

Effect of liver cancer on the accumulation and hepatobiliary transport of per- and polyfluoroalkyl substances

In this study, we examined the distribution of per- and polyfluoroalkyl substances (PFASs) in liver and bile tissues from the patients with liver cancer (n = 202) and healthy controls (n = 30), and calculated the hepatobiliary transport efficiency (TB-L) of PFASs. Among 21 PFASs, 13 PFASs were frequently detected in the liver (median: 8.80–16.3 ng/g) and bile (median: 11.03–14.26 ng/mL) samples. PFAS concentrations in liver were positively correlated with age, with higher levels of PFASs in the older. Variance analysis showed that gender and BMI (Body Mass Index) have an important impact on the distribution of PFASs. A U-shaped trend in TB-L of PFASs with the increasing of carbon chain length was found for the first time, and the TB-L of most PFASs in the control was higher than that of those in cases (p < 0.05), suggesting that hepatic injury would affect their transport. PFASs were positively associated with liver injury biomarkers, including γ-glutamyl transferase (GGT), alanine aminotransferase (ALT), and total bilirubin (TB) levels (p < 0.05). This is the first study on examining the hepatobiliary transport characteristics of PFASs, which may help understand the connection between PFAS accumulation and liver cancer risk.

Survival Analysis for Multimode Ablation Using Self-Adapted Deep Learning Network Based on Multisource Features.

Novel multimode thermal therapy by freezing before radio-frequency heating has achieved a desirable therapeutic effect in liver cancer. Compared with surgical resection, ablation treatment has a relatively high risk of tumor recurrence. To monitor tumor progression after ablation, we developed a novel survival analysis framework for survival prediction and efficacy assessment. We extracted preoperative and postoperative MRI radiomics features and vision transformer-based deep learning features. We also combined the immune features extracted from peripheral blood immune responses using flow cytometry and routine blood tests before and after treatment. We selected features using random survival forest and improved the deep Cox mixture (DCM) for survival analysis. To properly accommodate multitype input features, we proposed a self-adapted fully connected layer for locally and globally representing features. We evaluated the method using our clinical dataset. Of note, the immune features rank the highest feature importance and contribute significantly to the prediction accuracy. The results showed a promising C td-index of 0.885 ±0.040 and an integrated Brier score of 0.041 ±0.014, which outperformed state-of-the-art method combinations of survival prediction. For each patient, individual survival probability was accurately predicted over time, which provided clinicians with trustable prognosis suggestions.

Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements

Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and is regarded as an excellent free-radical scavenger. Apoptotic cell death of cancer cells caused by quercetin has been demonstrated by many prior studies. It is present in many fruits, vegetables, and herbs. Quercetin targets apoptosis, by upregulating Bax, caspase-3, and p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, and Bcl-2. Additionally, it has been reported to increase STAT3 protein degradation in liver cancer cells while decreasing STAT3 activation. Quercetin has a potential future in chemoprevention, based on substantial research on its anticancer effects. The current review discusses quercetin's mechanisms of action, nanodelivery strategies, and other potential cellular effects in liver cancer.

Micro RNA miR-1303 Promotion of Proliferation, Migration and Invasion of Human Liver Cancer Cells Is Enhanced by Low Talin 1 (TLN1) Expression.

Liver cancer is the third-most lethal cancer worldwide. Abnormal expression of microRNAs (miRNAs) modulates gene expression to exert oncogenic or tumor-suppressive effects in liver cancer. However, the biological role of miR-1303 in the progression of liver cancer and its regulatory mechanism has not been elucidated. The expression levels of miR-1303 were measured in liver-cancer tissues of patients and cell lines by RT-qPCR. Huh-7 and HepG2 liver-cancer cells were co-transfected by TLN1 and miR-1303 constructs. Cell viability was measured by the CCk-8 assay and colony-formation assay. Flow cytometry was used to measure cell apoptosis. Cell migration and invasion were determined by wound-healing and transwell-chamber assays. RT-PCR and western-blotting were used to determine miR-1303 inhibitor-associated marker expression, such as Bax, cleaved-caspase-3 and cleaved-caspase-9. miR-1303 expression was strongly up-regulated in liver-cancer tissues and cells. Knockdown of miR-1303 attenuated cell proliferation, migration and invasion, and induced apoptosis in liver-cancer cells. Talin 1 (TLN1) and miR-1303 expression were negatively correlated, possibly by miR-1303 targeting the TLN1 gene. TLN1 expression enhanced the efficacy of an miR-1303 inhibitor to reduce liver-cancer cell proliferation and invasion. miR-1303 plays an important role in liver cancer, which is inhibited by TLN1 expression.

