Implications In Hepatocellular Carcinoma Research Articles

Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: pathogenic role and therapeutic target.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and one of the leading causes of cancer-related deaths worldwide. The Wnt/β-Catenin signaling pathway is a highly conserved pathway involved in several biological processes, including the improper regulation that leads to the tumorigenesis and progression of cancer. New studies have found that abnormal activation of the Wnt/β-Catenin signaling pathway is a major cause of HCC tumorigenesis, progression, and resistance to therapy. New perspectives and approaches to treating HCC will arise from understanding this pathway. This article offers a thorough analysis of the Wnt/β-Catenin signaling pathway's function and its therapeutic implications in HCC.

Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma

Background & AimsMcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1Δhep) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC. MethodsLivers of young Mcl-1Δhep and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1Δhep tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. ResultsIn young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1Δhep tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. ConclusionsOur study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. Impact and implicationsAlthough Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.

Transmembrane protein 147, as a potential Sorafenib target, could expedite cell cycle process and confer adverse prognosis in hepatocellular carcinoma.

TMEM147 was identified as a core component of ribosome-bound translocon complex at ER/NE. So far, sparse studies reported its expression profiling and oncological implications in hepatocellular carcinoma (HCC) patients. Here we inspected TMEM147 expression levels in HCC cohorts from public databases and tumor tissues. TMEM147 was augmented at transcriptional levels (p < 0.001) and protein levels in HCC patients. A series of bioinformatics tools implemented in R studio were orchestrated in TCGA-LIHC to evaluate the prognostic significance, compile relevant gene clusters, and explore the oncological functions and therapy responses. It is suggested that TMEM147 could predict poor clinical outcomes effectively and independently (p < 0.001, HR = 2.231 for overall survival (OS) vs. p = 0.04, HR = 2.296 for disease-specific survival), and was related to risk factors including advanced histologic tumor grade (p < 0.001), AFP level (p < 0.001) and vascular invasion (p = 0.007). Functional enrichment analyses indicated that TMEM147 was involved in cell cycle, WNT/MAPK signaling pathways and ferroptosis. Expression profiling in HCC cell lines, mouse model, and a clinical trial revealed that TMEM147 was a considerable target and marker for adjuvant therapy in vitro and in vivo. Subsequentially, in vitro wet-lab experimentation authenticated that TMEM147 would be downregulated by Sorafenib administration in hepatoma cells. Lentivirus-mediated overexpression of TMEM147 could promote cell cycle progression from S phase into G2/M phase, and enhance cell proliferation, thus attenuating drug efficacy and sensitivity of Sorafenib. Further explorations into TMEM147 may inspire a fresh perspective to predict clinical outcomes and improve therapeutic efficacy for HCC patients.

Deciphering the immune heterogeneity dominated by natural killer cells with prognostic and therapeutic implications in hepatocellular carcinoma

Belonging to type 1 innate lymphoid cells (ILC1), natural killer (NK) cells play an important role not only in fighting microbial infections but also in anti-tumor response. Hepatocellular carcinoma (HCC) represents an inflammation-related malignancy and NK cells are enriched in the liver, making them an essential component of the HCC immune microenvironment. In this study, we performed single-cell RNA-sequencing (scRNA-seq) analysis to identify the NK cell marker genes (NKGs) and uncovered 80 prognosis-related ones by the TCGA-LIHC dataset. Based on prognostic NKGs, HCC patients were categorized into two subtypes with distinct clinical outcomes. Subsequently, we conducted LASSO-COX and stepwise regression analysis on prognostic NKGs to establish a five-gene (UBB, CIRBP, GZMH, NUDC, and NCL) prognostic signature-NKscore. Different mutation statuses of the two risk groups stratified by NKscore were comprehensively characterized. Besides, the established NKscore-integrated nomogram presented enhanced predictive performance. Single sample gene set enrichment analysis (ssGSEA) analysis was used to uncover the landscape of the tumor immune microenvironment (TIME) and the high-NKscore risk group was characterized with an immune-exhausted phenotype while the low-NKscore risk group held relatively strong anti-cancer immunity. T cell receptor (TCR) repertoire, tumor inflammation signature (TIS), and Immunophenoscore (IPS) analyses revealed differences in immunotherapy sensitivity between the two NKscore risk groups. Taken together, we developed a novel NK cell-related signature to predict the prognosis and immunotherapy efficacy for HCC patients.

Identification and Experimental Validation of the Prognostic Significance and Immunological Correlation of Glycosylation-Related Signature and ST6GALNAC4 in Hepatocellular Carcinoma.

Glycosylation has been demonstrated to be involved in tumorigenesis, progression, and immunoregulation, and to present specific profiles in different tumors. In this study, we aimed to explore the specific glycosylation-related gene (GRG) signature and its potential immunological roles and prognostic implications in hepatocellular carcinoma (HCC). The GRG expression profile was defined using the transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate and the least absolute shrinkage and selection operator Cox analyses were performed to develop a GRG-based risk score model. A nomogram was subsequently established and validated. Its correlation with cancer immune microenvironment and drug susceptibility was further analyzed. The role and immunological correlation of ST6GALNAC4 were further experimentally validated at the tissue and cellular levels in HCC. A total of 87 GRGs were identified to be significantly dysregulated in HCC, and a novel risk score model was constructed using eight critical GRGs, which demonstrated superior prognostic discrimination and predictive power in both training and validation groups. High risk scores in HCC patients were associated with lower OS. The model was also identified as an independent risk factor for HCC, and a novel nomogram was subsequently constructed and validated. Notably, significant correlations were found in risk scores with immune cells infiltration, tumor immunophenotyping, immune checkpoint genes' expression, and sensitivities to multiple drugs. Furthermore, we validated in local HCC samples that ST6GALNAC4 was significantly upregulated and its knockdown significantly inhibited the tumor proliferation, migration and invasion ability and affected the expression of immune checkpoints on hepatoma cells. We identified a novel GRG-based model which showed significant prognostic and immunological correlations in HCC, and the oncogenic role of ST6GALNAC4 has been validated and may serve as a potential drug target.

Mesenchymal circulating tumor cells and Ki67: their mutual correlation and prognostic implications in hepatocellular carcinoma

BackgroundMesenchymal circulating tumor cells (M-CTCs) may be related to tumor progression, and Ki67 expression is known to be involved in tumor proliferation. The aim of the present study was to explore the relationship between M-CTCs and Ki67 in hepatocellular carcinoma (HCC) and their ability to predict prognosis.MethodsPeripheral blood samples were obtained from 105 HCC patients before radical surgery. CTCs were isolated using CanPatrol enrichment and classified via in situ hybridization. Ki67 expression in HCC tissue was assessed through immunohistochemistry. Potential relationships of M-CTC, Ki67 with clinicopathological factors and prognosis were evaluated. Overall survival (OS) was analyzed using the Kaplan–Meier method and Cox regression. The prognostic efficacy of M-CTC, Ki67 and both together (M-CTC + Ki67) was assessed in terms of time-dependent receiver operating characteristic (ROC) curves and Harrell's concordance index.ResultsOf the 105 patients, 50 were positive for M-CTCs (count ≥ 1 per 5 mL) and 39 showed high Ki67 expression (≥ 50% tumor cells were Ki67-positive). The presence of M-CTC was significantly associated with alpha-fetoprotein (AFP) ≥ 400 ng/mL (P = 0.007), tumor size ≥ 5 cm (P = 0.023), multiple tumors (P < 0.001), poorly differentiated tumors (P = 0.003), incomplete tumor capsule (P < 0.001), Barcelona Clinic liver cancer (BCLC) stage B or C (P < 0.001), microvascular invasion (MVI) (P = 0.05) and portal vein tumor thrombosis (PVTT) (P = 0.006). High Ki67 expression correlated with AFP ≥ 400 ng/mL (P = 0.015), tumor size ≥ 5 cm (P = 0.012), incomplete tumor capsule (P < 0.001), MVI (P = 0.001), PVTT (P = 0.003), advanced BCLC stage (P = 0.01), and vessel carcinoma embolus (VCE) (P = 0.001). M-CTC positively correlated with Ki67. Patients positive for M-CTCs had a significantly shorter OS than patients negative for them. Similarly, high Ki67 expression was associated with a significantly lower OS. The high-risk group (positive for M-CTCs and high Ki67 expression) had worse OS than the other groups (P < 0.0001). Uni- and multivariate analyses showed that OS was independently predicted by M-CTC [hazard ratio (HR) 1.115; P < 0.001], Ki67 (HR 1.666; P = 0.046) and the combination of both (HR 2.885; P = 0.008). Based on ROC curves and the concordance index, the combination of M-CTC and Ki67 was superior to either parameter alone for predicting the OS of HCC patients.ConclusionsThe presence of M-CTC correlates with high Ki67 expression in HCC patients, and both factors are associated with poor prognosis. Furthermore, the combination of M-CTC and Ki67 is a useful prognostic indicator for predicting OS in patients with HCC after hepatectomy, performing better than either parameter on its own.

