Poor Prognostic Factor For Hepatocellular Carcinoma Research Articles

The impact of liver fibrosis on the progression of hepatocellular carcinoma via a hypoxia-immune-integrated prognostic model

The impact of liver fibrosis on the deterioration of hepatocellular carcinoma (HCC) remains controversial. We hope to explore this issue through establishing a fibrosis-hypoxia-glycolysis-immune related prognostic model. Liver fibrosis-related genes from Molecular Signatures Database were used to evaluate the degree of fibrosis in HCC patients from the TCGA database. The patients were divided into two groups using the fibrosis-related expression matrix based on the algorithm uniform manifold approximation and projection (UMAP) and evaluated for fibrosis by UMAP cluster and gene enrichment analysis. Prognostic model was constructed by differential analysis, LASSO, and multivariate regression analysis. Immune-infiltration analysis was performed by CIBERSORT. Quantitative PCR and immunohistochemistry were performed to measure the gene expression levels in HCC patients from our hospital. In 365 HCC patients from the TCGA database, 111 HCC patients with high fibrosis score have a worse prognosis than those with low fibrosis based on 129 genes related to liver fibrosis, which may be caused by the interaction between fibrosis, angiogenesis, hypoxia, glycolysis, inflammatory response, and high immune infiltration. We constructed a Fibrosis-Hypoxia-Glycolysis-Immune Prognostic Model (FHGISig), which could significantly predict disease progression in HCC patients. Furthermore, we revealed a close correlation between FHGISig and immune cell infiltration level as well as immune checkpoints. Finally, PCR results found TFF3 mRNA was significantly lower in cirrhotic HCC patients compared with non-cirrhotic ones. Liver fibrosis is a poor-prognostic factor for HCC, and our FHGISig could significantly predict disease progression, which could also be a potential predictive marker for immunotherapy in HCC patients.

Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma.

Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

Progress on the molecular mechanism of portal vein tumor thrombosis formation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with poor prognosis and high mortality. Early-stage HCC has no obvious clinical symptoms, and most patients are already at an advanced stage when they are diagnosed. Portal vein tumor thrombus (PVTT) is the most common complication and a poor prognostic factor for HCC, which frequently leads to portal vein hypertension, ascites, gastrointestinal bleeding, and tumor metastasis. The formation of PVTT is related to the complex structure and hemodynamic changes of the portal vein and is closely related to changes at the cellular and molecular levels. The differentially-expressed genes (DEGs) between PVTT and primary tumor (PT) suggest that the two tissues may have different clonal origins. Epigenetic and proteomic analyses also suggest complex and diverse mechanisms for the formation of PVTT. In addition, the tumor microenvironment and energy metabolism pathways are interrelated in regulating the invasion and progression of PVTT. Aerobic glycolysis and the tumor immune microenvironment have been the focus of recent studies on PVTT. In this review, we summarize the mechanism of PVTT formation at the cellular and molecular levels to provide information to guide better prevention and treatment of PVTT in the clinic.

Prognostic value and morphological findings of overexpression of glypican-3 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the seventh most common cancer all worldwide and is second in cancer-related deaths. In HCC, whose prognosis is still not good despite current treatments, there is a need for prognostic markers as well as early diagnosis. Glypican (GPC)-3 has been proposed as a potential serologic and histochemical marker specific to HCC. This study aimed to determine the relationship between GPC3 overexpression and HCC prognosis and clinicomorphologic features. In total 152 patients who were diagnosed as a result of hepatectomy, lobectomy or liver transplantation were enrolled. The patients were divided into two groups, GPC3-positive (overexpression) (>10%) and GPC3-negative (<10%). The demographic data of the patients, tumor characteristics and survival times were recorded. Survival was significantly lower in the GPC3+ group. In the multivariate analysis, hepatitis C, AFP, tumor number, tumor focality, portal vein tumor thrombosis and GLP3 positivity were found to be independent risk factors for survival. Our study shows that GPC3 overexpression is a poor prognostic factor in HCC. GPC3 positivity were found to be an independent risk factor for survival.

Decaprenyl Diphosphate Synthase Subunit 1 (PDSS1): A Potential Prognostic Biomarker and Immunotherapy-Target for Hepatocellular Carcinoma.

PurposePDSS1 (decaprenyl diphosphate synthase subunit 1) plays an important role in the progression of several types of tumor. However, the biological functions of PDSS1 remain unclear in patients with hepatocellular carcinoma (HCC). In this study, We attempted to determine the role of PDSS1 in predicting the survival and efficacy of immunotherapy for HCC patients.MethodsWe analyzed the expression of PDSS1 in pan-cancer by Tumor Immune Estimation Resource (TIMER) and UALCAN database. Next, we investigated the correlations between the expression and potential prognostic value of PDSS1 in pan-cancer by Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter and further confirmed our finding in our study of 139 patients with HCC. Furthermore, we correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules in HCC tissue by TIMER. Finally, its potential immune-related mechanism was explored by Gene Set Enrichment Analysis (GSEA).ResultsMultiple datasets demonstrate that PDSS1 is up-regulated in HCC tissues compared with adjacent tissues, which was validated at mRNA (databases) and protein levels (our cohort). Patients with higher PDSS1 expression had shorter overall survival and relapse-free survival. In addition, PDSS1 expression was positively related to early recurrence and served as an independent poor prognostic factor for HCC. Patients with higher PDSS1 expression had lower CD8+ T cells in HCC tissue, and PDSS1 deteriorates T cell exhaustion by promoting T cell surface inhibitory receptors’ secretion and immunosuppressive cell proliferation. Furthermore, PDSS1 was positively correlated with the WNT, TGFβ, VEGF, and other signaling pathways in HCC.ConclusionPDSS1 is a potential prognostic biomarker and immunotherapy target for hepatocellular carcinoma.

Integrative Analysis of HMMR as a Potential Target of Prognosis and Therapy in Hepatocellular Carcinoma

Background: Previous work has indicated Hyaluronic acid-mediated motor receptor (HMMR) plays an important role in regulating tumor metastasis. However, few researchers address the clinical significance of HMMR and its underlying mechanisms for regulating hepatocellular carcinoma (HCC). This study focuses on the underlying effect of HMMR in the development and prognosis of HCC. Materials and Methods: In the present study, data of RNA and miRNA sequencing array were obtained from Oncomine dataset or The Cancer Genome Atlas (TCGA) dataset, the distinctive genomic patterns associated with HMMR expression and its correlation with prognosis were analysed by using R package. Gene set enrichment analysis (GSEA) were performed on genes expressed aberrantly. We also performed Reverse Transcription-polymerase Chain Reaction (RT-PCR), Immunohistochemical (IHC) staining and Western blotting analysis to evaluate the expression of HMMR in liver cancer cell lines or 12 HCC samples from The Affiliated Hospital of Southwest Medical University. Results: A total of 407 tumor tissue samples in TCGA dataset were evaluated, combined with analysis in Oncomine dataset, we found HMMR expression was increased in HCC compared to normal tissues. Higher expression of HMMR was correlated with poorer overall survival and disease-free survival outcomes. Moreover, multivariate Cox regression analysis revealed that HMMR expression was an independent risk factor for overall survival (HMMR: hazard ratio [HR] = 1.154, 95% confidence interval [CI] = 1.080-1.233, p&lt;0.001). Consistently, RT-PCR, IHC staining and Western blotting analysis further confirmed that HMMR expression was increased in HCC compared with patient-matched adjacent normal liver tissues. Notably, GSEA analysis revealed that differential gene expression in HMMR-high patients (compared with HMMRlow patients) were enriched in cell proliferation and p53 signaling pathway. Moreover, comprehensive analysis showed a strong correlation between HMMR upregulation and miRNA changes. Conclusion: The high expression of HMMR is a poor prognostic factor in HCC and might serve as a potential target of therapy in patients with HCC.

LRP1B or TP53 mutations are associated with higher tumor mutational burden and worse survival in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have been proved to be beneficial for advanced HCC. Tumor mutational burden (TMB) is an important predictor for efficacy of ICIs. However, the genetic landscape of Chinese HCC patients and the association between TMB and frequently mutated genes of HCC remain unclear.Methods: Whole-exome sequencing data of 369 liver tumors from the Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 657 liver tumors from Chinese clinical dataset were included.Results: TP53 (61.8%) was the most frequently mutated gene in the Chinese cohort, followed by CTNNB1 (17.2%), RB1 (13.7%), and LRP1B (12.3%). The PI3K-Akt signaling (11.2%), the Rap1 signaling (8.1%), and Ras signaling (7.7%), were significantly mapped. LRP1B mutations were significantly associated with higher TMB in both TCGA cohort (P = 0.0003) and Chinese cohort (P = 0.0005). And TP53 mutations were also associated with higher TMB in the TCGA and Chinese cohort (P = 0.0005 and 0.0010, respectively). Prognosis analysis performed in TCGA cohort revealed LRP1B mutations were significantly associated with shorter overall survival (OS, median, 20.9 vs 61.7 months; HR, 2.22; P = 0.0012). TP53 mutation was an independent risk factor affecting both OS (HR 1.58, P = 0.0109) and PFS (HR 1.59, P = 0.0027).Conclusions: The results suggest that LRP1B or TP53 mutations are associated with higher TMB and a poor prognostic factor in HCC.

Myopenia as a significant prognostic factor in BCLC-B intermediate-stage hepatocellular carcinoma treated with sorafenib.

e15639 Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.

Expression of lncRNA TCONS_00027978 in hepatocellular carcinoma and its influence on prognosis and survival.

Long noncoding RNAs (lncRNAs) have been reported to have crucial roles in the regulation of various tumors. Recently, lncRNA TCONS_00027978 (TCONS_00027978) was found to be downregulated in hepatocellular carcinoma (HCC). This study aims at analyzing the value of TCONS_00027978 in valuing the prognosis of HCC patients. The expression of TCONS_00027978 was detected using qRT-PCR in 241 hepatocellular specimens and matched adjacent normal tissues. The association between TCONS_00027978 expression levels and clinicopathological factors was examined. Survival and Cox proportional-hazards regression analyses were performed to explore the association between TCONS_00027978 expression levels and prognosis in HCC patients. We found that the TCONS_00027978 expression level was significantly decreased in HCC tissues compared with matched normal tissues (p < 0.01). TCONS_00027978 was positively associated with TNM stage (p = 0.002), lymph node metastasis (p = 0.001) and histologic grade (p = 0.002) in HCC patients. In addition, Kaplan-Meier analysis indicated that low levels of TCONS_00027978 expression were associated with poorer overall survival (p = 0.002) and disease-free survival (p =0.001). Subsequently, multivariate analyses indicated that low TCONS_00027978 expression was an independent poor prognostic factor for HCC patients. Our study is the first to demonstrate the TCONS_00027978 expression as an independent prognostic factor in HCC.

Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma

BackgroundThe role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated.MethodsIn this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated.ResultsPeritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis.ConclusionsThese results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.

Expression and prognostic significance of p21-activated kinase 6 in hepatocellular carcinoma

Backgroundp21-activated protein kinase (PAK) 6 is a serine-threonine kinase belonging to the PAK family. Previous studies have indicated that abnormal expressions of PAK1, PAK2, and PAK5 played critical roles in hepatocellular carcinoma (HCC). Recent studies suggested that deregulation of PAK6 expression played an important role in oncogenesis. To explore the potential roles of PAK6 in HCC, expression of PAK6 was detected in human HCC specimens. MethodsImmunohistochemistry and Western blot analysis were performed for PAK6 in 121 HCC samples. The data were correlated with clinicopathologic features. The univariate and multivariate survival analyses were also performed to determine their clinical prognostic significance. ResultsPAK6 was overexpressed in HCC as compared with the adjacent noncancerous liver tissues. High expression of PAK6 was associated with Edmondson–Steiner grade (P = 0.006) and number of tumor nodules (P < 0.001), and PAK6 was positively correlated with proliferation marker Ki-67 (P < 0.01). Univariate analysis suggested that PAK6 expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that PAK6 and Ki-67 protein expressions were independent prognostic markers for HCC (P = 0.0245 and 0.0331, respectively). ConclusionsOur results suggest that PAK6 overexpression is involved in the pathogenesis of HCC; it may be an independent poor prognostic factor for HCC.

A comment on ‘A morpho-molecular prognostic model for hepatocellular carcinoma’

Sir, We read with great interest the recent study by Srivastava et al (2012) regarding a new staging model for hepatocellular carcinoma (HCC). In this study, the authors constructed a new risk model for the prognostic evaluation of HCC. In the final system, CD31, p53, AFP, CD44, tumour size and vascular invasion were included for risk score calculation. Patients were dichotomised into high- and low-score groups using the cut-off point, 3.240, which was found to be the median final score in the study population. Srivastava et al (2012) demonstrated significantly decreased overall survival in the high-score group and validated these results in another cohort. We would like to discuss a couple of points about the patient characteristics and risk factors included in the study. First, we feel that there is not enough description of the study population regarding the status of the underlying liver disease, which is also an independent predictor of survival in patients with HCC. The authors did not specify pertinent parameters to assess liver disease, such as the Child–Pugh score, or the incidence of cirrhosis, on the basis of imaging or pathological criteria. Second, although CD44 overexpression is a cancer stem cell marker (Zhu et al, 2010) and was found to be a poor prognostic factor in HCC, it was not found to be significantly overexpressed in tumour tissue compared with in adjacent non-tumour hepatic tissue in this study. Increased expression of CD44, which was considered in this study to be a cancer stem cell marker, was also observed in inflammation and mediates tumorigenesis (Heldin et al, 2008). In animal models, CD44 knockdown was shown to decrease inflammation in the liver (Kimura et al, 2008). Therefore, CD44 expression in non-tumour hepatic may indicate an underlying ongoing inflammation in liver. Thus, in this study, the poor prognostic value of overexpressed CD44 may partially reflect the severity of the underlying liver disease rather than being a marker of tumour cell stemness. In conclusion, although this morpho-molecular prognostic model for HCC promisingly identified HCC patients with different risk factors, the absence of parameters pertinent to the underlying liver function will make it challenging to interpret the study results. Moreover, the role of CD44 in this staging model should be also clarified.

Thrombin is a therapeutic target for metastatic osteopontin-positive hepatocellular carcinoma

We previously identified osteopontin (OPN) as a promoter and thus a potential therapeutic target for hepatocellular carcinoma (HCC) metastasis. The serine protease thrombin interacts with OPN and can modify its biological activity. To explore the role of thrombin alone or in conjunction with OPN in HCC, we studied the correlation of thrombin levels to HCC prognosis in patients with various OPN levels, and evaluated the effects of OPN fragments generated by thrombin cleavage on proliferation and adhesion of HCC cells. We found that the thrombin level was strongly associated with the metastatic potential of HCC cell lines, and that thrombin was remarkably overexpressed in HCC tissue compared with adjacent nontumor tissue. In addition, HCC tissue from patients with recurrent disease displayed much higher thrombin levels, particularly in those with elevated OPN levels. Only HCCs with elevated OPN levels had a significant correlation between high thrombin levels and overall survival (OS; P < 0.01), or time to recurrence (TTR; P < 0.0001) of HCC. Multivariate analysis revealed that thrombin was an independent prognostic indicator. In vitro assays demonstrated that thrombin promotes the proliferation and adhesion of OPN+ HCC cells. Furthermore, thrombin activated the focal adhesion kinase (FAK) pathway of OPN+ HCC cells, which was blocked by the inhibition of integrin β1. Thrombin plays an important role in OPN-mediated aggressive phenotype of HCC through activation of integrin β1-FAK signaling, and is an independent poor prognostic factor for HCC. Thus, thrombin may be a potential therapeutic target to inhibit HCC metastasis in OPN+ patients.

Intratumoral neutrophils: A poor prognostic factor for hepatocellular carcinoma following resection

Neutrophil infiltration has been linked to clinical outcome of various cancer types. However, its role in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated prognostic values for intratumoral and peritumoral neutrophils in HCC patients undergoing curative resection. The expression of CD66b, CD8, TGF-beta, and CD34 was assessed by immunohistochemistry in tissue microarrays containing paired intratumoral and peritumoral tissues from 197 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated. Intratumoral CD66b(+) neutrophils significantly correlated with CD8(+) T cells (r=0.240, p=0.004), TGF-beta expression (p=0.012), BCLC stage (p=0.016), and early recurrence (p=0.041). Increased intratumoral neutrophils were significantly associated with decreased RFS/OS (p=0.001 and p<0.001, respectively) in univariate analysis and were identified as an independent prognostic factor (HR=1.845, 95% CI=1.169-2.911, p=0.008 for RFS; HR=2.578, 95% CI=1.618-4.106, p<0.001 for OS) in multivariate analysis. Intratumoral neutrophil-to-CD8(+) T cell ratio (iNTR) better predicted the outcome in terms of minimum p values. Intratumoral neutrophils were also demonstrated to be statistically predictive for RFS/OS in the normal AFP subgroup, small HCC subgroup, and validation cohort. However, peritumoral neutrophils were not associated with the outcome of HCC. The presence of intratumoral neutrophils was a poor prognostic factor for HCC after resection. Intratumoral neutrophil-to-CD8(+) T cell ratio was a better predictor of outcome.