Background and Aims Heparin‐binding epidermal growth factor (HB‐EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB‐EGF to promote angiogenesis and HCC progression. Approach and Results A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB‐EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia‐inducible factor 1 α signaling pathway. In addition, HB‐EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3‐kinase/Akt signaling pathway. The level of HB‐EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence‐free survival, which suggests that HB‐EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB‐EGF inhibitor cross‐reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. Conclusions HB‐EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB‐EGF inhibitor cross‐reacting material 197 with sorafenib might be used for individualized treatment of HCC.

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BackgroundEarly identification of patients who will benefit from immune checkpoint inhibitors (ICIs) has recently become a hot issue in cancer immunotherapy. Peripheral cytokines are key regulators in the immune system that can induce the expression of immune checkpoint molecules; however, the association between peripheral cytokines and the efficiency of ICIs remains unclear.MethodsA systematic review was conducted in several public databases from inception through 3 February 2022 to identify studies investigating the association between peripheral cytokines (i.e., IL-1β, IL-2, IL-2RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF-α, IFN-γ, and TGF-β) and ICI treatment. Survival data, including overall survival (OS) and/or progression-free survival (PFS), were extracted, and meta-analyses were performed.ResultsTwenty-four studies were included in this analysis. The pooled results demonstrated that the pretreatment peripheral levels of IL-6 (univariate analysis: HR = 2.53, 95% CI = 2.21–2.89, p < 0.00001; multivariate analysis: HR = 2.21, 95% CI = 1.67–2.93, p < 0.00001) and IL-8 (univariate analysis: HR = 2.17, 95% CI = 1.98–2.38, p < 0.00001; multivariate analysis: HR = 1.88, 95% CI= 1.70–2.07, p < 0.00001) were significantly associated with worse OS of cancer patients receiving ICI treatment in both univariate and multivariate analysis. However, high heterogeneity was found for IL-6, which might be attributed to region, cancer type, treatment method, sample source, and detection method.ConclusionThe peripheral level of IL-8 may be used as a prognostic marker to identify patients with inferior response to ICIs. More high-quality prospective studies are warranted to assess the predictive value of peripheral cytokines for ICI treatment.

Background and AimImmune checkpoint inhibitors (ICIs) have been widely used in hepatocellular carcinoma (HCC), while only a subset of patients experience clinical benefit. We aimed to investigate the effects of viral etiology on response to ICIs in HCC and depict the tumor immune microenvironment (TIME) of virally infected and uninfected HCC.MethodsA systematic search was conducted in PubMed, Web of Science, Embase, and the Cochrane central register of controlled trials up to August 2021. Clinical trials reporting the efficacy of ICIs in HCC were eligible. Baseline characteristics including first author, year of publication, National Clinical Trials (NCT) registry number, study region, sample sizes, interventions, line of treatment, and viral status were extracted. Meta-analysis was conducted to generate combined odds ratios (ORs) with 95% confidence intervals (CI) based on random or fixed effect model, depending on heterogeneity. Tumor immune microenvironment was depicted using ESTIMATE and CIBERSORT algorithm.ResultsEight studies involving 1,520 patients were included. Combined data suggested that there was no significant difference of objective response rate (ORR) between virally infected HCC and non-viral HCC patients [OR = 1.03 (95% CI, 0.77–1.37; I2 = 30.9%, pH = 0.152)]. Similarly, difference was not observed on ORR between HBV-HCC and HCV-HCC patients [OR = 0.74 (95% CI, 0.52–1.06; I2 = 7.4%, pH = 0.374)]. The infiltration of immune cells in the tumor microenvironment did not differ by etiology except for M0 macrophages, M2 macrophages, regulatory T cells, naive B cells, follicular helper T cells, activated dendritic cells, activated mast cells, and plasma cells. Despite differences in infiltration observed in specific cell types, the immune score and stromal score were generally comparable among etiology groups.ConclusionViral etiology may not be considered as the selection criteria for patients receiving ICIs in HCC, and viral status has little impact on TIME remodeling during HCC tumorigenesis.

Background and AimsThe clinical benefit of adjuvant antiviral therapy after curative therapy for HCC in patients with high preoperative HBV-DNA loads has been studied widely but that in patients with low preoperative HBV-DNA loads remains controversial. The purpose of this study was to determine the effect of antiviral treatment prophylaxis on HBV reactivation, overall survival (OS), and postoperative liver function in patients with low preoperative HBV-DNA levels undergoing curative resection.MethodsA meta-analysis was conducted by searching Web of Science, PubMed, Embase, and Cochrane Library until May 2020. We used REVMAN for data analysis and completed the study under the PRISMA guidelines.ResultsThree randomized trials and seven cohort studies, comprising of 1,131 individuals, were included in the meta-analysis. Antiviral treatment significantly reduced the rate of HBV reactivation after curative treatment of HCC, with a pooled risk ratio of 0.12 (95% c.i. 0.07 to 0.21; P < 0.00001). The trials were consistently favorable for the antiviral group, with a pooled hazard ratio of 0.52 (95% c.i. 0.37 to 0.74; P = 0.0002) in respect of OS rate. However, by pooling the data from studies that reported ALT on the 30th day postoperatively, the result didn’t reach statistical significance (mean difference −4.38, 95% c.i. −13.83 to 5.07; P = 0.36). The I² values of the heterogeneity test for the above three comparisons are zero.ConclusionAntiviral therapy during curative resection is effective in reducing HBV reactivation and improving OS rate in HCC patients with low viral load.