An anoikis-based signature for predicting prognosis in hepatocellular carcinoma with machine learning.

Background: Hepatocellular carcinoma (HCC) is a common malignancy with high mortality worldwide. Despite advancements in diagnosis and treatment in recent years, there is still an urgent unmet need to explore the underlying mechanisms and novel prognostic markers. Anoikis has received considerable attention because of its involvement in the progression of human malignancies. However, the potential mechanism of anoikis-related genes (ANRGs) involvement in HCC progression remains unclear. Methods: We use comprehensive bioinformatics analyses to determine the expression profile of ANRGs and their prognostic implications in HCC. Next, a risk score model was established by least absolute shrinkage and selection operator (Lasso) Cox regression analysis. Then, the prognostic value of the risk score in HCC and its correlation with clinical characteristics of HCC patients were further explored. Additionally, machine learning was utilized to identify the outstanding ANRGs to the risk score. Finally, the protein expression of DAP3 was examined on a tissue microarray (TMA), and the potential mechanisms of DAP3 in HCC was explored. Results: ANRGs were dysregulated in HCC, with a low frequency of somatic mutations and associated with prognosis of HCC patients. Then, nine ANRGs were selected to construct a risk score signature based on the LASSO model. The signature presented a strong ability of risk stratification and prediction for overall survival in HCC patients.Additionally, high risk scores were closely correlated with unfavorable clinical features such as advanced pathological stage, poor histological differentiation and vascular invasion. Moreover, The XGBoost algorithm verified that DAP3 was an important risk score contributor. Further immunohistochemistry determined the elevated expression of DAP3 in HCC tissues compared with nontumor tissues. Finally, functional analyses showed that DAP3 may promote HCC progression through multiple cancer-related pathways and suppress immune infiltration. Conclusion: In conclusion, the anoikis-based signature can be utilized as a novel prognostic biomarker for HCC, and DAP3 may play an important role in the development and progression of HCC.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

The Association of Glycemic Index, Glycemic Load, and Daily Carbohydrates Intake with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Background: Glycemic index (GI), glycemic load (GL) and daily carbohydrates intake have been associated with a variety of cancers, but their implications in hepatocellular carcinoma (HCC) remain controversial. The purpose of our study is to investigate the association of GI, GL and daily carbohydrates intake with the risk of HCC. Methods: Systematic searches were conducted in PubMed, Embase and Web of Science until November 2020. According to the degree of heterogeneity, random effect model or fixed effect model was chosen to obtain the pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs). Results: Four cohort studies and three case-control studies were eventually included. The pooled results showed no significant association of GI (RR = 1.11, 95% CI = 0.80-1.53), GL (RR = 1.09, 95% CI = 0.76-1.55), and daily carbohydrates intake (RR = 1.09, 95% CI = 0.84-1.32) with the risk of HCC in the general population. Subgroup analysis revealed that in hepatitis B virus (HBV) or/and hepatitis C virus (HCV)-positive group, GI was irrelevant to the risk of HCC (RR = 0.65, 95% CI = 0.32-1.32), while a high GL diet was associated with a higher risk of HCC (RR = 1.52, 95% CI = 1.04-2.23). In contrast, in HBV and HCV-negative group, both GI (RR = 1.23, 95% CI = 0.88-1.70) and GL (RR = 1.17, 95% CI = 0.83-1.64) were not associated with the risk of HCC. Conclusion: A high GL diet increases the risk of HCC in those with viral hepatitis. A low GL diet is recommended for them to reduce the risk of HCC.

Recreational Drugs and the Risk of Hepatocellular Carcinoma.

Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis' potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. Long-term follow-up studies of subjects who have developed injuries in association with the use of recreational drugs are warranted so as to better define the risk of developing hepatocellular carcinoma in association with these substances and, thus, to implement health care policies to combat this preventable cause of cancer.