Analysis on liver cancer mortality and cause eliminated life expectancy in key areas of 4 provinces, China, 2008-2018

Objective: To explore the changes of liver cancer mortality and the effect of liver cancer on life expectancy in key areas of four provinces in China from 2008 to 2018 and provide the basis for the evaluation of comprehensive prevention and control of cancer and promotion of the rational allocation of health resources. Methods: Based on the national cause-of-death surveillance in key areas of the 4 provinces from 2008 to 2018, we analyzed the mortality of liver cancer, cause eliminated life expectancy (CELE) and potential gains in life expectancy (PGLEs). Software Joinpoint 4.9.0.0 was used to calculate the average annual percentage change (AAPC). Arriaga's decomposition method was used to estimate the contribution of the changes of liver cancer mortality in each age group to life expectancy. Results: The standardized mortality of liver cancer in key areas of the 4 provinces showed a downward trend from 2008 to 2018 (AAPC=-4.37%, P<0.001). The changes of liver cancer mortality had a positive effect on the increase of life expectancy, with a contribution value of 0.240 years and a contribution degree of 5.62%. The positive effect was greatest in age group 45-49 years (0.041 years, 0.96%), and the negative effect was greatest in age group 50-54 years (-0.015 years, -0.35%). Compared with 2008, the life expectancy increased by 4.27 years (AAPC=0.59%, P<0.001), the liver cancer CELE increased by 4.20 years (AAPC=0.58%, P<0.001), the PGLEs decreased by 0.07 years (AAPC=-0.62%,P<0.001), and life loss rate decreased by 0.13% (AAPC=-1.18%, P=0.001). The liver cancer PGLEs increased in Yongqiao district, Anhui province (0.09 years), and decreased in other districts (counties), with the largest decline was in Fugou county, Henan province (-0.21 years). Conclusions: From 2008 to 2018, the standardized mortality rate of liver cancer in key areas of the 4 provinces decreased gradually, contributing to the growth of life expectancy. The life loss caused by liver cancer decreased gradually, but the PGLEs varied with districts (counties).

Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis.

Propofol is a commonly used drug for sedation and general anesthesia during cancer surgery. Previous studies indicate that propofol exerts anti-tumor effect in various cancers. The aim of this study was to investigate the underlying molecular mechanism of propofol in liver cancer. The effects of propofol on liver cancer cells were evaluated by cell viability assay, colony formation assay, and tumor xenograft model. Dysregulated lncRNAs of propofol-treated liver cancer cells were evaluated by transcriptome RNA sequencing. The underlying molecular mechanisms of lncRNA cancer susceptibility candidate 9 (CASC9) in propofol-induced anti-tumor effects were evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), wound scratch healing assay, transwell cell migration and invasion assay, TUNEL staining, fluorescence in situ hybridization, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP). We found that propofol suppressed proliferation, migration, invasion, and tumor xenograft growth of liver cancer cells in a dose-dependent manner. Exosomes transfer from propofol-treated cells inhibited proliferation, migration, and invasion and promoted apoptosis of liver cancer cells. Transcriptional profiling of propofol-treated liver cancer cells identified CASC9 as significantly downregulated lncRNA in cells and exosomes. Enforced CASC9 expression partially rescued the inhibitory effects of propofol on liver cancer cells. Furthermore, CASC9 was found to interact directly with EZH2 and epigenetically regulated PTEN expression. Restoration of CASC9 partially abrogated the inhibition of propofol on Akt/mTOR signaling. Our results indicated that propofol exerted anti-tumor effects by downregulating CASC9, and subsequently suppressed Akt/mTOR signaling. Our findings provided a novel insight into propofol-induced anti-tumor effects in liver cancer.

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Research Progress on the Antitumor Effect of Polysaccharides from Fungus Used in Traditional Chinese Medicine

Cancer is a serious threat to human health. Fungal polysaccharide is a polar biological macromolecule with low toxicity. It has a wide range of biological activities, including immune regulation, antitumor activity, and antiviral activity. In recent years, the research results have shown that polysaccharides from fungus in traditional Chinese medicine have excellent antitumor effect in liver cancer, gastric cancer, breast cancer, colon cancer, esophageal cancer, and lung cancer. Therefore, the research and development of fungal polysaccharides are of great significance for the development of antitumor drugs in the future.

Ameliorative Effects of Aspergillus awamori against the Initiation of Hepatocarcinogenesis Induced by Diethylnitrosamine in a Rat Model: Regulation of Cyp19 and p53 Gene Expression.

Hepatocellular carcinoma (HCC) is the most common cancer in humans. Despite advances in its treatment, liver cancer remains one of the most difficult cancers to treat. This study aimed to investigate the ameliorative action and potential mechanism of Aspergillus awamori (ASP) administration against the initiation process of liver carcinogenesis induced by diethylnitrosamine (DEN) in male Wistar rats. Seventy-two male rats were divided equally into eight groups as follows, Group 1: untreated control; Group 2: DEN (200 mg/kg bw) intra-peritoneally for the initiation of HCC; Groups 3–5: DEN + ASP at a dose of 1, 0.5, and 0.25 mg/kg bw and groups 6–8: ASP at a dose of 1, 0.5, and 0.25 mg/kg bw. Supplementation of A. awamori significantly lightened the adverse impacts induced by DEN via restoring the leukogram to normal, lowering the elevated serum aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Furthermore, it enhanced the hepatic antioxidant capacity through increasing the reduced glutathione (GSH) level and catalase (CAT) activity with a marked reduction in malondialdehyde (MDA) level. In addition, it decreased the positive GST-P foci. Likewise, a significant alteration of DEN-associated hepatocarcinogenesis occurred through inhibiting cytochrome P450 (Cyp19) and activating p53 gene expression. In conclusion, supplementation of A. awamori counteracts the negative effects of DEN, inhibits the early development of GST-P-positive foci and could be used as a new alternative strategy for its chemo-preventive effect in liver cancer. To the best of our knowledge, the present study is the first to report the hepato-protective effect of A. awamori in induced hepatocarcinogenesis.

Luteolin enhances the antitumor efficacy of oncolytic vaccinia virus that harbors IL-24 gene in liver cancer cells.

BackgroundInterleukin 24 (IL‐24) is an IL‐10 family member and a secreted cytokine characterized by cancer‐targeted toxicity and can activate apoptosis by sensitizing cancer cells to chemotherapy. Cytotoxic effects of luteolin on different types of cancer cells suppress their growth by acting on the components of the apoptosis signaling cascade. Therefore, our study aimed to prove whether oncolytic vaccinia virus (VV) that harbors IL‐24 (VV‐IL‐24) combine with luteolin exerts a synergistic inhibitory effect in liver cancer cells.MethodsImpacts on cell viability of VV‐IL‐24 and luteolin were assessed by MTT in various liver cancer cell lines. Then, liver cancer cell apoptosis was analyzed via flow cytometry and Western blotting. Besides, the MHCC97‐H xenograft mouse model was employed as a means of assessing in vivo antitumor efficacy.ResultsMTT assay confirmed that the combination treatment decreased liver cancer cells viability to a greater degree than treatment with VV‐IL‐24 or luteolin alone. Flow cytometry and Western blot assay proved that VV‐IL‐24 plus luteolin induced more liver cancer cells apoptosis than single treatment. Furthermore, in the MHCC97‐H xenograft model, 15 days of treatment with VV‐IL‐24 plus luteolin inhibited tumor growth significantly more than single treatment.ConclusionThese data confirm that the synergistic mechanism of VV‐IL‐24 and luteolin elicits a stronger tumor growth inhibition than any single therapy. Thus, the combination of VV‐IL‐24 and luteolin could provide the basis for preclinical research in the treatment of liver cancer.

Plantamajoside modulates the proliferation, stemness, and apoptosis of lung carcinoma via restraining p38MAPK and AKT phosphorylation.

