Advancement Of Hepatocellular Carcinoma Research Articles

Exploring the Role of DNA Methylation Located in Cuproptosis-Related Genes: Implications for Prognosis and Immune Landscape in Hepatocellular Carcinoma.

Copper dysregulation has been linked to liver disease, cardiac dysfunction, neuropathy, and anemia. Previous investigations have been undertaken to demonstrate the impact of cuproptosis-related genes (CRGs) on the poor prognosis of hepatocellular carcinoma (HCC), while the prognostic significance and beneath molecular basis of DNA-methylation sites located in CRGs remain unknown. This study aims to identify CRG-located DNA-methylation sites linked to patient prognosis and establish a novel prognostic biomarkers combination for CRG-located DNA-methylation signature. The prognostic biomarkers combination was established through multivariate-Cox-regression after CRG-located DNA-methylation sites tied to the outcome of patients emerged by univariate-Cox-regression. The correlation between signature and immune cell infiltration levels, immune-checkpoint-associated genes was analyzed using spearman correlation and the difference was contrasted between different groups utilizing the Mann-Whitney-U test. Real-time quantitative methylation-specific polymerase chain reaction (RT-qMSP) was used to identify gene methylation. A novel prognostic biomarkers combination for CRG-located DNA-methylation signature was established. Subsequently, the independence of this methylation signature from clinical features and its correlation with immune infiltrative and immune checkpoints in HCC were also investigated. DNA methylation alterations can influence the onset, development, and treatment of various tumors by regulating the transcription of corresponding genes. Our analysis found that cg05706061 contained in prognosis signature was located in the promoter region of the cuproptosis-related gene SLC31A2. The DNA-methylation level of cg05706061 demonstrated significantly different between tumor and normal tissue, and significantly correlated with the expression of SLC31A2. We further investigated the promoter methylation status of SLC31A2 by qMSP, the result showed that the DNA-methylation level of SLC31A2 in HCC cell lines were significantly decreased compared with normal liver cells. Our findings reveal possible mechanisms of CRG-located DNA-methylation on the advancement of HCC and offers new perspectives for prognostic assessment and treatment options.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

Global research status and frontiers on autophagy in hepatocellular carcinoma: a comprehensive bibliometric and visualized analysis.

An extensive body of research has explored the role of autophagy in hepatocellular carcinoma (HCC), revealing its critical involvement in the disease's pathogenesis, progression, and therapeutic targeting. However, there is a discernible deficit in quantitative, analytical studies concerning autophagy in the context of HCC. Accordingly, this investigation endeavored to meticulously assess the evolution of autophagy research, employing bibliometric citation analysis to offer a comprehensive evaluation of the findings in this field. The authors conducted a literature search on 2 August 2023, to extract relevant publications spanning from 2013 to 2022, indexed in the Science Citation Index-Expanded (SCIE) of the Web of Science Core Collection (WOSCC). Subsequently, the authors performed a bibliometric assessment of the compiled documents using visualization tools such as CiteSpace and VOSviewer. The search yielded 734 publications penned by 4699 authors, encompassing contributions from 41 countries and 909 institutions, disseminated across 272 journals, and comprising 26295 co-cited references from 2667 journals. Notably, China led in publication volume with 264 articles (amounting to 35.9%) and exhibited the most robust collaboration with the United States. The mechanisms underlying autophagy's influence on the emergence and advancement of HCC, as well as the implicated proteins and genes, have garnered significant attention. In recent years, investigations of targeting autophagy and the resistance to sorafenib have surfaced as pivotal themes and emerging frontiers in this domain. This study rigorously collated and distilled the prevailing research narratives and novel insights on autophagy in HCC. The resultant synthesis provides a substantive foundation for medical professionals and researchers, as well as pivotal implications for future investigative endeavors in this arena.

Exosomal microRNA profiling revealed enhanced autophagy suppression and anti-tumor effects of a combination of compound Phyllanthus urinaria and lenvatinib in hepatocellular carcinoma.