IFNγ−IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ− Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ− Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ− Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ− Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ− Tc17 and its implications in HCC progression.

Development and validation of four ferroptosis-related gene signatures and their correlations with immune implication in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This tumor presents with an insidious onset, rapid progression, and frequent recurrence. Ferroptosis is a newly discovered mode of programmed cell death that may play a key role in the progression of HCC. This study aimed to investigate the prognostic value of ferroptosis-related genes (FRGs) in HCC and their impact on tumor immune function, thereby providing new insights into targeted therapy for HCC. First, 43 differentially expressed FRGs were identified using the TCGA database, and four prognostically relevant methylation-driven FRGs (G6PD, HELLS, RRM2, and STMN1) were screened via survival and methylation analyses. Gene co-expression, mutation, and clinicopathological characterization indicated that these four pivotal FRGs play essential roles in tumor progression. We also validated these four genes using transcriptomic and proteomic data as well as cohort samples from our patients. Moreover, receiver operator characteristic (ROC) curves confirmed that the signatures of the four FRGs were independent prognostic factors in HCC. Gene set enrichment analysis of the four FRGs showed statistically significant associations with pathways related to HCC proliferation. Finally, the TIMER and TISIDB databases indicated that the four FRGs were statistically significantly correlated with tumor-infiltrating immune cells and immune checkpoint expression. Taken together, this study provides information guiding a novel therapeutic strategy targeting FRGs for HCC treatment.

Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide, but its pathogenesis remains largely unknown. Nevertheless, genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity. Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects, which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression. Histone deacetylases (HDACs) have been shown to impair a variety of cellular processes of genome stability, including the regulation of DNA damage and repair, reactive oxygen species generation and elimination, and progression to mitosis. In this review, we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.

Transcriptome sequencing of hepatocellular carcinoma uncovers multiple types of dysregulated ncRNAs.

Transcriptome profiling of hepatocellular carcinoma (HCC) by next-generation sequencing (NGS) technology has been broadly performed by previous studies, which facilitate our understanding of the molecular mechanisms of HCC formation, progression, and metastasis. However, few studies jointly analyze multiple types of noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and micro-RNAs (miRNAs), and further uncover their implications in HCC. In this study, we observed that the circRNA cZRANB1 and lncRNA DUXAP10 were not only significantly upregulated in tumor tissues, but also higher expressed in blood exosomes of HCC as compared with healthy donors. From the analysis of subclass-associated dysregulated ncRNAs, we observed that DLX6-AS1, an antisense RNA of DLX6, and the sense gene DLX6 were highly expressed in S1, a subclass with a more invasive/disseminative phenotype. High correlation between DLX6-AS1 and DLX6 suggested that DLX6-AS1 may function via promoting the transcription of DLX6. Integrative analysis uncovers circRNA–miRNA, lncRNA–miRNA, and competing endogenous RNA networks (ceRNAs). Specifically, cZRANB1, LINC00501, CTD-2008L17.2, and SLC7A11-AS1 may function as ceRNAs that regulate mRNAs by competing the shared miRNAs. Further prognostic analysis demonstrated that the dysregulated ncRNAs had the potential to predict HCC patients’ overall survival. In summary, we identified some novel circRNAs and miRNAs, and dysregulated ncRNAs that could participate in HCC tumorigenesis and progression by inducing transcription of their neighboring genes, increasing their derived miRNAs, or acting as miRNA sponges. Moreover, our systematic analysis provides not only rich data resources for related researchers, but also new insights into the molecular basis of how different ncRNAs coordinately or antagonistically participate in the pathogenesis process of diseases.

A comprehensive prognostic and immunological analysis of ephrin family genes in hepatocellular carcinoma.

