ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(13), P. 5001 - 5018

Published: Jan. 1, 2022

Hepatocellular carcinoma is one of the most common malignant tumors.M6A a novel epigenetic modification that have been emerged as vital regulators for progression HCC.However, regulatory role, clinical significance and details modification, such impact on local tumor environment, remain largely unclear.Our study showed ALKBH5 was highly expressed in HCC high expression predicted worse prognosis patients.Prediction function by tissue samples single cell sequencing Gene Set Variation Analysis.Primary CD3 + T lymphocytes bone marrow-derived macrophages were used to evaluate effect immune microenvironment.The results indicated promote proliferation, metastasis PD-L1+macrophage recruitment.Mechanistically regulates MAP3K8 m6A dependent manner which mediates proliferation cells.ALKBH5 also promotes activation JNK ERK pathways through upregulating MAP3K8, thus regulating IL-8 promoting macrophage recruitment.Taken together, these data show growth, recruitment ALKBH5/MAP3K8 axis it may serve potential diagnostic marker target treatment patients.

Language: Английский

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Gut‐liver axis‐mediated mechanism of liver cancer: A special focus on the role of gut microbiota

Cancer Science, Journal Year: 2021, Volume and Issue: 112(11), P. 4433 - 4443

Published: Sept. 17, 2021

Gut microbiota and the mammalian host share a symbiotic relationship, in which provides suitable ecosystem for gut bacteria to digest indigestible nutrients produce useful metabolites. Although primarily reside influence intestine, they also regulate liver function via absorption subsequent transfer of microbial components metabolites through portal vein liver. Due this transfer, may be continuously exposed gut-derived components. For example, short-chain fatty acids (SCFA) produced by microbiota, fermentation dietary fiber, can suppress inflammation regulatory T cell induction SCFA-induced epigenetic mechanisms. Additionally, secondary bile (BA), such as deoxycholic acid, 7α-dehydroxylation primary BAs, are thought induce DNA damage contribute remodeling tumor microenvironments. Other substances that include lipopolysaccharides (components outer membrane gram-negative bacteria) lipoteichoic acid (cell wall component Gram-positive bacteria), ligands innate immune receptors, Toll-like receptor-4, receptor-2, respectively, inflammatory signaling is elicited. In review, we focus on role microenvironment, describing anatomy gut-liver axis, metabolites, relationships exist between diseases, including cancer.

Language: Английский

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The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

Biomedicines, Journal Year: 2021, Volume and Issue: 9(6), P. 687 - 687

Published: June 17, 2021

A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication steatohepatitis (NASH), as well threatening evolution hepatocellular carcinoma (HCC), is supported by numerous experimental clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance cells closely related inflammation immune responses. Here, we reviewed recent findings regarding this topic, focusing on of NOXs different stages describing current knowledge about their mechanisms action. We conclude that, although there a consensus that NOX-produced ROS toxic non-neoplastic conditions due vicious cycle sustaining NAFLD NASH, effect controversial neoplastic towards HCC. In regard, indications differential NOX isoforms, since NOX1 NOX2 play detrimental role, whereas increased NOX4 expression appears be correlated with better HCC prognosis some Further studies needed fully unravel action relationships signaling pathways modulating steatosis cancer development.

Language: Английский

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Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(9), P. 1359 - 1376.e7

Published: Aug. 15, 2022

Language: Английский

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The Dynamic Role of NK Cells in Liver Cancers: Role in HCC and HBV Associated HCC and Its Therapeutic Implications

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 20, 2022

Hepatocellular carcinoma (HCC) remains an important complication of chronic liver disease, especially when cirrhosis occurs. Existing treatment strategies include surgery, loco-regional techniques, and chemotherapy. Natural killer cells are distinctive cytotoxic lymphocytes that play a vital role in fighting tumors infections. As constituent the innate immune system against cancer, phenotypic functional deviations NK have been demonstrated HCC patients who also exhibit perturbation NK-activating receptor/ligand axis. The rate recurrence tumor-infiltrating circulating positively associated with survival benefits prognostic significance, suggesting cell dysfunction is closely related to progression. first-line effector viral hepatitis significant by directly clearing virus-infected or activating antigen-specific T producing IFN-γ. In addition, chimeric antigen receptor (CAR) engineered suggest exclusive opportunity produce CAR-NKs several specificities fewer side effects. present review, we comprehensively discuss landscape liver, particularly cells, impact tumor microenvironment (TIME) on function biological HCC. Furthermore, HBV-induced has elaborated. We elaborate available cell-based immunotherapeutic approaches summarize current advancements This review will facilitate researchers understand importance lead devising innovative for systematic

Language: Английский

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Emerging role of aging in the progression of NAFLD to HCC

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 84, P. 101833 - 101833

Published: Dec. 22, 2022

Language: Английский

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Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 10, 2022

Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment HCC been a challenge, for decades was limited to with tyrosine kinase inhibitors (TKIs) until application immune checkpoint (ICIs) became available. Due drug resistance unsatisfactory therapeutic effects monotherapy TKIs or ICIs, multi-ICIs, combination ICIs antiangiogenic drugs novel strategy treat HCC. Antiangiogenic mostly include (sorafenib, lenvatinib, regorafenib, cabozantinib so on) anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common anti-programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, atezolizumab, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), tremelimumab ipilimumab. Combination therapies involving two may have synergistic action shown greater efficacy In this review, we present overview current knowledge recent clinical developments ICI-based provide outlook on future prospects.

Language: Английский

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Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities

Cancers, Journal Year: 2022, Volume and Issue: 14(16), P. 4028 - 4028

Published: Aug. 20, 2022

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of liver, accounting for 90% all recorded cases. HCC third common cause cancer-related death, with a 5-year survival rate just 3%. In advanced stages, systemic treatments allow doctors to obtain clinical benefits, although prognosis remains very poor. past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was first oral kinase inhibitor (TKI) approved treatment in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, vascular endothelial growth factor (VEGFR) inhibitors such as Ramucirumab VEGF Bevacizumab first- or second-line treatments. More recently, combination immune checkpoint (Atezolizumab plus Bevacizumab) analyzed HCC. On basis poor prognoses meager benefits deriving from available therapies, research into extremely necessary. this review, we focus on HCC, look toward future.

Language: Английский

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New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(7), P. 2775 - 2794

Published: Jan. 1, 2022

Hepatocellular carcinoma (HCC) is one of the most lethal tumors in China and worldwide, although first-line therapies for HCC, such as atezolizumab bevacizumab, have been effective with good results, researches on new attracted much attention.With deepening research tumor immunology, role operation mechanism immune cells microenvironment (TME) HCC explained, programmed cell death protein 1 (PD-1) binding to ligand could cause T exhaustion reduce IFN-γ secretion, cytotoxic lymphocyte 4 (CTLA-4) CD28 mediate immunosuppression by competing B7 disrupting signal transduction pathway, which also lays foundation development application more checkpoint inhibitors (ICIs).The biological behavior various checkpoints has proved PD-1, (PD-L1), CTLA-4 so on, leading a series clinical trials.Currently, FDA approved nivolumab, pembrolizumab nivolumab plus ipilimumab treatment HCC.However, ICI disadvantages low response rate many side effects, combination ICIs other (such VEGF or VEGFR inhibition, neoadjuvant adjuvant therapy, locoregional therapies) derived.Further studies mechanisms may reveal therapeutic targets future.

Language: Английский

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Role of baicalin as a potential therapeutic agent in hepatobiliary and gastrointestinal disorders: A review

World Journal of Gastroenterology, Journal Year: 2022, Volume and Issue: 28(26), P. 3047 - 3062

Published: July 7, 2022

Baicalin is a natural bioactive compound derived from Scutellaria baicalensis, which extensively used in traditional Chinese medicine. A literature survey demonstrated the broad spectrum of health benefits baicalin such as antioxidant, anticancer, anti-inflammatory, antimicrobial, cardio-protective, hepatoprotective, renal protective, and neuroprotective properties. hydrolyzed to its metabolite baicalein by action gut microbiota, further reconverted via phase 2 metabolism liver. Many studies have suggested that exhibits therapeutic potential against several types hepatic disorders including fibrosis, xenobiotic-induced liver injury, fatty disease, viral hepatitis, cholestasis, ulcerative colitis, hepatocellular colorectal cancer. During vitro vivo examinations, it has been observed showed protective role gut-associated abnormalities modifying signaling pathways nuclear factor-kappa B, transforming growth factor beta 1/SMAD3, sirtuin 1, p38/mitogen-activated protein kinase/Janus kinase, calcium/calmodulin-dependent kinase kinaseβ/adenosine monophosphate-activated kinase/acetyl-coenzyme carboxylase pathways. Furthermore, also regulates expression fibrotic genes smooth muscle actin, connective tissue factor, β-catenin, inflammatory cytokines interferon gamma, interleukin-6 (IL-6), tumor necrosis factor-alpha, IL-1β, attenuates production apoptotic proteins caspase-3, caspase-9 B-cell lymphoma 2. However, due low solubility poor bioavailability, widespread applications still remain challenge. This review summarized gastrointestinal attributes with an emphasis on molecular mechanisms regulate interaction microbiota.

Language: Английский

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