Compound Phyllanthus urinaria (CP), a traditional Chinese herbal remedy, possesses strong anti-cancer effects and is extensively employed in the clinical management of hepatocellular carcinoma (HCC). While lenvatinib and other oral tyrosine kinase inhibitors have been authorized as initial treatments for advanced unresectable HCC, the survival of patients is ultimately restricted due to the gradual development of drug resistance. Fortunately, the co-administration of CP and lenvatinib holds promise for anti-cancer applications. Our objective was to understand the molecular-level mechanisms of bioactive phytocompounds in CP, in order to explore the anti-HCC effects of combining CP and lenvatinib treatment and reveal the underlying mechanisms. Furthermore, we discovered new miRNAs associated with autophagy that are common to both HepG2-derived exosomes and HepG2 cells. These miRNAs play a role in the advancement of HCC and were identified through the utilization of CP and lenvatinib. To assess the anti-HCC effects of CP in combination with lenvatinib, both an in vitro CCK-8 assay and an in vivo xenograft model assay were performed. TEM, NTA, and nano-flow cytometry were employed for the identification of isolated exosomes. To ascertain the miRNA expression patterns in HepG2 cells and HepG2-derived exosomes, miRNA-sequencing analysis was conducted. Further investigation involved the use of real-time PCR, examination of the fusion protein GFP-mRFP-LC3, TEM analysis, and western blotting. In vitro and in vivo, the combination of CP and lenvatinib showed a stronger and more powerful impact on HCC compared to either CP or lenvatinib alone. The combination of CP and lenvatinib had a significant impact on autophagy-related miRNAs in HepG2-derived exosomes and HepG2 cells, as demonstrated by cellular and exosomal miRNA sequencing. Additional tests indicated that the increased inhibition of autophagy in HepG2 cells subjected to CP treatment, as well as the combination of CP and lenvatinib, was accomplished through the regulation of Beclin-1, LC3-II, and P62 expression. In conclusion, our results indicate that the combination of CP and lenvatinib can effectively inhibit HCC by promoting the exosome-mediated suppression of autophagy. This novel therapeutic option is highly efficient and durable, making it a promising treatment for HCC. Moreover, the miRNAs that are differentially expressed and associated with exosome-mediated autophagy, which have been discovered in this study, could potentially be targeted for clinical treatment of HCC.

Serum resistin and the risk for hepatocellular carcinoma in diabetic patients.

Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC's development and progression, as well as identify possible avenues for prevention and therapy.

Unveiling the Mystery of SUMO-activating enzyme subunit 1: A Groundbreaking Biomarker in the Early Detection and Advancement of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The discovery and research of effective biomarkers have become prevailing trends. SUMO-activating enzyme subunit 1 (sae1), an E1-activating enzyme, is indispensable for protein SUMOylation. In this study, we conducted a comprehensive analysis of database contents and found that sae1 is highly expressed in HCC and is correlated with poor prognosis. We also identified its regulated transcription factor, rad51, and related signaling pathways. We conclude that sae1 is a promising cancer metabolic biomarker with diagnostic and prognostic value in HCC.

Association between smoking and non-alcoholic fatty liver disease in Southeast Asia.

An estimated 8 million people die each year from tobacco smoking, with an increasing frequency recently being observed in Southeast Asian countries, which is a preventable risk factor for mortality. NAFLD, fibrosis, advancement of hepatocellular carcinoma, and prognosis for those with severe liver disease are all negatively influenced. NAFLD and cigarette usage seem to be a direct link. Oxidative stress and oncogenic signals have been implicated in cancer development in animal models and human clinical trials. The elevated risk of cardiovascular disease and malignancies in those with steatohepatitis and those who have had liver transplants is exacerbated by smoking. We found that smoking cessation may increase treatment response and fibrosis regression rates, decrease hepatocellular carcinoma incidence, and improve liver transplant outcomes. In the last segment, we'll look at electronic cigarettes, a hot subject in public health right now, as well as additional repercussions of smoking.

Developing and Validating an Autophagy Gene-Set-Based Prognostic Signature in Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC), a major type of cancer affecting the lives of people across the world, is one of many diseases whose advancement is thought to be influenced by autophagy dysfunction. Here, the prognostic significance of autophagy in HCC will be investigated. The Cancer Genome Atlas (TCGA) database was employed in this work to identify 62 differentially-expressed Autophagy-Related Genes (ARGs) in HCC patients. Functional enrichment studies revealed that autophagy played a tumor-promoting role in the advancement of HCC. Based on RNA sequencing of 116 tumor samples and 114 paracancerous tissue samples acquired from HCC patients at the Guangxi Medical University Cancer Hospital, 866 differentially expressed prognosis-related genes were identified. Using lasso regression analysis, two ARGs (BIRC5 and BAK1) linked to prognosis were discovered after intersecting the differential genes derived from the prognosis-related groups. A risk score based on ARGs was developed using a Cox proportional hazards regression model. RNA sequencing data were used to construct this model. Finally, the TCGA and The Human Protein Atlas Databases (THPA) were used to validate the clinical data of 116 HCC patients. Elevated expression level of the BAK1 and BIRC5 genes is linked to poor prognosis. The two ARGs were used to calculate the risk score as follows: (0.0253*BAK1) + (0.0051*BIRC5). Risk score served as the independent prognostic factor as per the multivariate analysis. TCGA, THPA, and data from the Guangxi Medical University Cancer Hospital were used to confirm the predictive validity of risk scores for the prognosis of HCC patients. This study offers molecular insights regarding the involvement of autophagy in HCC patients, along with a probable prognostic signature for determining the outcome (prognosis) of HCC patients.

Three Effects of Β-Catenin Factors in Liver Cancer and Its Treatment

Liver cancer is a typical malignant tumor and the fourth most typical cancer in the Earth. Clinically, more than 90% of patients with primary liver cancer are caused by hepatocellular carcinoma. Epidemiological and experimental data show that human infection with HBV and HCV hepatitis virus is firmly connected with the occurrence of liver cancer. In the past 20 years, the level of diagnosis and cure of liver cancer in China has been greatly improved, but little progress has been made in the study of liver cancer markers. For then, with the understanding of Wnt signal transduction pathway, it is found that β-catenin, as a key molecule in Wnt signal transduction pathway, is closely associated to the incidence of HCC. Recently, more and more studies have shown that the abnormal activation of classical Wnt signal pathway plays a compelling part in the occurrence and advancement of hepatocellular carcinoma. Hepatocytes because of hidden onset, early rise can be no clinical symptoms, so the clinical discovery is mostly late, the mortality rate is high. At present, the clinical methods for the treatment of hepatocellular carcinoma are liver transplantation, radiotherapy and chemotherapy. However, hepatocellular carcinoma is easy to metastasize and has a high recurrence rate, so the mortality rate of hepatocellular carcinoma is still high. Wnt/β-catenin signal pathway has become major topic of debate in cancer research. In this paper, we begin with the classification of liver cancer and some pathogenic mechanisms. The effects of β-catenin protein on the occurrence, metastasis and immune regulation of hepatocellular carcinoma were also discussed. Under the background of the popular "signal transduction therapy" in recent years, to explore the therapeutic effect of targeted drugs targeting Wnt/β-catenin signal pathway in hepatocellular carcinoma. Because of the high degree of malignancy and limited treatment of hepatocellular carcinoma, we will mainly discuss the effect of Wnt signal pathway on the metastasis of hepatocellular carcinoma and its effect on the differentiation of immune cells. Abnormal activation of Wnt signaling pathway in hepatocellular carcinoma.

Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma (HCC) represents a worldwide health challenge, ranking globally as the third most common cause of cancer-related mortality. Current advancements in the HCC therapeutic armamentarium succeeded in challenging HCC conventional therapy. Systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) come at the forefront of novel HCC therapeutic modalities. However, emerging drug resistance remains an obstacle during HCC therapy. According to the ongoing genomic analysis of HCC, a complex mutational landscape lies behind HCC pathogenesis and hence, affects the response of the tumor to the applied therapy. This review aims at categorizing and summarizing the different resistance mechanisms confronting tyrosine kinase inhibitors, represented by sorafenib, as well as ICIs, during HCC therapy. In addition, giving an insight into how genomic heterogeneity can influence the response of HCC to the aforementioned therapies.Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.

FAT10 promotes hepatocellular carcinoma (HCC) carcinogenesis by mediating P53 degradation and acts as a prognostic indicator of HCC.

With the advancement of hepatocellular carcinoma (HCC) treatment technology, the treatment options for HCC patients have increased. However, due to high heterogeneity, among other reasons, the five-year survival rate of patients is still very low. Currently, gene expression prognostic models can suggest more appropriate strategies for the treatment of HCC. This study investigates the role of FAT10 in hepatocarcinogenesis and its underlying mechanism. The expression of FAT10 was detected by immunohistochemical method using tissue arrays containing 4 specimens of patients with digestive cancer. The expression of FAT10 was determined by a tissue microarray which included 286 pairs of HCC samples and corresponding normal mucosae and was further confirmed by real-time polymerase chain reaction (PCR) and western blot. The Kaplan-Meier survival curve was used to determine the correlation of FAT10 expression with patients' recurrence and overall survival (OS) rate. In vivo, liver fibrosis, cirrhosis, and HCC models were established to assess the FAT10 expression. Moreover, FAT10 over-expressing cell lines were used to determine the molecular mechanism underlying the FAT10-induced cell proliferation and hepatocarcinogenesis by reporter gene measure, real-time PCR, and western blot. Based on TCGA database, signal pathways associated with FAT10 and HCC invasion and metastasis were analyzed by KEGG enrichment analyze. Overexpression of FAT10 in HCC was observed in this study compared with its expression in other digestive tumors. Clinicopathological analysis revealed that FAT10 expression levels were closely associated with tumor diameters and poor prognosis of HCC. This study also confirmed through in vivo experiments that the expression of FAT10 in liver fibrosis, cirrhosis, and HCC gradually increases. Further study revealed that forced FAT10 expression enhanced the growth ability of HCC cells and mediated the degradation of the critical anti-cancer protein p53, which led to carcinogenesis. Finally, 9 signal pathways related to HCC metastasis were obtained through bioinformatics analysis. FAT10 may act as a proto-oncogene that facilitates HCC carcinogenesis by mediating p53 degradation, and the expression of FAT10 is negatively correlated with the prognosis of HCC patients. FAT10 is expected to become a potential combined target and prognostic warning marker for HCC treatment.

HCC advances in diagnosis and prognosis: Digital and Imaging.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Understanding of the pathogenesis of HCC has significantly improved in the past few years due to advances in genetics, molecular biology and pathology. Several subtypes have been identified with different backgrounds and outcomes, leading to possible changes in disease management and challenging the role of imaging. Indeed, despite its pivotal role in the diagnostic workup, prognosis, and the decision-making process in patients with HCC, these recent developments are progressively redefining the role of imaging. First and most important, liver imaging is shifting from a purely qualitative to a quantitative paradigm, integrating quantitative imaging and radiomics in a digital era. Second, to improve patient management, imaging has gradually moved beyond tumor-centered assessment to include a broader evaluation of the liver and its function. This review describes and discusses these advances in the imaging for the diagnosis and prognosis of HCC.

Application of ASCO Value Framework to Treatment Advances in Hepatocellular Carcinoma

