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Simple Summary: Hepatocellular carcinoma has a clear male predominance, but gender-specific differences remain incompletely understood. Our findings look specifically at the Louisiana population, which has some of the highest rates of hepatitis, alcoholic liver disease, and metabolic syndrome—thus providing important data to better evaluate HCC trends. Our findings help illustrate specific gender differences in this disease, which remains one of the leading causes of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a male-dominated disease. Currently, gender differences remain incompletely defined. Data from the state tumor registry were used to investigate differences in demographics, comorbidities, treatment patterns, and cancer-specific survival (HSS) among HCC patients according to gender. Additional analyses were performed to evaluate racial differences among women with HCC. 2627 patients with HCC were included; 498 (19%) were women. Women were mostly white (58%) or African American (39%)—only 3.8% were of another or unknown race. Women were older (65.1 vs. 61.3 years), more obese (33.7% vs. 24.2%), and diagnosed at an earlier stage (31.7% vs. 28.4%) than men. Women had a lower incidence of liver associated comorbidities (36.1% vs. 43%), and more often underwent liver-directed surgery (LDS; 27.5% vs. 22%). When controlling for LDS, no survival differences were observed between genders. African American women had similar HSS rates compared to white women (HR 1.14 (0.91,1.41), p = 0.239) despite having different residential and treatment geographical distributions. African American race and age >65 were predictive for worse HSS in men, but not in women. Overall, women with HCC undergo more treatment options—likely because of the earlier stage of the cancer and/or less severe underlying liver disease. However, when controlling for similar stages and treatments, HCC treatment outcomes were similar between men and women. African American race did not appear to influence outcomes among women with HCC as it did in men. [ABSTRACT FROM AUTHOR]

Background: CXCL11 has been reported to be up-regulated in hepatocellular carcinoma (HCC) tissues and cancer-associated fibroblasts (CAFs), and CAF-secreted CXCL11 has been found to promote HCC cell proliferation and migration. Knowledge on how CAFs promote HCC progression is imperative for the future design of anti-tumor drugs addressing the high rates of disease recurrence. Herein, we propose a mechanism by which LINC00152 positively regulates CXCL11 expression and, subsequently, HCC cell phenotypes and growth characteristics via miR-205-5p in CAFs. Methods: The expression of LINC00152, miR-205-5p in HCC/non-cancerous tissues, CAFs/NFs and HCC cell lines was determined by RT-qPCR. The CXCL11 expression and secretion were determined by westernblot and ELISA. Different expressions of LINC00152, CXCL11 and miR-205-5p in CAFs were achieved by transfection with corresponding overexpression/knockdown vectors or mimics/inhibitor. The interactions among LINC00152, miR-205-5p and CXCL11 were confirmed by FISH, luciferase, AGO2 and RNA-pulldown assays. Transwell, colony formation and MTT assays were performed to assess the role of CAFs conditioned medium (CM) in HCC cell phenotype. BALB/c nude mice xenografts were used to determine the role of CAFs on HCC growth in vivo. Results: We found that in vitro, CM from CAFs transfected with sh-LINC00152 dramatically suppressed HCC cell viability, colony formation and migration, and that CM from CAFs transfected with miR-205-5p inhibitor (CAF-CM (miR-205-5p inhibitor)) exerted opposite effects on HCC cell phenotypes. Exogenous overexpression of CXCL11 in CAFs or CAF-CM (miR-205-5p inhibitor) could partially attenuate the effects of LINC00152 knockdown. In contrast, CM from CAFs transfected with LINC00152 dramatically increased HCC cell viability, colony formation and migration, and CM from CAFs transfected with miR-205-5p mimics (CAF-CM (miR-205-5p mimics)) exerted opposite effects on HCC cell phenotypes. Knockdown of CXCL11 in CAFs or CAF-CM (miR-205-5p mimics) could partially attenuate the effects of LINC00152 overexpression. In vivo, LINC00152 knockdown in CAFs inhibited tumor growth in a mouse model, which could be reversed by CXCL11 overexpression in CAFs. Mechanistically, we found that LINC00152 could act as a ceRNA to counteract miR-205-5p-mediated suppression on CXCL11 by directly binding to miR-205-5p and the 3'UTR of CXCL11. Conclusion: Our data indicate that a LINC00152/miR-205-5p/CXCL11 axis in HCC CAFs can affect the proliferative and migrative abilities of HCC cells in vitro and HCC tumor growth in vivo. [ABSTRACT FROM AUTHOR]

Background: Preoperative prediction of microvascular invasion (MVI) is critical for treatment strategy making in patients with hepatocellular carcinoma (HCC). We aimed to develop a deep learning (DL) model based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the MVI status and clinical outcomes in patients with HCC. Methods: We retrospectively included a total of 321 HCC patients with pathologically confirmed MVI status. Preoperative DCE-MRI of these patients were collected, annotated, and further analyzed by DL in this study. A predictive model for MVI integrating DL-predicted MVI status (DL-MVI) and clinical parameters was constructed with multivariate logistic regression. Results: Of 321 HCC patients, 136 patients were pathologically MVI absent and 185 patients were MVI present. Recurrence-free survival (RFS) and overall survival (OS) were significantly different between the DL-predicted MVI-absent and MVI-present. Among all clinical variables, only DL-predicted MVI status and a-fetoprotein (AFP) were independently associated with MVI: DL-MVI (odds ratio [OR] = 35.738; 95% confidence interval [CI] 14.027–91.056; p < 0.001), AFP (OR = 4.634, 95% CI 2.576–8.336; p < 0.001). To predict the presence of MVI, DL-MVI combined with AFP achieved an area under the curve (AUC) of 0.824. Conclusions: Our predictive model combining DL-MVI and AFP achieved good performance for predicting MVI and clinical outcomes in patients with HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is a fatal disease characterized by vast molecular heterogeneity. Although major advances in tumour genetics has led to the identification of new biomarkers, the prognosis of patients with HCC remains dismal. Methods: Quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) and western blot (WB) were used to evaluate meiosis‐specific nuclear structural 1 (MNS1) expression in HCC cells. Immunohistochemistry staining was used to evaluate MNS1 expression in HCC tissues. Clinical significance of MNS1 was evaluated by Cox regression analysis. Transwell assays were conducted to assess cells migration ability. Cell counting kit‐8 and colony formation assays were performed to detect cells proliferation ability. NOD/SCID/γc(null) (NOG) mice model was adopted to investigate functions of MNS1 in vivo. Results: The expression of MNS1, which is elevated in most HCC tissues, correlated with poor survival in HCC patients. Functional experiments revealed the oncogenic role of MNS1, which promotes HCC growth and metastasis through AKT‐dependent modulation of β‐catenin. β‐Catenin expression was crucial for MNS1's oncogenic effects. MNS1 indirectly translocated β‐catenin from the cytoplasm to the nucleus via the MNS1‐GSK3β axis. Conclusions: MNS1 promotes HCC growth and metastasis via activating PI3K/AKT signalling and may serve as an important prognostic biomarker as well as potential novel therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

T‐cell exhaustion is one of the hallmarks in cancer, but the mechanisms underlying T‐cell dysregulation remains unclear. Here, we reported that down‐regulation of transcription factor EOMES contributed to increased levels of inhibitory receptors in T cell among the tumour tissues and resulted in the poor prognosis of hepatocellular carcinoma (HCC). By analysing the correlation between EOMES in tumour‐infiltrating T cells and the clinical features, we demonstrated that the EOMES was related to the advanced stage and poor prognosis of HCC. Further mechanistic studies revealed that the EOMES mainly expressed in the CD8+ T cells and were down‐regulated in tumour samples. Moreover, we demonstrated that the EOMES directly bound at the transcriptional regulatory regions of the key inhibitory factors including PD‐1, CTAL‐4 and CD39, and lower levels of EOMES contributed to overexpression of these factors in T cells. Together, our studies provide new insight into the transcriptional deregulation of the inhibitory receptors on T cells during the tumorigenesis. [ABSTRACT FROM AUTHOR]

Purpose: To further clarify the association between abnormal levels of serum lipid components as the main features of dyslipidaemia and hepatocellular carcinoma, which remains unclear. Patients and Methods: We examined the serum level of lipids and apolipoproteins pattern in 471 patients undergoing curative resection for HCC, 193 patients with chronic liver disease, and 104 patients with benign liver diseases. We performed uni- and multivariate analyses to evaluate the predictive roles of lipids and apolipoproteins for recurrence and survival of HCC in a training cohort of 242 patients and then validated in a cohort of 229 patients. Results: The majority circulating lipid and apolipoprotein levels such as ApoA1, HDL, and LDL in chronic liver disease and HCC were slightly significantly decreased as compared to those in benign lesion. But no significant differential expression patterns of lipids and apolipoproteins were observed between chronic liver hepatitis and HCC. Multivariable analysis identified ApoA1 as a key parameter related to recurrence and survival in both training and validation cohorts. Moreover, we further demonstrated that low ApoA1 was an independent prognostic factor of poor early recurrence in two cohorts. Conclusion: Although the alterations of circulating lipids and apolipoproteins were observed in HCC, none of lipids or apolipoproteins could serve as a diagnostic marker. Serum ApoA1 merits consideration as a novel prognostic marker for patients with HCC undergoing surgery since it predicts early recurrence and survival, especially for early stage patients and may improve the prognostic stratification of patients for clinical management and promote HCC clinic outcomes. [ABSTRACT FROM AUTHOR]

Background: Radical resection is the treatment of choice for hepatocellular carcinoma (HCC). However, even with this treatment, HCC prognosis and the efficacy of current predictive models for such patients remain unsatisfactory. Here, we describe an accurate and easy-to-use prognostic index for patients with HCC who have undergone curative resection.Methods: The study population comprised of 1,041 patients with HCC who underwent curative resection at Zhongshan Hospital. This population was reduced to 768 patients who were treated in 2012 analyzed as the training cohort and 273 patients treated in 2007 who were used as a validation cohort.Results: The lactic dehydrogenase to albumin ratio (LAR) was identified as a significant prognostic index for both overall survival and recurrence-free survival in two independent cohorts. The optimal cutoff value for LAR was determined to be 5.5. The C-index of LAR was superior to other inflammatory scores and serum parameters. This biomarker was also shown to be a stable predictive index in the validation cohort. The new nomogram combining LAR with the Barcelona Clinic Liver Cancer staging system had an improved ability to discriminate overall survival and recurrence-free survival. Nomogram predictions were consistent with observations based on calibration and decisive curve analysis in both independent cohorts.Conclusion: LAR is a novel, convenient, reliable, and accurate prognostic predictor in patients with HCC undergoing curative resection. Our results suggest the recommendation of LAR to be used in routine clinical practice. [ABSTRACT FROM AUTHOR]

Background. The prognosis of patients with hepatocellular carcinoma (HCC) without portal vein tumor thrombosis (PVTT) after curative resection is at variance. We identified the risk factors of poor postoperative prognosis and consequently developed prognostic nomograms generating individual risk of death and recurrence for this subgroup of patients with HCC. Methods. The risk factors were identified and nomograms were developed based on a retrospective study of 734 patients in the primary cohort who underwent curative resection for HCC from 2010 to 2012. The predictive accuracy and discriminative ability of the nomograms were determined by concordance index (Cindex) and calibration curve and compared with traditional staging systems of HCC. The results were validated in an independent cohort of 349 patients operated at the same institution in 2007. Results. All of the independent factors for survival in multivariate analysis in the primary cohort were selected into the nomograms. The calibration curve for probability of survival showed good agreement between prediction by nomograms and actual observation. The C-indices of the nomograms for predicting overall survival and recurrence-free survival were 0.755 (95% confidence interval [CI], 0.752-0.758) and 0.665 (95% CI, 0.662-0.668), respectively, which were statistically higher than the C-indices of other HCC prognostic models. The results were further confirmed in the validation cohort. Conclusion. The proposed nomograms resulted in more accurate prognostic prediction for patients with HCC without PVTT after curative resection. [ABSTRACT FROM AUTHOR]

Background and Aim Regulatory T cells ( Treg) play a vital role in immunosuppressive crosstalk; however, Tregs from different locations lead to different clinical outcomes. Our aim was, therefore, to compare the prevalences and suppressive phenotypes of Tregs in the peripheral blood, peritumor, and intratumor of patients with hepatocellular carcinoma ( HCC). Methods The frequencies and phenotypes of CD4+ CD25+ CD127low/− CD49d− Tregs in the periphery, peritumor, and intratumor of 78 HCC patients and 12 healthy controls were evaluated by flow cytometry. Treg-cell suppressive activity was determined using an in vitro CD154 expression assay. Tregs from tumor and paired peritumor were then hybridized using an Agilent whole genome oligo microarray, and selected genes were validated by real-time polymerase chain reaction. Functional analysis of the microarray data was performed using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. Results Intratumoral Tregs exhibited higher frequencies and more suppressive phenotypic functions than those in peritumor and periphery, whereas there was no difference between the latter two. Functional analysis showed that complement cascades, p53, and glycosylphosphatidylinositol-anchor biosynthesis pathways were significantly upregulated in intratumoral Tregs; the salivary secretion pathway was significantly downregulated in intratumoral Tregs, and immune cells and tumor-immuno-related Gene Ontology terms were significantly affected. Conclusions Tregs in different locations exhibited different functional statuses. A higher prevalence and more suppressive phenotype suggested a critical role for intratumoral Tregs in the formation of multicellular immunosuppressive networks. HCC immunotherapy may be improved, therefore, by specific locational Tregs elimination or suppression. [ABSTRACT FROM AUTHOR]

Background & Aims: The immunosuppressive network within the tumor microenvironment is one of the major obstacles to the success of cancer immunotherapy. γδ T cells are attractive effectors for cancer immunotherapy. Nevertheless, the promising anti-tumor effect in vitro is partially if not totally mitigated in vivo. Thus, understanding the immune status of tumor-infiltrating γδ T cells is essential for orchestrating effective immunotherapy strategies. In this study, we have investigated the immunophenotype and function of γδ T cells in hepatocellular carcinoma (HCC) patients. Methods: The phenotype of γδ T cells in peripheral blood, and peritumoral and tumoral tissues of HCC patients (n=61) was characterized by flow cytometry. Functional analysis of the HCC-infiltrating γδ T cells was conducted directly after γδ T cell isolation. Results: The infiltration of γδ T cells in tumoral tissues was significantly reduced compared to paired peritumoral tissues. Impairment in degranulation of the granule pathway and downregulation of IFN-γ secretion were also demonstrated in HCC-infiltrating γδ T cells, which was in agreement with the results of gene microarray analysis, and further strengthened by the compromised specific cytotoxicity and IFN-γ secretion in vitro. Moreover, isolated HCC-infiltrating CD4+CD25+ regulatory T cells (Treg cells) directly suppressed the cytotoxic function and IFN-γ secretion of γδ T cells in a TGFβ- and IL-10-dependent manner. Conclusions: The effector function of γδ T cells was substantially impaired in HCC, which is partially mediated by Treg cells. We propose a new mechanism by which immune privilege develops within the tumor milieu. [Copyright &y& Elsevier]

Background and Aim: The high expression of the galectin-1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. Methods: Galectin-1 and tumor-infiltrating FoxP3+ regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients ( n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. Results: We found that galectin-1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence ( P = 0.025) and overall survival ( P = 0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression was also independently associated with shortened survival ( P < 0.001) and increased tumor recurrence ( P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting the poor prognosis of HCC. The galectin-1 level was positively related to the number of tumor-infiltrating FoxP3+ Tregs ( r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1high and FoxP3high were significantly poorer than the other groups (both P < 0.001). Conclusions: Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target. [ABSTRACT FROM AUTHOR]

Background & aims: Phosphatidylethanolamine-binding protein 1 (PEBP1, also RKIP) plays a pivotal role in cancer by regulating multiple cellular signaling processes and suppressing metastasis in animal models. We examined whether PEBP1 expression in hepatocellular carcinoma (HCC) correlated with the risk of recurrence and survival after resection. Methods: A randomly selected cohort of 240 Chinese HCC patients, predominantly hepatitis B related, formed the basis of the study. PEBP1 expression levels were evaluated by immunohistochemistry and real-time reverse-transcriptase PCR. Survival analysis was performed by univariate and multivariate analyses. The results were further validated in an independent series of 403 patients. The relevance of PEBP1 to phospho-ERK was determined by Western blot analysis on clinical samples and hepatoma cell lines. Results: PEBP1, prevalently down-regulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, lack of encapsulation, poor differentiation and large size). Both PEBP1 protein and mRNA levels were independent predictors for tumor recurrence (hazard ratio (HR)=1.877, p =0.001; HR=2.633, p =0.001; respectively), and patient survival (HR=1.796, p =0.004; HR=1.730, p =0.044; respectively). The prognostic value of PEBP1 was then confirmed in the validation cohort. In addition, Western blot suggested that loss of PEBP1 led to hyperactivity of MAPK signaling. Conclusions: Down-regulation of PEBP1 in HCC indicated aggressive tumor behaviors and predicted a worse clinical outcome, which may be a useful biomarker to identify the patients at high risk of post-operative recurrence. [ABSTRACT FROM AUTHOR]

Herpes virus entry mediator (HVEM) is overexpressed in several malignancies, including hepatocellular carcinoma (HCC). However, to the best of our knowledge, the clinical significance of HVEM in hepatitis B virus (HBV)-related HCC remains unclear. Thus, the present study aimed to explore the clinical significance of HVEM in HBV-related HCC. In the present study, HVEM expression was evaluated in HCC cell lines and HCC frozen samples. The prognostic value of HVEM was assessed in a cohort of 221 patients with HBV-related HCC, following radical resection. B- and T-lymphocyte attenuator (BTLA) expression in subsets of CD8+ T cells was determined via flow cytometry analysis. The results demonstrated high HVEM expression in HCC cell lines, and in HCC tissues compared with paired non-cancerous liver tissues. HVEM expression was demonstrated to be significantly associated with tumor encapsulation and vascular invasion. Furthermore, tumor HVEM status was significantly associated with infiltration of regulatory T cells, but not with CD8+ T cells. Notably, high HVEM expression in HCC was determined to be an independent predictor of an unfavorable outcome of patients with HCC following radical resection. Higher BTLA expression (the receptor of HVEM) was observed in both HCC-infiltrating CD8+ effector memory (CCR7− CD45RA−) and CD45RA+ effector memory (CCR7− CD45RA+) T cells in HCC tissues and blood compared with those in paired peritumor tissues or peripheral blood. Taken together, the results of the present study suggest that HVEM may serve a critical role in HBV-related HCC, most likely by promoting tumor progression and tumor immune evasion, thus the HVEM/BLTA signaling pathway may be a potential target in tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies. [ABSTRACT FROM AUTHOR]

Hepatocarcinogenesis is a complicated process that is affected by a variety of microenvironmental factors, such as secretory chemokines and cell-extracellular matrix (ECM). Retinoic acid receptor-related orphan receptor (ROR)-α has been shown to attenuate tumor invasiveness by inducing suppressive cell microenvironment, and its low expression was associated with a worse prognosis in HCC patients. In the present study, we attempted to investigate the role and mechanism of the dominant transcript of ROR-α, ROR-α-1, in HCC development and progression. Among the four transcripts (ROR-α-1/-2/-3/-4), overexpression of ROR-α-1 dramatically suppressed the capacity of MHCC97H cells to proliferate, migrate and invade. We analyzed the differentially expressed genes in ROR-α-1-overexpressed and non-overexpressed MHCC97H cells, performed Gene Ontology (GO) enrichment analysis on these differentially-expressed genes, and found out that factors involved in the tumor microenvironment and ECM are related to the anti-tumor effects of ROR-α-1. Among these factors, chemokine CXCL5 was significantly downregulated by ROR-α-1 overexpression. Overexpression of ROR-α-1 remarkably inhibited the capacity of HCC cells to proliferate, migrate, invade, and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1, and N-cadherin, suggesting the tumor-suppressive role of ROR-α-1 in MHCC97H cells. Moreover, overexpression of CXCL5 dramatically attenuated the suppressive effects of cell proliferation, migration and invasion induced by ROR-α-1 overexpression in MHCC97H, suggesting that ROR-α-1 exerts its anti-tumor effects via downregulating CXCL5. In conclusion, we demonstrate the tumor-suppressive role of ROR-α-1 in MHCC97H cells and that ROR-α-1 might play a tumor-suppressive role via regulation of chemokine CXCL5. [ABSTRACT FROM AUTHOR]