Receptors In Hepatocellular Carcinoma Research Articles

Mechanisms and therapeutic targets of ErbB family receptors in hepatocellular carcinoma: a narrative review.

Hepatocellular carcinoma (HCC) is a highly heterogeneous and aggressive tumor. In recent years, the incidence of HCC has been increasing worldwide. Despite notable advancements in treatment methodologies, the prognosis of HCC patients remains unsatisfactory. ErbB family proteins play important roles in the occurrence, progression, and metastasis of HCC, and their abnormal expression is often closely associated with poor patient prognosis. This article sought to investigate the current status and research progress of ErbB family protein targeted therapy in HCC in recent years to provide a reference for basic research and clinical treatment. We performed a comprehensive, narrative review of the latest literature to define the current progress of ErbB family receptors in HCC in both the pre-clinical and clinical arenas. The ErbB family belongs to the tyrosine kinase (TK) receptor family that comprises four members. These members are closely associated with proliferation, cell cycle regulation, and migration during HCC development through multiple signaling pathways. ErbB-targeted therapy has shown tremendous potential and prospects in the treatment of HCC. Through in-depth research and the application of ErbB-targeted therapy, broader avenues will be opened for the treatment of HCC and other tumors, leading to more personalized and precise treatment approaches.

Identification of therapeutic targets and prognostic biomarkers among CXC chemokines in hepatocellular carcinoma microenvironment.

Hepatocellular carcinoma (HCC) is characterized by occult onset, rapid progression and poor prognosis. CXC chemokines play an important role in tumor microenvironment and development. The potential mechanistic values of CXC chemokines as clinical biomarkers and therapeutic targets in HCC have not been fully clarified. ONCOMINE, UALCAN, GEPIA, cBioPortal, SurvExpress, MethSurv, SurvivalMeth, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this study. The transcriptional levels of CXCL9/16/17 in HCC tissues were significantly elevated while CXCL1/2/5/6/7/12/14 were significantly reduced. significant correlation was found between the expression of CXC3/5 and the pathological stage of HCC patients. High level of CXCL4 was associated with a longer disease-free survival. For overall survival, lower expressions of CXCL1/3/5/8 and higher expressions of CXCL2 were associated with a better outcome. In addition, the prognostic values of CXC chemokines signature in HCC were explored in four independent cohorts, the high-risk group displayed unfavorable survival outcome compared with the low-risk group. And for the prognostic value of the DNA methylation of CXC chemokines, we identified the CpGs which were significantly associated with prognosis in HCC patients. DNA methylation signature analysis also showed a statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in HCC were performed, the transcription factor targets, kinase targets, and miRNA targets of CXC chemokines were also identified in HCC. We also found significant correlations among CXC chemokines expression and the infiltration of immune cells, the tumor infiltration levels among HCC with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR2/6/8/12, B_cell, macrophage and dendritic _cell were significantly related to the clinical outcome of HCC patients. CXC chemokines might serve as therapeutic targets and prognostic biomarkers in HCC.

Upregulated UBE4B expression correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major human health concern. Increasing evidence has demonstrated that ubiquitin ligase E4B (UBE4B) may be involved in the occurrence and development of various human cancers and may affect prognosis. However, the specific role and mechanism of UBE4B in HCC is unclear. A pan-cancer analysis of UBE4B expression, clinicopathological features, and prognosis was performed using bioinformatics techniques. Subsequently, the expression, prognosis, and correlation of UBE4B and its upstream miRNAs and lncRNAs were analyzed. We investigated the relationship between UBE4B expression and immune cell infiltration, immunomodulatory factors, and chemokines in HCC. The expression levels of UBE4B and its upstream lncRNAs (FGD5-AS1, LINC00858, and SNHG16) and miRNAs (hsa-miR-22-3p) were evaluated in HCC cell lines using qRT-PCR. UBE4B expression increased in HCC and was correlated with a poor survival rate in patients with HCC. A ceRNA network was established to identify the UBE4B-hsa-miR-22-3p-FGD5-AS1/LINC00858/SNHG16 regulatory axis in HCC. UBE4B expression was significantly associated with immune cell infiltration, immunomodulators, chemokines, and their receptors in HCC. The mRNA expression of FGD5-AS1, LINC00858, SNHG16, and UBE4B was higher in the HCC cell lines (7721 and HepG2) than in the normal hepatocyte line (LO2), and the expression of hsa-miR-22-3p mRNA showed a decreasing trend. Our findings showed that upregulation of UBE4B was associated with poor prognosis and tumor immune infiltration in HCC. These findings will aid in understanding the relevant functions of UBE4B and provide new strategies for drug development and exploration of prognosis-related biomarkers.

Immunohistochemical expression of CB1 receptors in the liver of patients with HBV related-HCC

Background and aimsThe most common cause of hepatocellular carcinoma (HCC), which has a high death rate, is hepatitis B virus (HBV) infection. This study aimed to examine immunoexpression of CB1 receptors in the livers of patients with HBV-related HCC in comparison with HCC and chronic HBV as well as healthy people.Patients and methodsParticipants in this case-controlled study were patients with only HBV (HBV; 40), only HCC (HCC; 41), and HBV-related HCC (HBV + HCC; 40) and a healthy control group (C; 30). Tissue expression of CB1 at the protein level was studied using immunohistochemical methods. ResultsAll groups were significantly different in terms of expression of CB1 protein (P < 0.001). The expression levels of CB1 in the liver tissue of the HBV and C groups were not significantly different (P = 0.072). The expression levels of CB1 in the liver tissue of the HBV-related HCC and HCC groups had a statistically significant increase compared to the C and HBV groups (P < 0.001). Also, the CB1 expression levels in the liver tissues of HBV-related HCC and HCC groups were significantly different (P = 0.008). The sensitivity and specificity of immunohistochemistry tests in the diagnosis of HCC using CB1 were 63.4 and 91.2, respectively. Positive and negative predictive values were 90.0 % and 65.1 %, respectively. There was no relationship between the expression of CB1and other clinicopathological variables (P < 0.05). ConclusionThe present findings revealed a tumor promoting function of the CB1 receptor in HCC. CB1 is also a pathological valuable factor for identifying the pathway of inflammation during infection.

Genomic Relevance of FGFR2 on the Prognosis of HCV-Induced Hepatocellular Carcinoma Patients.

The Fibroblast Growth Factor Receptors (FGFRs) are known to regulate cancer metabolism in different tumor types, including hepatocellular carcinoma (HCC). Several risk factors are associated with HCC, of which viral infections (Hepatitis B and C) and cirrhosis are prominent. In Pakistan as well as in highly developed countries like the United States, hepatitis C virus HCV infections are most commonly reported in HCC. Here, we aimed to investigate the clinical relevance of FGFR receptors in HCC and their role in HCV-positive HCC cases. 264 HCC samples along with their clinical information and 96 normal liver samples were collected. qPCR was done to estimate the expression of FGFR1, FGFR2, FGFR3 and FGFR4. Three independent HCV-induced HCC cohorts (containing 293 HCC samples) were used for validation. According to in vitro results, FGFR1 was upregulated in HCV+ HCC patients. However, in all three independent cohorts of HCC, significant a down-regulation of FGFR1 was observed. FGFR2 overexpression was observed in the in vitro cohort as well as in three independent HCC cohorts. Interestingly, a strong correlation of FGFR2 expression was observed between cirrhosis and HCV in all four HCC cohorts. Our study suggested that FGFR2 expression can be used to classify HCC patients based on HCV infection. This FGFR2-based classification may lead to new therapeutic strategies against HCV-positive HCC subtypes.

Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition.

Simple SummarySorafenib is a treatment for advanced HCC which demonstrated a poor objective response rate due to important induction of resistance. We demonstrated that induction of acquired-resistance to sorafenib in Huh-7 cell line leads to the loss of SLAMF3 expression, a tumor suppressor receptor in HCC. In these cells, the sorafenib-resistant phenotype is characterized by the increase of aggressiveness and induction of the epithelial-to-mesenchymal transition. Acquired-resistance to sorafenib induce a multipotent mesenchymal stem cells characteristic. Interestingly, SLAMF3 overexpression reversed the epithelial-to-mesenchymal transition and decreased metastatic potential in sorafenib-resistant cells through the control of ERK1/2 and mTOR signaling pathways. SLAMF3 seems to be a theranostics tools to the management of sorafenib treatment.Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.

Research progress of chemokines and their receptors in hepatocellular carcinoma

Chemokines and their receptors play an important role in the occurance and development of hepatocellular carcinoma(HCC). The effects of chemokines and their receptors in HCC are different, chemokines and their receptors associated with HCC are mostly expressed in promoting tumor cell proliferation, angiogenesis and invasion, but some chemokines and their receptors play an anti-tumor role. This reviews focus on the role of chemokines and their receptors in HCC. Key words: Chemotactic factors; Carcinoma, hepatocellular; Chemokine receptor; Chemokine CXCL12

Deregulation of Frizzled Receptors in Hepatocellular Carcinoma.

G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a “cancer driver”. Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway is frequently activated and it is associated with an aggressive HCC phenotype. Frizzled (FZD) receptors, a family member of GPCRs, are known to mediate Wnt signaling. Accumulating findings have revealed the deregulation of FZD receptors in HCC and their functional roles have been implicated in HCC progression. Given the important role of FZD receptors in HCC, we summarize here the expression pattern of FZD receptors in HCC and their corresponding functional roles during HCC progression. We also further review and highlight the potential targeting of FZD receptors as an alternative therapeutic strategy in HCC.

In vitro, In silico and In vivo Antitumor Activity of Crude Methanolic Extract of Tetilla dactyloidea (Carter, 1869) on DEN Induced HCC in a Rat Model

Tetilla dactyloidea (Carter, 1869) is a marine sponge classified under Demospongia and recent studies have demonstrated that active constituents of Demospongia class have exhibited several potential medical applications. However, no preliminary pharmacological studies have been reported so far. The present investigation was carried out to evaluate the zoo-chemical status, antioxidant potential and anticancer activity of Crude Methanolic Extract of Tetilla dactyloidea (CMETD). Hepatocellular Carcinoma (HCC) was induced in the liver of male Sprague Dawley (SD) rats by treating with diethylnitrosamine (DEN). Nodule incidence, body weight, liver marker enzymes, enzymatic and non-enzymatic antioxidant, phase I metabolizing and liver macromolecular damaging enzymes and immuno-histopathological changes were assessed in DEN and DEN+CMETD treated rats. Oral administration of CMETD at a dose of 400mg/kg body weight to DEN treated rats restored the above parameters to near normal levels compared to control. The biochemical results were consistent with histopathological observations suggesting marked hepatoprotective effect of CMETD in a dose dependent manner. The GCMS of CMETD analysis showed the presence of six compounds. In in silico analysis 9-Octadecenoic acid (Z)-, 2-hydroxy-1-(hydroxymethyl) ethyl ester ligand showed an effective binding energy of −7.1kcal/mol against Cox-2 receptor. The compounds showed desirable pharmacokinetic properties and significant molecular interactions with the HCC receptors. To conclude, our results clearly suggested that CMETD treatment prevented liver damage, protected the antioxidant defense system and possessed anti-carcinogenic potential in DEN induced hepatic carcinoma.

Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels.

Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression. In patients with primary HCC, neither LPA2 nor LPA6 mRNA levels were associated with recurrence. However, when serum ATX levels were combined for analysis as a surrogate for plasma LPA levels, the cumulative intra-hepatic recurrence rate was higher in patients in whom both serum ATX levels and LPA2 or LPA6 mRNA levels were higher than the median. However, the mRNA level of phosphatidic acid-selective phospholipase A1ɑ, another LPA-generating enzyme, in HCC patients was not associated with pathological findings or recurrence, even in combination with the expression of LPA receptors. Higher LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels. ATX and LPA receptors merit consideration as therapeutic targets of HCC.

Neuropeptide Y1 receptor inhibits cell growth through inactivating mitogen-activated protein kinase signal pathway in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers, and its incidence is increasing worldwide. Neuropeptide Y (NPY) broadly expressed in the central and peripheral nervous system. It participates in multiple physiological and pathological processes through specific receptors. Evidences are accumulating that NPY is involved in development and progression in neuro- or endocrine-related cancers. However, little is known about the potential roles and underlying mechanisms of NPY receptors in HCC. In this study, we analyzed the expression of NPY receptors by real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Correlation between NPY1R levels and clinicopathological characteristics, and survival of HCC patients were explored, respectively. Cell proliferation was researched by CCK-8 in vitro, and tumor growth was studied by nude mice xenografts in vivo. We found that mRNA and protein level of NPY receptor Y1 subtype (NPY1R) significantly decreased in HCC tissues. Low expression of NPY1R closely correlated with poor prognosis in HCC patients. Proliferation of HCC cells was significantly inhibited by recombinant NPY protein in vitro. This inhibitory effect could be blocked by selected NPY1R antagonist BIBP3226. Furthermore, overexpression of NPY1R could significantly inhibit HCC cell proliferation. Knockdown of NPY1R promoted cell multiplication in vitro and increased tumorigenicity and tumor growth in vivo. NPY1R was found to participate in the inhibition of cell proliferation via inactivating mitogen-activated protein kinase signal pathway in HCC cells. Collectively, NPY1R plays an inhibitory role in tumor growth and may be a promising therapeutic target for HCC.

Notchl and Notch4 are markers for poor prognosis of hepatocellular carcinoma

Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC. We investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC. Cytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade III (P=0.038), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-free survival. Cytoplasmic Notch3 expression tended to be an independent predictor of shorter disease-free survival (P=0.055). Notch1 expression (P=0.039), Notch4 overexpression (P=0.012), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-specific survival. On univariate analysis, Notch1 expression tended to show an unfavorable influence on disease-specific survival (P=0.063) and Notch4 overexpression did not show an unfavorable influence on disease-specific survival (P=0.103). Notch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease-specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease-specific survival.

Expression, Cellular Distribution, and Prognostic Relevance of TRAIL Receptors in Hepatocellular Carcinoma

After the advent of targeted therapies for hepatocellular carcinoma (HCC), much work is being done to provide a comprehensive description of the different signaling pathways contributing to cell survival and proliferation in this tumor. Apoptotic signaling mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an important mechanism of tumor surveillance, but its importance in the development of HCC is not known. We thus investigated the cellular distribution and the prognostic importance of TRAIL receptors in HCC. Immunohistochemical staining for TRAIL receptors was evaluated in HCC tissues and in matched surrounding nontumor tissues of 157 HCC patients treated with liver transplantation or partial hepatectomy. Survival was analyzed in 93 patients who underwent partial hepatectomy. The fraction of HCC samples with positive membrane staining for TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) was 1.4- and 2.7-fold lower compared with that of hepatocytes from surrounding tissues (P = 0.01). Loss of either TRAIL-R1 or TRAIL-R2, as confirmed by a multivariate analysis, significantly worsened 5-year survival of HCC patients {survival, 27% versus 52% and 15% versus 43%; hazard ratio (HR), 2.3 [95% confidence interval (CI), 1.1-4.4] and 2.4 (95% CI, 1.1-5.2), respectively}. Loss of both TRAIL receptors further decreased survival of patients [HR, 5.72 (95% CI, 2.1-15.5) versus double-negative staining; P = 0.001], indicating an additive effect on survival of TRAIL-R1 and TRAIL-R2. This pilot study suggests that loss of TRAIL receptors is a frequent feature of HCCs and an independent predictor of survival in patients undergoing partial hepatectomy. Future therapeutic protocols are likely to profit from the characterization of their expression and cellular distribution. Clin Cancer Res; 16(22); 5529-38. ©2010 AACR.

Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

BackgroundNumerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT), a known mediator of cellular immortalization.MethodsWe investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3) and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes.ResultsWe showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs) in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC.ConclusionsWe propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

Biological activity of bevacizumab and erlotinib in patients with advanced hepatocellular carcinoma (HCC)

4522 Purpose: HCC is the fifth most common solid tumor worldwide and the incidence is rising in western countries. Current standard of care for advanced HCC is sorafenib based on median survival (MS) of 10.7 months (mos), median time to progression 5.5 mos. HCC are highly vascular tumors, and due to the prevalence of vascular endothelial growth factor and epidermal growth factor receptors in HCC, a phase II single-arm open-label trial of B and E in patients (pts) with HCC has been completed. Patients and Methods: Eligibility criteria include biopsy-proven unresectable HCC, Child-Pugh class A or B cirrhosis, bilirubin ≤2.0 mg/dL, transaminase (TA) levels ≤5 times the upper limit of normal, platelets ≥50,000/μL and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. Prior allowed therapies are surgery, external radiotherapy, ablation, transarterial chemoembolization (TACE) and 1 systemic therapy. Pts received B 10 mg/kg every 14 days plus E 150 mg orally daily. Results: The primary endpoint was the percent of pts alive and progression-free after 16 weeks of therapy (PFS16) based on historic median PFS of 3 to 5 mos. Response was evaluated by RECIST. 57 pts have been enrolled and were evaluable for analysis on an intent to treat basis. For all pts, the median age was 62.8 years (range 29–82), 44 (77%) male, 25 (43.9%) Caucasian; 25 (43.9%); ECOG PS of 0, 31 (54.4%) pts PS of 1. 14 pts (24.6%) had prior therapy (6 sorafenib). Of the 57 pts enrolled, 14 (28%) had confirmed partial responses, 31 (62%) had stable disease and 5 (10%) had progressive disease. PFS16, was 73% (95% CI 60%, 84%). The median PFS is 7.9 mos (95% CI 5.7, 9.5) and the OS is 12.8 mos, 95% CI (9.5, 17.9). 6 pts were removed for toxicity; there was one on-study death. The most common grade 1 or 2 toxicities are folliculitis, anorexia, diarrhea, dry skin, and epistaxis. Grade 3 or 4 toxicities were transaminase elevation, diarrhea, fatigue, hyperkalemia, hypertension, proteinuria, pulmonary embolus, leukoencephalopathy and gastrointestinal bleed. Conclusions: The combination of B and E appears to have significant clinically meaningful activity in HCC. A multi-institution randomized phase II trial is planned. [Table: see text]

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERalpha alone until 1996 when ERbeta isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.

Hormonal Treatment of Human Hepatocellular Carcinoma

Animal models of experimental liver carcinogenesis and epidemiological studies in humans suggest a relationship between sex hormones and hepatocellular carcinoma (HCC). In 1997, a systematic review of the existing, small randomized trials evaluating the antiestrogen tamoxifen yielded a positive result, but the large randomized CLIP-1 trial showed no survival advantage from the addition of tamoxifen to best supportive care. A possible explanation for the negative results is the lack of patient selection, but the expression of estrogen (ER) and progesterone (PgR) receptors in HCC does not clearly affect the survival outcome of the patients treated with tamoxifen. In the last years, it has been proposed that negative results might be due to the fact that tamoxifen in HCC could act via an ER-independent pathway, which requires much higher doses than those usually administered, but a double-blind Asian randomized trial conducted to assess possible dose-response effect showed no efficacy for tamoxifen, with an inversely negative impact with increasing dose. According to the results of large trials and of the Cochrane systematic review, neither further trials are warranted with tamoxifen in HCC, nor should any use in clinical practice be considered. Interesting results have been obtained when the type of hormonal treatment (tamoxifen or megestrol) has been chosen according to the presence of wild-type or variant ER, but these results should be confirmed in large randomized trials. Negative results have been obtained with antiandrogen therapy. In conclusion, hormonal treatment should not be a part of the current management of HCC patients.

Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: impact on intrahepatic recurrence after hepatic resection.

Seventy-eight patients in whom androgen or oestrogen receptors, or both, were assayed in hepatocellular carcinoma (HCC) and the surrounding liver were discharged from hospital after curative resection of the tumour. Intrahepatic recurrence was evaluated retrospectively after 28-128 months follow-up to determine the association with receptor status. Androgen and oestrogen receptors in HCC significantly influenced the intrahepatic recurrence rate. The recurrence-free 5-year survival rate was 55 per cent for patients who had androgen receptor-negative tumours, 24 per cent for oestrogen receptor-negative, 10 per cent for oestrogen receptor-positive and 0 for androgen receptor-positive (P = 0.0322). Recurrence-free 5-year survival in 57 patients who had both receptor assays was 75 per cent for patients who had androgen receptor-negative, oestrogen receptor-negative tumours, 50 per cent for androgen receptor-negative, oestrogen receptor-positive, but 0 for androgen receptor-positive, oestrogen receptor-positive and androgen receptor-positive, oestrogen receptor-negative (P = 0.0104). The presence or absence of androgen or oestrogen receptor in the liver, however, was not associated with intrahepatic recurrence (P = 0.7534). Thus, androgen receptors are strongly associated with intrahepatic recurrence of HCC, while oestrogen receptors are weakly associated. Receptor status in the normal liver was not related to intrahepatic recurrence.

Regulatory peptide receptors in human hepatocellular carcinomas

BACKGROUNDOverexpression of regulatory peptide receptors in selected human tumours is of diagnostic and therapeutic relevance.AIMSTo evaluate the expression of somatostatin, vasoactive intestinal peptide (VIP), substance P, cholecystokinin (CCK) A and...

Gene expression of hepatocyte growth factor and its receptor in HCC and nontumorous liver tissues.

AIM:To study the changes of gene expression of hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (HGFr) in hepatocellular carcinoma (HCC) tissue and nontumorous liver tissue and the relationship between these changes and the biological behavior of the tumor.METHODS:Gene expression of HGF and HGFr in 26 cases of HCC tissue and their adjacent nontumorous liver tissues was determined with digoxigenin labeled DNA probes.RESULTS:Positive expression of HGF in HCC tissue was similar to that in the adjacent nontumorous liver tissue, but positive rate of HGF expression was lower than HGFr gene expression. However, HGFr expression was higher in the metastatic cases than in those without metastasis. It was found that HGFr was overexpressed in HCC tissue as well as in the adjacent nontumorous liver tissue.CONCLUSION:There seems to be a close relationship between overexpression of HGFr gene and tumor metastasis, and the HGF and HGFr system plays an important role in regulating tumor growth and metastasis.