Background: Ephrins, a series of Eph-associated receptor tyrosine kinase ligands, play an important role in the tumorigenesis and progression of various cancers. However, their contributions to hepatocellular carcinoma (HCC) remain unclear. Thus, we aimed to explore their prognostic value and immune implications in HCC. Methods: Multiple public databases, such as TCGA, GTEx, and UCSC XENA, were used to analyze the expression of ephrin genes across cancers. Kaplan-Meier analysis and Cox regression were used to explore the prognostic role of ephrin genes in HCC. A logistic regression model was utilized to evaluate the association between ephrin gene expression and clinical characteristics. Gene set enrichment analysis (GSEA) was conducted to elucidate their potential biological mechanisms. Various immune algorithms were utilized to investigate the correlation between ephrin genes and tumor immunity. We also analyzed their association with drug sensitivity, and gene mutations. Finally, RT–qPCR was performed to validate the expression of ephrin family genes in HCC cells and clinical tissues. Results: The expression of EFNA1, EFNA2, EFNA3, EFNA4, EFNB1, and EFNB2 was upregulated in most cancer types, while EFNA5 and EFNB3 was downregulated in most cancers. In HCC, the expression levels of EFNA1, EFNA3, EFNA4, EFNB1, and EFNB2 were significantly higher in tumor tissues than in normal tissues. High expression of EFNA3, EFNA4, and EFNB1 was associated with tumor progression and worse prognosis in HCC patients. The expression of EFNA3 and EFNA4 was negatively associated with the stromal/ESTIMATE scores, while EFNB1 was positively correlated with the immune/stromal/ESTIMATE scores. Moreover, these ephrin genes were closely relevant to the infiltration of immune cells, such as B cells, CD4+ T cells, CD8+ T cells, neutrophil cells, macrophage cells, and dendritic cells. EFNB1 expression was positively associated with most immune-related genes, while EFNA3/EFNA4 was positively related to TMB and MSI. In addition, EFNA3, EFNA4, and EFNB1 were related to drug sensitivity and affected the mutation frequency of some genes in HCC. Conclusion: EFNA3, EFNA4, and EFNB1 are independent prognostic factors for HCC patients and are closely correlated with tumor immunity, which may provide a new direction for exploring novel therapeutic targets and biomarkers for immunotherapy.

Poly(ADP-Ribose) Polymerase Inhibition as a Promising Approach for Hepatocellular Carcinoma Therapy.

Simple SummaryLiver cancer has very high incidence and mortality rates, making it a major public health problem. Indeed, the available treatments are not numerous, and few strategies exist for patients with advanced cancers. Thus, there is an urgent need to search for new treatment targets. This review provides an overview of one potential target, poly(ADP)ribose polymerase 1, a protein involved in DNA repair pathways and its expression profiles in liver cancer. Inhibition of this protein could potentiate the effects of current treatments and improve therapeutic outcomes for patients.Primary liver cancer is the sixth most common cancer in men and seventh in women, with hepatocellular carcinoma (HCC) being the most common form (75–85% of primary liver cancer cases) and the most frequent etiology being viral infections (HBV and HCV). In 2020, mortality represented 92% of the incidence—830,180 deaths for 905,677 new cases. Few treatment options exist for advanced or terminal-stage HCC, which will receive systemic therapy or palliative care. Although radiotherapy is used in the treatment of many cancers, it is currently not the treatment of choice for HCC, except in the palliative setting. However, as radiosensitizing drugs, such as inhibitors of DNA repair enzymes, could potentiate the effects of RT in HCC by exploiting the modulation of DNA repair processes found in this tumour type, RT and such drugs could provide a treatment option for HCC. In this review, we provide an overview of PARP1 involvement in DNA damage repair pathway and discuss its potential implication in HCC. In addition, the use of PARP inhibitors and PARP decoys is described for the treatment of HCC and, in particular, in HBV-related HCC.

The Heterogeneity of Immune Cell Infiltration Landscape and Its Immunotherapeutic Implications in Hepatocellular Carcinoma.

Immunotherapy, closely associated with immune infiltration and tumor mutation burden (TMB), is emerging as a promising strategy for treating tumors, but its low response rate in hepatocellular carcinoma (HCC) remains a major challenge. Herein, we applied two algorithms to uncover the immune infiltration landscape of the immune microenvironment in 491 HCC patients. Three immune infiltration patterns were defined using the CIBERSORT method, and the immune cell infiltration (ICI) scores were established using principal component analysis. In the high ICI score group, the activation of the Wnt/β-catenin pathway was significantly enriched and expressions of immune checkpoint genes increased, which showed a pessimistic outcome. The low ICI score group was characterized by increased TMB and enrichment of metabolism-related pathways. Further analysis found that the ICI score exhibited a significant difference in age ≥65/age <65, grade I/grade II–IV, and response to immunotherapy. Moreover, the CTNNB1 mutation status was found to be closely associated with prognosis and immunotherapeutic efficiency, significantly affecting the ICI score and TMB, which might be regarded as a potential marker for the treatment of HCC. The evaluation of immune infiltration patterns can improve the understanding of the tumor immune microenvironment and provide new directions for the study of individualized immunotherapy strategies for HCC.

Alternative Splicing-Based Differences Between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Genes, Immune Microenvironment, and Survival Prognosis.

Alternative splicing (AS) event is a novel biomarker of tumor tumorigenesis and progression. However, the comprehensive analysis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is lacking. Differentially expressed analysis was used to identify the differentially expressed alternative splicing (DEAS) events between HCC or ICC tissues and their normal tissues. The correlation between DEAS events and functional analyses or immune features was evaluated. The cluster analysis based on DEAS can accurately reflect the differences in the immune microenvironment between HCC and ICC. Forty-five immune checkpoints and 23 immune features were considered statistically significant in HCC, while only seven immune checkpoints and one immune feature in ICC. Then, the prognostic value of DEAS events was studied, and two transcripts with different basic cell functions (proliferation, cell cycle, invasion, and migration) were produced by ADHFE1 through alternative splicing. Moreover, four nomograms were established in conjunction with relevant clinicopathological factors. Finally, we found two most significant splicing factors and further showed their protein crystal structure. The joint analysis of the AS events in HCC and ICC revealed novel insights into immune features and clinical prognosis, which might provide positive implications in HCC and ICC treatment.

Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma.

Simple SummaryAn abnormal alpha-fetoprotein (AFP) test is often associated with hepatocellular carcinoma (HCC) development, although as many as 40% of HCC diagnoses are made in the absence of an abnormal AFP test. In Japan and other Asian countries, Lens culinaris agglutinin-reactive AFP fraction (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are used in combination with AFP for HCC diagnosis. Combined testing with all three biomarkers increases early diagnosis in addition to providing a patient-specific profile of HCC aggressiveness. The utility of AFP, AFP-L3, and DCP for HCC prognosis in the bridge to liver transplantation has not been established. The goal of this study is to define prognosis to first-line HCC treatment and the risk of progression prior to liver transplantation associated with biomarker profile at diagnosis. Biomarker profiling may have future implications in precision therapeutic management of HCC as a bridge to transplantation.The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.

CCT6A expression in hepatocellular carcinoma and its correlation with clinical characteristics, liver function indexes, tumor markers and prognosis

BackgroundChaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) plays roles in cancer progression, but its clinical implication in hepatocellular carcinoma (HCC) management needs further exploration. This study aimed to explore the correlation of CCT6A with clinical characteristics, liver function indexes, tumor markers and prognosis in HCC patients. Methods240 HCC patients were retrospectively enrolled. 240 pairs of cancer and adjacent specimens were used to evaluate CCT6A protein expression by immunohistochemistry assay; among which 184 pairs were used to assess CCT6A mRNA expression by reverse transcription-quantitative polymerase chain reaction. ResultsBoth CCT6A protein expression and CCT6A mRNA expression were higher in HCC tumor tissue than in adjacent tissue (P < 0.001). The receiver operating characteristic (ROC) curve showed that CCT6A had certain potential in discriminating tumor tissues from adjacent tissues. In addition, CCT6A protein expression was positively correlated with multifocal tumor nodule (P = 0.001), ≥ 5.0 cm tumor size (P = 0.028), BCLC stage (P = 0.002) and abnormal AFP (P = 0.021). Besides, CCT6A mRNA expression was associated with multifocal tumor nodule (P = 0.025), ≥ 5.0 cm tumor size (P = 0.018), higher BCLC stage (P = 0.036), abnormal CA199 (P = 0.027) and abnormal AFP (P = 0.008). However, no correlation was found in CCT6A with liver function indexes (all P ≥ 0.05). Moreover, CCT6A protein and mRNA high expressions were both correlated with poor accumulating overall survival (OS) (P = 0.004, P = 0.002, respectively). Furthermore, CCT6A protein high expression (vs. low) independently predicted shorter OS (P = 0.027). ConclusionsCCT6A serves as a possible biomarker reflecting tumor features and prognostication in HCC patients.