Determination of the comparative efficacy of one therapy over another for hepatocellular carcinoma (HCC) can be challenging. Application of a recognized value framework to published studies could objectively compare the potential benefit across available therapies. An umbrella review of phase III trials for HCC therapies was performed. ASCO Value Framework Net Health Benefit Score version 2 (ASCO-NHB v2) scores, the primary analysis, and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 scores, the secondary analysis, were computed using selected drug registration trials. Both scores were compared between drugs that were Food and Drug Administration (FDA)-approved by 2020 and those that were not. Of the 22 studies identified, nine were FDA-approved and 13 were not. Across 22 trials, the median overall survival (OS) was 9.2 months (range, 1.9-16.4 months), with a median gain of 0.35 month (range, 2.3-3.3 months). HCC therapies that were FDA-approved showed longer OS (median 10.7 v 7.9 months, P < .01) and higher ASCO NHB scores (+18.4 v -5.7 scores, P < .01). The median gain in OS was 2.2 months in the approved treatments compared with -0.3 months in the unapproved group, with no difference in progression-free survival between the two groups. The nine FDA-approved therapies for HCC have higher mean NHB score than those that were not FDA-approved. The application of ASCO-NHB v2 and other proposed value frameworks could examine data of future therapies for HCC through a patient-oriented approach.

Circular RNA hsa_circ_0061395 accelerates hepatocellular carcinoma progression via regulation of the miR-877-5p/PIK3R3 axis

BackgroundCircular RNA hsa_circ_0061395 (circ_0061395) has been reported to accelerate the advancement of hepatocellular carcinoma (HCC). However, the regulatory mechanism by which circ_0061395 modulates the progression of HCC is unclear.MethodsThe morphology and size of exosomes were analyzed by transmission electron microscope (TEM) and nanoparticle-tracking analysis (NTA). Protein levels were detected by western blotting. Expression levels of circ_0061395, microRNA (miR)-877-5p, and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) mRNA were assessed by quantitative real time polymerase chain reaction (qRT-PCR). The proliferation, invasion, migration, cell cycle progression, and apoptosis were analyzed by cell counting kit-8 (CCK-8), plate clone, transwell, or flow cytometry assays. The targeting relationship between circ_0061395 or PIK3R3 and miR-877-5p was verified using the dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Xenograft assay was performed to confirm the biological function of circ_0061395 in HCC.ResultsCirc_0061395 was upregulated in HCC tissues, serum, cells, and serum-derived exosomes. Circ_0061395 silencing decreased tumor growth in vivo, and induced cell cycle arrest, apoptosis, repressed proliferation, invasion, and migration of HCC cells in vitro. MiR-877-5p was downregulated while PIK3R3 was upregulated in HCC. Circ_0061395 regulated PIK3R3 expression via competitively binding to miR-877-5p. MiR-877-5p inhibitor overturned circ_0061395 knockdown-mediated influence on malignant behaviors of HCC cells. PIK3R3 overexpression reversed the suppressive influence of miR-877-5p mimic on malignant behaviors of HCC cells.ConclusionCirc_0061395 facilitated HCC progression via regulating the miR-877-5p/PIK3R3 axis, providing a new perspective on the advancement of HCC.

Exosomal MiR-744 Inhibits Proliferation and Sorafenib Chemoresistance in Hepatocellular Carcinoma by Targeting PAX2.

BackgroundHepatocellular carcinoma (HCC) is a commonly occurring liver malignancy. Its prognosis remains unsatisfactory. Accumulating evidence has revealed that exosomal microRNAs (miRNAs) act as biomarkers and play crucial roles in the advancement of HCC. The current study explored the biological role and fundamental mechanism of exosomal miR-744 in HCC.Material/MethodsThe serum exosomes of HCC patients were isolated by differential ultracentrifugation. MiR-744 expression in HCC tissues, cell lines and serum exosomes were detected by quantitative real-time polymerase chain reaction (qRT-PCR). EdU (5-ethynyl-2′-deoxyuridine) assay and Cell Counting Kit-8 (CCK-8) assay were conducted to show the impacts of miR-744 or exosomal miR-744 on proliferation and sorafenib resistance in HepG2 cells. The target of miR-744 was ascertained by regulating the level of miR-744 in HepG2 cells.ResultsMiR-744 is downregulated in HCC tissues and cell lines as well as in exosomes derived from patient serum and HepG2 cells. Additionally, downregulated miR-744 promotes HepG2 cell proliferation and inhibits the chemosensitivity of HepG2 cells to sorafenib. PAX2 was identified as the functional target of miR-744. Interestingly, miR-744 is decreased in exosomes derived from sorafenib-resistant HepG2 cells. Furthermore, when treated with the miR-744-enriched exosomes, the proliferation of HepG2 cells was significantly suppressed, and the sorafenib resistance was reduced.ConclusionsMiR-744 has an imperative role in the propagation and chemoresistance of HCC. Serum exosomal miR-744 might act as a biomarker of HCC, and exosomal miR-744 might offer an innovative strategy for HCC treatment.

Combination Therapy of Angiotherapy, Radiation Therapy, and Radiofrequency Ablation for Pulmonary Metastasis of Hepatocellular Carcinoma Accompanied by Nontuberculous Mycobacteria

With the advances in hepatocellular carcinoma (HCC) treatment, the lung metastasis of HCC is becoming increasingly important. In treating the lung metastasis of HCC, a multidisciplinary approach can lead to better results than systemic chemotherapy alone. Here, we report on a patient who presented with pulmonary masses, while the HCC was being controlled in the abdominal cavity. The presence of nontuberculous mycobacteria was identified during the diagnosis of the pulmonary masses. The pulmonary metastases of HCC were treated with a combination of angiotherapy, radiation therapy, and radiofrequency ablation. The patient showed a satisfactory progress with this multidisciplinary localized treatment. We report the clinical progress and review the recent literature regarding the treatment of pulmonary metastasis without intrahepatic HCC herein. (J Liver Cancer 2019;19:79-84)

Radiomics and its advances in hepatocellular carcinoma.

Liver cancer is the second leading cause of cancer-related death worldwide, so early detection and prediction for response to treatment is of great benefit to hepatocellular carcinoma (HCC) patients. Currently, needle biopsy and conventional medical imaging play a significant and basic role in HCC patients' management, while those two approaches are limited in sample error and observer-dependence. Radiomics can make up for this deficiency because it is an emerging non-invasive technic that is capable of getting comprehensive information relevant to tumor situation across spatial-temporal limitation. The basic procedure for radiomics includes image acquisition, region of interest segmentation and reconstruction, feature extraction, selection and classification, and model building and performance evaluation. The current advances and potential prospect of radiomics in HCC studies are involved in diagnosis, prediction for response to treatment, prognosis evaluation and radiogenomics.

A four-gene-based prognostic model predicts overall survival in patients with hepatocellular carcinoma.

With the development of new advances in hepatocellular carcinoma (HCC) management and noninvasive radiological techniques, high‐risk patient groups such as those with hepatitis virus are closely monitored. HCC is increasingly diagnosed early, and treatment may be successful. In spite of this progress, most patients who undergo a hepatectomy will eventually relapse, and the outcomes of HCC patients remain unsatisfactory. In our study, we aimed to identify potential gene biomarkers based on RNA sequencing data to predict and improve HCC patient survival. The gene expression data and clinical information were acquired from The Cancer Genome Atlas (TCGA) database. A total of 339 differentially expressed genes (DEGs) were obtained between the HCC (n = 374) and normal tissues (n = 50). Four genes (CENPA, SPP1, MAGEB6 and HOXD9) were screened by univariate, Lasso and multivariate Cox regression analyses to develop the prognostic model. Further analysis revealed the independent prognostic capacity of the prognostic model in relation to other clinical characteristics. The receiver operating characteristic (ROC) curve analysis confirmed the good performance of the prognostic model. Then, the prognostic model and the expression levels of the four genes were validated using the Gene Expression Omnibus (GEO) dataset. A nomogram comprising the prognostic model to predict the overall survival was established, and internal validation in the TCGA cohort was performed. The predictive model and the nomogram will enable patients with HCC to be more accurately managed in trials testing new drugs and in clinical practice.

The NCX1/TRPC6 Complex Mediates TGFβ-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells

TGFβ plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.Significance: TGFβ induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFβ on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564-76. ©2018 AACR.

Epithelial-to-Mesenchymal Transition: A Mediator of Sorafenib Resistance in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC.