Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators’ roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.

Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice. 

Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis and high mortality. This study aimed to explore the oncogenic mechanisms of TRAF5 in HCC and provide a novel therapeutic strategy for HCC. Methods Human HCC cell lines (HepG2, HuH7, SMMC-LM3, and Hep3B), normal adult liver epithelial cells (THLE-2), and human embryonic kidney cells (HEK293T) were utilized. Cell transfection was performed for functional investigation. qRT-PCR and western blotting were used to detect mRNA expression of TRAF5, LTBR, and NF-κB and protein expression of TRAF5, p-RIP1(S166)/RIP1, p-MLKL(S345)/MLKL, LTBR, and p-NF-κB/NF-κB. Cell viability, proliferation, migration, and invasion were evaluated using CCK-8, colony formation, wound healing, and Transwell assays. Cell survival, necrosis, and apoptosis were assessed using flow cytometry and Hoechst 33342/PI double staining. Co-immunoprecipitation and immunofluorescence were performed to determine the interaction between TRAF5 and LTBR. A xenograft model was established to validate the role of TRAF5 in HCC. Results TRAF5 knockdown inhibited HCC cell viability, colony formation, migration, invasion, and survival but enhanced necroptosis. Additionally, TRAF5 is correlated with LTBR and TRAF5 silencing down-regulated LTBR in HCC cells. LTBR knockdown inhibited HCC cell viability, while LTBR overexpression eliminated the effects of TRAF5 deficiency on inhibiting HCC cell proliferation, migration, invasion, and survival. LTBR overexpression abolished the promotive function of TRAF5 knockdown on cell necroptosis. LTBR overexpression undid the suppressive effect of TRAF5 knockdown on NF-κB signaling in HCC cells. Moreover, TRAF5 knockdown suppressed xenograft tumor growth, inhibited cell proliferation, and promoted tumor cell apoptosis. Conclusions TRAF5 deficiency facilitates necroptosis in HCC by suppressing LTBR-mediated NF-κB signaling.

Silencing of TRAF5 enhances necroptosis in hepatocellular carcinoma by inhibiting LTBR-mediated NF-κB signaling

Background: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of RPL3L in DCM. Methods: Genetic correlation, expression quantitative trait loci (eQTL) mapping, differential expression analysis and comparative functional analysis were performed using cardiac gene expression data from the patients and murine genetic reference populations (GRPs) of BXD mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice). Additionally, immune infiltration analysis was performed to understand the relationship between DCM, immune cells and RPL3L expression. Results: Systems genetics analysis identified high expression of Rpl3l mRNA, which ranged from 11.31 to 12.16 across murine GRPs of BXD mice, with an ~1.8-fold difference. Pathways such as “diabetic cardiomyopathy”, “focal adhesion”, “oxidative phosphorylation” and “DCM” were significantly associated with Rpl3l. eQTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l. The mRNA expression of Rpl3l, Myl4 and Sdha was significantly correlated with multiple echocardiography traits in BXD mice. Immune infiltration analysis revealed a significant association of RPL3L and SDHA with seven immune cells (CD4, CD8-naive T cell, CD8 T cell, macrophages, cytotoxic T cell, gamma delta T cell and exhausted T cell) that were also differentially infiltrated between heart samples obtained from DCM patients and normal individuals. Conclusions: RPL3L is highly expressed in the heart tissue of humans and mice. Expression of Rpl3l and its upstream regulators, Myl4 and Sdha, correlate with multiple cardiac function traits in murine GRPs of BXD mice, while RPL3L and SDHA correlate with immune cell infiltration in DCM patient hearts, suggesting important roles for RPL3L in DCM and CHF pathogenesis via immune inflammation, necessitating experimental validations of Myl4 and Sdha in Rpl3l regulation.

Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach

With the wide application of bromuconazole (BRO), a kind of triazole fungicide, the environmental problems caused by BRO have been paid more and more attention. In this study, adult male zebrafish were exposed to environmental related concentration and the maximum non-lethal concentration for zebrafish larvae (0,50 ng/L and 7.5 mg/L) for 7 days, respectively. Zebrafish exposed to BRO exhibited a significant reduction in body length and an increase in fatness index, indicating adverse physiological changes. Notably, the exposed zebrafish showed enlarged heart ventricular volumes and thinner heart walls. Transcriptome analysis of heart samples showed that BRO exposure mainly affected pathways related to cardiac energy metabolism. In addition, the amount of ATP in the heart tissue was correspondingly reduced, and the expression levels of genes related to controlling ion balance and myosin synthesis in the heart were also altered. The study extended its findings to the rat cardiomyocytes (H9C2), where similar cardiotoxic effects including changes in transcription of genes related to energy metabolism and heart function were also observed, suggesting a potential universal mechanism of BRO-induced cardiotoxicity. In a doxorubicin (DOX) induced larval zebrafish heart failure model, the expression of lymphoid enhancer-binding factor 1(LEF1), a key gene in the Wnt/β-catenin signaling pathway, was significantly increased in larval zebrafish and adult fish heart tissues and cardiomyocytes, suggesting that LEF1 might play an important role in BRO-induced cardiotoxicity. Taken together, BRO exposure could interfere with cardiac function and metabolic capacity by abnormal activation the expression of LEF1. The study emphasized the urgent need for monitoring and regulating BRO due to its harmful effects on the hearts of aquatic organisms. 

Bromuconazole exposure induces cardiac dysfunction by upregulating the expression LEF1.

To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy.We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear.Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction.MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis. 

https://doi.org/10.1016/j.redox.2023.102606

Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation

Background New biomarkers are needed to detect hepatocellular carcinoma at an earlier stage and to individualize treatment strategies. IL-6 has been proven to be associated with liver cancer in numerous studies. Aim To evaluate the value of the IL-6 promoter methylation level as a noninvasive biomarker for the diagnosis of liver cancer. Methods A retrospective analysis of 165 patients with HBV-associated hepatocellular carcinoma (HCC), 198 patients with chronic hepatitis B (CHB) and 31 healthy controls were involved. The methylight was detected the methylation level of the IL-6 promoter in peripheral blood mononuclear cells (PBMCs), clinical and laboratory parameters were obtained. Results IL-6 promoter methylation levels were significantly lower in patients with HCC (median 53.59%, interquartile range 52.01–54.75%) than in those with CHB (median 56.05%, interquartile range 54.65–57.67%; P<0.001). The level of IL-6 mRNA in patients with HCC (median 0.371, interquartile range 0.173-0.671) was significantly higher than that in patients with CHB (median 0.203, interquartile range 0.108-0.354; P<0.001) and HCs (median 0.189, interquartile range 0.140-0.262; P=0.001). Meanwhile, the PMR value of IL-6 was notably negatively correlated with the mRNA expression level (Spearman’s R=-0.201, P<0.001). The IL-6 PMR value of HCC patients in age (Spearman’s R=0.193, P=0.026) and TBIL (Spearman’s R=0.186, P=0.032) were very weak correlated. At the same time, the level of IL-6 promoter methylation was also an independent factor in the development of liver cancer. When the IL-6 promoter methylation level was used to diagnose HCC, its detective value was superior to AFP [area under the receiver operating characteristic curve (AUC) 0.773 vs. 0.686, P=0.027], And the combined use of AFP and IL-6 methylation level can improve the area under the receiver operating characteristic curve (p=0.011). Conclusion IL-6 promoter hypomethylation is present in hepatocellular carcinoma, and it may be used as a noninvasive biomarker to detect early liver cancer.

/pdf/il-6-promoter-hypomethylation-acts-as-a-diagnostic-biomarker-2ssdzbqo.pdf

IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Atrial fibrillation (AF) is a common cardiac disease with high prevalence in the general population. Despite a mild manifestation at the onset stage, it causes serious consequences, including sudden death, when the disease progresses to the late stage. Most available treatments of AF focus on symptom management or alleviation, due to a lack of fundamental knowledge and the fact that considerable variations of AF exist. With the popularisation of the next-generation sequencing technology, several causal genetic factors, including MYL4, have been discovered to contribute to AF, giving hope to developing its gene therapies. In this study, we attempted to treat a previously established rat AF model, which carried Myl4E11K/E11K loss of function mutation, via overexpression of exogenous wild-type Myl4 by AAV9 vectors. Our results showed that delivery of Myl4 expressing AAV9 to postnatal rat models rescued the symptoms of AF, indicating the therapeutic potential that early gene therapy intervention can achieve long-term effects in treating cardiac arrhythmias caused by gene mutations. 

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy

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Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation

IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy