Development Of Hepatic Cancer Research Articles

Association between Metabolic-Dysfunction-Associated Steatotic Liver Disease and Hepatic Cancer: Current Concepts and Future Challenges.

Background: This study systematically reviewed the association between metabolic-dysfunction-associated steatotic liver disease (MASLD) and the development of hepatic cancer. Previous research has highlighted MASLD as a predisposing condition. Aim: To collect recent global data on the relationship between MASLD and hepatic cancer. Methods: A systematic review was conducted, which included an analysis of studies on the relationship between MASLD and the incidence of hepatic cancers, focusing on the role of fibrosis and MASLD severity as predictors of cancer risk. Following standard methodological frameworks for the assessment of longitudinal studies, the review gathered information on fibrosis scores, hepatocellular carcinoma (HCC) incidence, and other types of hepatic neoplasms. Results: A total of 522 studies were initially identified, of which 6 studies were appropriate for the review. They collectively revealed that the stage of fibrosis in MASLD is a significant independent predictor of mortality and liver-related events, with higher fibrosis stages correlating with greater risk. Longitudinal data showed that increases in FIB-4 scores were linked to a higher risk of developing HCC and cirrhosis. MASLD was also associated with an increased risk of non-hepatic cancers such as colorectal cancer in males and breast cancer in females. The severity of MASLD was found to be a modifiable risk factor for biliary tract cancer (BTC), with the risk further amplified by diabetes. Moreover, lifestyle factors and comorbidities, such as smoking and diabetes, were identified as modifiers of cancer risk in MASLD patients. Conclusions: The systematic review identified the association between MASLD and an elevated risk of hepatic cancer, establishing a clear link between the severity of liver fibrosis and the incidence of HCC and other hepatic neoplasms. This supports the need for screening for hepatic cancer in patients with MASLD, particularly in the presence of advanced fibrosis or other risk-modifying factors.

Unlocking the Potential: Novel NSAIDs Hybrids Unleash Chemopreventive Power toward Liver Cancer Cells through Nrf2, NF-κB, and MAPK Signaling Pathways.

HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates of non-steroidal anti-inflammatory drugs (NSAIDs)-Ibuprofen and Ketoprofen-with oleanolic acid oximes derivatives (OAO) were synthesized, and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells, and HCC-derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells, treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB, it was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivative conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.

Involvement of NF-κB/PI3K/AKT signaling pathway in the protective effect of prunetin against a diethylnitrosamine induced hepatocellular carcinogenesis in rats.

Prunetin (PRU) is an O-methylated flavonoid that is present in various natural plants and a primary significant compound found in isoflavone. Liver cancer creates major carcinogenic death despite recently advanced therapies. Hepatocellular carcinoma (HCC) treatment and prognosis are better in people with secure liver function. In the present study, we evaluated the action of PRU on diethylnitrosamine (DEN) alone HCC in a rat model through inflammation-mediated cell proliferative phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway analysis. Male Wistar rats were dividedinto four groups of six rats each. Group I, normal rats; Group II, DEN alone; Group III, DEN + PRU, and Group IV, PRU-alone. All groups of rats carried outhepatic cancer development by hypothesis antioxidant, biochemical, cell proliferative, apoptosis, cytokines protein, and gene expression status profiles. In tumor incidence DEN + PRU, 100% delayed the tumor growth disappearance of the lesion, and reversal of normal liver architecture was observed. Liver marker enzymes levels decreased when antioxidant levels (superoxidase dismutase, catalase, glutathione peroxidase, and glutathione reductase) were in Group III. Proinflammatory markers nuclear factor-κB, interleukin (IL)-6, IL-1β, and tumor necrosis factor α, were elevated in the rat's serum in Group III. Cell proliferative markers proliferating cell nuclear antigen and Cyclin-D1 protein expressions were downregulated; in contrast, Bcl-2, Bax, caspase-3, and caspase-9 gene expressions were upregulated and then it followed that protein expression of PI3K/AKT wasdownregulated in PRU-treated groups. PRU assisted reversal of liver damage, antioxidant enzyme restoration cytokine balance, protein, and gene expression to control levels. Taken together, PRU improves functions of the liver, and as such prevents HCC. PRU can be used together with chemopreventives for HCC.

18S rRNA gene sequencing for environmental aflatoxigenic fungi and risk of hepatic carcinoma among exposed workers

Aspergillus exposure causes an increase in aflatoxin (AF) levels among exposed workers thereby increasing their risk of developing hepatocellular carcinoma (HCC). This study attempted to determine the presence of airborne aflatoxigenic fungi in environment of waste water treatment plant (WWTP); and study the hepatic cancer risks among exposed workers, emphasizing the role of glutathione S-transferases (GST) gene polymorphism protecting against the risk of hepatic cancer development due to exposure to AFs. The study isolated and identified different Aspergillus species producing AFs in air samples from WWTP sites using 18S ribosomal ribonucleic acid (18S rRNA) gene sequencing technique. GST gene polymorphisms were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). A significant increase in blood AF levels was found among WWTP exposed workers. The occurrence of GSTT1& M1 gene polymorphism in 6% of the workers was accompanied by significant decrease in the levels of AFs and alpha fetoprotein (AFP). In conclusion, Aspergillus-producing AFs were found in air of WWTP. Continuous exposure to AF-producing fungi caused elevated AF-levels in exposed workers. However only workers with heterozygous GSTT1& M1 genotypes can detoxify AFs, thereby decreasing the risk of HCC development among exposed workers.

Molecular Immune Mechanism of Intestinal Microbiota and Their Metabolites in the Occurrence and Development of Liver Cancer.

Intestinal microorganisms are closely associated with immunity, metabolism, and inflammation, and play an important role in health and diseases such as inflammatory bowel disease, diabetes, cardiovascular disease, Parkinson’s disease, and cancer. Liver cancer is one of the most fatal cancers in humans. Most of liver cancers are slowly transformed from viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease. However, the relationship between intestinal microbiota and their metabolites, including short-chain fatty acids, bile acids, indoles, and ethanol, and liver cancer remains unclear. Here, we summarize the molecular immune mechanism of intestinal microbiota and their metabolites in the occurrence and development of liver cancer and reveal the important role of the microbiota-gut-liver axis in liver cancer. In addition, we describe how the intestinal flora can be balanced by antibiotics, probiotics, postbiotics, and fecal bacteria transplantation to improve the treatment of liver cancer. This review describes the immunomolecular mechanism of intestinal microbiota and their metabolites in the occurrence and development of hepatic cancer and provides theoretical evidence support for future clinical practice.

Prognostic Value of a Novel Signature With Nine Hepatitis C Virus-Induced Genes in Hepatic Cancer by Mining GEO and TCGA Databases.

BackgroundHepatitis C virus-induced genes (HCVIGs) play a critical role in regulating tumor development in hepatic cancer. The role of HCVIGs in hepatic cancer remains unknown. This study aimed to construct a prognostic signature and assess the value of the risk model for predicting the prognosis of hepatic cancer.MethodsDifferentially expressed HCVIGs were identified in hepatic cancer data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases using the library (“limma”) package of R software. The protein–protein interaction (PPI) network was constructed using the Cytoscape software. Functional enrichment analysis was performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Univariate and multivariate Cox proportional hazard regression analyses were applied to screen for prognostic HCVIGs. The signature of HCVIGs was constructed. Gene Set Enrichment Analysis (GSEA) compared the low-risk and high-risk groups. Finally, the International Cancer Genome Consortium (ICGC) database was used to validate this prognostic signature. Polymerase chain reaction (PCR) was performed to validate the expression of nine HCVIGs in the hepatic cancer cell lines.ResultsA total of 143 differentially expressed HCVIGs were identified in TCGA hepatic cancer dataset. Functional enrichment analysis showed that DNA replication was associated with the development of hepatic cancer. The risk score signature was constructed based on the expression of ZIC2, SLC7A11, PSRC1, TMEM106C, TRAIP, DTYMK, FAM72D, TRIP13, and CENPM. In this study, the risk score was an independent prognostic factor in the multivariate Cox regression analysis [hazard ratio (HR) = 1.433, 95% CI = 1.280–1.605, P < 0.001]. The overall survival curve revealed that the high-risk group had a poor prognosis. The Kaplan–Meier Plotter online database showed that the survival time of hepatic cancer patients with overexpression of HCVIGs in this signature was significantly shorter. The prognostic signature-associated GO and KEGG pathways were significantly enriched in the risk group. This prognostic signature was validated using external data from the ICGC databases. The expression of nine prognostic genes was validated in HepG2 and LO-2.ConclusionThis study evaluates a potential prognostic signature and provides a way to explore the mechanism of HCVIGs in hepatic cancer.

LncRNA LINC00152 knockdown suppressed hepatic cancer biological activity

IntroductionHepatic cancer is one of the most lethal cancers and has a poor prognosis. The purpose of this study was to evaluate whether lncRNA LINC 00152 had effects on the development of hepatic cancer and the related mechanisms.Material and methodsMeasuring LINC 00152 in different tissues. In in vitro experiments, we knocked down LINC 00152 expression using si-LINC00152 in HepG2 cells and evaluated cell proliferation by MTT, apoptosis by flow cytometry, invasion by Transwell, and migration by wound healing. The relative protein was evaluated by western blot. In vivo experiments included measuring tumour size and weight, using TUNEL to evaluate cell apoptosis, and measurement of relative protein expression by IHC assay.ResultsIn our present study, first, we found that long non-coding RNA LINC00152 expression was significantly enhanced in hepatic cancer tissues and cell lines. Second, we revealed that LINC00152 knockdown had the effect of suppressing cell proliferation and metastasis and stimulating cell apoptosis in vitro. Third, LINC00152 down-regulation significantly suppressed tumour growth and increased cell apoptosis in an in vivo experiment. Mechanistic analyses showed that LINC00152 could regulate EGFR/PI3K/AKT/P21/MMP2/9 pathways in in vitro and in vivo experiments.ConclusionsOur results suggest that LINC00152 contributes to the oncogenic potential of hepatic cancer and that the EGFR/PI3K/AKT/P21/MMP2/9 signalling pathway might be a potential therapeutic target for hepatic cancer.

Identification of Susceptibility Genes in Hepatic Cancer Using Whole Exome Sequencing and Risk Prediction Model Construction

Abstract Objective: To identify the susceptible single nucleotide polymorphisms (SNPs) loci in HCC patients in Guangxi Region, screen biomarkers from differential SNPs loci by using predictors, and establish risk prediction models for HCC, to provide a basis of screening high-risk individuals of HCC. Methods: Blood sample and clinical data of 50 normal participants and 50 hepatic cancer (HCC) patients in Rui Kang Hospital affiliated to Guangxi University of Traditional Chinese Medicine were collected. Normal participants and HCC patients were assigned to training set and testing set, respectively. Whole Exome Sequencing (WES) technique was employed to compare the exon sequence of the normal participants and HCC patients. Five predictors were used to screen the biomarkers and construct HCC prediction models. The prediction models were validated with both training and testing set. Results: Two-hundred seventy SNPs were identified to be significantly different from HCC, among which 100 SNPs were selected as biomarkers for prediction models. Five prediction models constructed with the 100 SNPs showed good sensitivity and specificity for HCC prediction among the training set and testing set. Conclusion: A series of SNPs were identified as susceptible genes for HCC. Some of these SNPs including CNN2, CD177, KMT2C, and HLADQB1 were consistent with the previously identified polymorphisms by targeted genes examination. The prediction models constructed with part of those SNPs could accurately predict HCC development.

Effect of subcellular localization of P21 on proliferation and apoptosis of HepG2 cells

This study examined the effect of subcellular localization of P21 on the proliferation and apoptosis of HepG2 cells. The coding genes of the wild and the mutant P21 were amplified by mega primer PCR from the plasmid pCEP-WAF1 which contains human P21 cDNA in the nuclear localizational signal (NLS) sequence, and then inserted into the eukaryotic expression vector pDsRed1-C1. The recombinants were transfected into HepG2 cells. The transcription and expression of P21 were determined by RT-PCR and fluorescence microscopy. The cell proliferation was measured by MTT, and the cell cycle and apoptosis of HepG2 cells by flow cytometry. The results of restriction analysis, DNA sequencing and fluorescence microscopy confirmed the construction of the wild and the mutant P21 in the eukaryotic expression plasmid. The plasmid containing the mutant P21 was found to accelerate cell proliferation and the wild P21 plasmid to inhibit cell proliferation. Cell cycle analysis showed that the cell ratio of G(0)/G(1) in the wild type group was significantly increased as compared with that in the mutant type group, and cell apoptosis analysis revealed that the apoptosis rate in the wild type group was much higher than that in the mutant type group. It was concluded that the subcellular localization of P21 may contribute to the development of hepatic cancer.

Therapeutic approaches for patients with adult-onset type II citrullinemia (CTLN2): effectiveness of treatment with low-carbohydrate diet and sodium pyruvate

Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease characterized by highly elevated plasma levels of citrulline and ammonia due to the urea cycle dysfunction associated with citrin deficiency. Patients with CTLN2 show various neurological symptoms with hyperammonemia closely resembling those of hepatic encephalopathy. Since 1990, 26 CTLN2 patients (17 males and 9 females) have been admitted and treated at Shinshu University Hospital. Twelve of the 26 patients received living related partial liver transplantation (LRLT). After LRLT, neurological symptoms soon disappeared, and all patients returned to their previous social lives. Among the 14 patients that did not undergo LRLT, 6 died of intractable encephalopathy or the development of hepatic cancer, but 8 patients have had relatively good clinical courses (follow-up range 0.5-8 years) with oral intake of L-arginine and low-carbohydrate and relatively protein-rich diet. Six patients have been also given sodium pyruvate and the frequency of attacks of encephalopathy markedly decreased in 5 of 6 patients. Our observations indicated that liver transplantation is a very promising type of therapy but that other therapeutic approaches, including low-carbohydrate diet and pyruvate, are being established.

Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643.

Previous studies demonstrated that dietary glycine prevents elevated rates of cell proliferation following treatment with the peroxisome proliferator and liver carcinogen WY-14,643. Since increased cell replication is associated with the development of hepatic cancer caused by peroxisome proliferators, glycine may have anti-cancer properties. Therefore, experiments were designed to test the hypothesis that dietary glycine would inhibit the hepatocarcinogenic effect of WY-14,643. Male F344 rats were fed four different NIH 07-based diets: 5% glycine; 5% valine for nitrogen balance (control); 0.1% WY-14,643 + 5% valine (WY-14,643); 0.1% WY-14,643 + 5% glycine (WY-14,643 + glycine). Food consumption did not differ among the groups, but WY-14,643-fed rats weighed 10-25% less than expected based on previous studies. Serum glycine levels were elevated 4-5-fold by glycine-containing diets; however, the 10-fold increase in peroxisomal enzyme activity caused by WY-14,643 was unaffected by the addition of 5% glycine to the diet. After 22 weeks, livers from rats fed WY-14,643 had a similar incidence and multiplicity of proliferative lesions (foci and adenomas) to those fed WY-14,643 + glycine. Moreover, cell proliferation in the surrounding 'normal' parenchyma (labeling index approximately 4%) and foci (labeling index approximately 50%) did not differ between WY-14,643 and WY-14,643 + glycine-fed rats. However, after 51 weeks of dietary exposure to WY-14,643, glycine prevented formation of small (0-5 mm diameter) tumors by 23% and inhibited the development of medium size (5-10 mm) tumors by 64%. Furthermore, glycine prevented the formation of the largest tumors (>10 mm) by nearly 80%. Thus, glycine did not inhibit early foci formation; however, it significantly decreased their ability to progress to tumors. Moreover, the inhibitory effect of glycine was greater with increasing tumor size. These studies demonstrate that dietary glycine prevents the development of hepatic tumors caused by the peroxisome proliferator WY-14,643 consistent with the idea that it may be an effective chemopreventive agent.

Primary liver cancer and drug therapy.

An attempt to evaluate the role of drug therapy in the development of primary liver cancer was made by investigating 37 consecutive patients diagnosed during a period of 10 years. 14 patients had previously been apparently healthy, 21 had been treated with drugs, and 2 were chronic alcoholics. The most notable finding was that 9 of the patients had used compounds known to alter the activity of drug-hydroxylating enzymes in the liver. In microscopic examination, the differentiation pattern of the cancer in these 9 patients was of the hepatocellular type, whereas in others a mixture of differentiation types was found. The findings evoke the question of whether long-term therapy with drugs changing the activity of metabolizing enzymes in the liver has some causality for the development of hepatic cancer in man.