BackgroundPlantamajoside (PMS), an active anti-inflammatory component and antioxidant derived from Herba Plantaginis, has been reported to exert a suppressive effect in liver cancer in vivo. In this study, we tested the effects of PMS on the metastatic 95D cell line.Methods95D cells were characterized as most sensitive to PMS across several lung cancer cell lines. Cell viability within 24 h was tested with CCK-8. Different concentrations of PMS (0, 50, 100, and 200 µg/mL) and 5 µg/mL of cisplatin were established for later 24 h treatment. Relative mRNA and protein expression were assessed with PCR and Western blotting. Cell proliferation and stemness were indicated with colony and sphere formation. Cell metastasis was evaluated with wound healing and Transwell. Apoptotic cells and mitochondrial membrane potential were investigated with flow cytometry.ResultsCCK-8 assay showed PMS to inhibit the viability of 95D cells in a dose-dependent manner. PMS decreased colony formation and inhibited stemness in 95D cells. Invasion and migration were also inhibited. Moreover, PMS induced cell apoptosis, and decreased mitochondrial membrane potential. All of these effects were dose dependent. Interestingly, PMS treatment reduced the protein expression of p-p38 MAPK and p-AKT but not that of p38 MAPK and AKT.ConclusionsPMS inhibited proliferation, stemness, and migration, and initiated apoptosis in 95D cells, possibly through p38 MAPK and AKT dephosphorylation and mitochondria dysfunction. These findings support the promise of PMS as a prodrug in lung cancer treatment.

MicroRNA‑373 exerts anti‑tumor functions in human liver cancer by targeting Rab22a

Liver cancer is a one of the most frequent types of tumor worldwide. It has long been recognized that microRNAs are important participants in the progression of various types of cancer. The present study explored the role of microRNA‑373 (miR‑373) in liver cancer development. Reverse transcription‑quantitative polymerase chain reaction was performed to evaluate the transcription level of miR‑373 in 96 liver cancer tissues and adjacent normal liver tissues. The association of miR‑373 with clinicopathological characteristics was analyzed using the χ2 test. Kaplan‑Meier univariate analysis and multivariate hazard analysis were performed to identify the clinical potential of miR‑373 in the prognosis of liver cancer patients. Transfection of miR‑373 mimics into Hep3B and HepG2 liver cancer cell lines was conducted to reveal the underlying mechanism in regulating liver cancer progression. The functional assays included proliferation, migration, invasion and luciferase assays. The findings of the present study demonstrated that miR‑373 transcription level was markedly downregulated in liver cancer tissues compared with the adjacent normal tissues and was associated with the clinical prognosis of liver cancer patients. Overexpressing miR‑373 mimics in liver cancer cell lines decreased cell proliferation and invasion, suggesting that miR‑373 exerts anti‑tumor effects in liver cancer. In addition, data from the present study demonstrated the direct effect of miR373 on inhibiting the expression and signaling of Ras‑related protein Rab22a, a well‑known oncoprotein. Taken together, the results from the present study suggested that miR‑373 suppresses liver cancer progression and may serve as a promising prognosis prediction biomarker.

Inverse Association of Fibrates and Liver Cancer: A Population-Based Case-Control Study in Taiwan.

This large-scale case-control study in Taiwan elucidated the potential connection between fibrate use and liver cancer by using the Longitudinal Health Insurance Database 2005 with a propensity-score-matching design. In total, 4173 patients diagnosed as having liver cancer were included as cases, and 4173 propensity-score-matched patients without liver cancer were identified as controls. The association between previous fibrate use and liver cancer occurrence was demonstrated using conditional logistic regression. Fibrate use was noted in 371 (8.89%) cases and 481 (11.53%) controls. After adjustments, the cases had significantly lower odds of previous fibrate use than did the controls (adjusted odds ratio 0.70, 95%CI 0.60-0.82); moreover, regardless of the patients' sex, age group, and comorbidities, the cases were less likely to have used fibrates than were the controls. Dose-dependent analysis revealed that 1-695 cumulative defined daily doses of fibrates may significantly induce a protective effect for liver cancer. Although other fibrate dose intervals did not reach statistical significance, the dose-response curve presented the trend of a protective effect for liver cancer among the fibrate users. In summary, fibrate use had a significant protective effect against liver cancer in this Asian population.

Multifunctional nanoplatform based on star-shaped copolymer for liver cancer targeting therapy

With high morbidity and death rates, liver cancer has become one of the most common cancers in the world. But, most chemotherapeutic anticancer drugs have high toxicity as well as low specificity. To improve the treatment modalities and enhance the therapeutic effect of liver cancer, a brand new liver-targeting nanoparticle (NP), Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid (5 F)-loaded cholic acid (CA)-functionalized star-shaped poly (lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-lactobionic acid (LA) (5 F-loaded CA-PLGA-PEG-LA), was developed. The particle size, zeta potential, size distribution, surface morphology, drug loading content, drug encapsulation efficiency and drug release of 5 F-loaded NPs were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be internalized by HepG2 cells. Furthermore, the cellular uptake efficiency of coumarin 6-loaded CA-PLGA-PEG-LA NPs was much better in compare with that of CA-PLGA-PEG and CA-PLGA NPs. Moreover, LA-conjugated NPs (CA-PLGA-PEG-LA NPs) enhanced fluorescence of HepG2 cells via ligand-mediated endocytosis. The antitumor effects of 5 F-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted 5 F-loaded CA-PLGA-PEG-LA NPs were significantly superior to free 5 F and 5 F-loaded CA-PLGA-PEG NPs. All the results indicated the 5 F-loaded CA-PLGA-PEG-LA NPs can be employed as a novel potentially targeting drug delivery system for liver cancer therapy.

Exosomes derived from HBV‑associated liver cancer promote chemoresistance by upregulating chaperone‑mediated autophagy

Liver cancer, which is the second leading cause of tumor-associated mortality, is of great concern worldwide due to its resistance to chemotherapeutic drugs. Transcatheter arterial chemoembolization (TACE) has previously been used as a treatment for unresectable liver tumors in China; however, the response to TACE treatment differs between patients. It has been reported that hepatitis B virus (HBV)-as sociated tumors are less sensitive to TACE treatment compared with non-HBV-associated liver cancer. Previous studies have demonstrated that exosomes serve a crucial role in hepatic carcinoma chemoresistance. We therefore hypothesized that HBV may modulate chemosensitivity via exosomes. The aim of the present study was to investigate how exosomes affect chemoresistance by assessing their role in chaperone-mediated autophagy (CMA)-dependent chemoresistance in HBV-associated liver cancer. Iconography data from HBV-positive and HBV-negative patients with hepatic carcinoma receiving TACE treatment were assessed, and it was revealed that the tumor volume was decreased in the patients with non-HBV-associated liver cancer compared with that in the patients with HBV-associated tumors following TACE therapy. Furthermore, it was revealed that exosomes from HBV-infected liver cancer cells were able to downregulate cell apoptosis when treated with oxaliplatin compared with exosomes from normal HepG2 cells. Furthermore, the results demonstrated that HBV-associated exosomes modulate cell death via activating the CMA pathway, and its key molecule, lysosome-associated membrane protein (Lamp2a), was also upregulated. Lamp2a-knockdown was also found to reverse anti-apoptotic effects in liver cancer. Taken together, the results of the present study suggest that chemoresistance in patients with HBV-associated hepatic tumors may be mediated by exosomes, and thus may provide a basis for the development of novel treatment strategies for chemoresistant liver cancer.

MicroRNA-146a-5p enhances ginsenoside Rh2-induced anti-proliferation and the apoptosis of the human liver cancer cell line HepG2.

Liver cancer is one of the leading causes of malignancy-associated mortality worldwide and its clinical therapy remains very challenging. Ginsenoside Rh2 (Rh2) has been reported to have antitumor effects on some types of cancer, including liver cancer. However, its regulatory mechanism has not been extensively evaluated. In the present study, Rh2 increased the expression of microRNA (miR)-200b-5p, miR-224-3p and miR-146a-5p, and decreased the expression of miR-26b-3p and miR-29a-5p. Of the three upregulated miRs, miR-146a-5p exhibited the highest fold elevation. In accordance with a previous study, Rh2 effectively inhibited the survival of liver cancer cells in vitro and in a mouse model. In addition, it was observed that Rh2 markedly promoted liver cancer apoptosis and inhibited colony formation. Cell apoptosis and the inhibition of cell survival as well as colony formation induced by Rh2 were enhanced and weakened by miR-146a-5p overexpression and inhibition, respectively. The results of the present study provide further evidence of the antitumor effect of Rh2 in liver cancer and also demonstrate that this effect may be mediated via the regulation of miR-146a-5p expression in the liver cancer cell line HepG2. The results indicated that miR-146a-5p may be a promising regulatory factor in Rh2-mediated effects in liver cancer.