Gene targets with therapeutic potential in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide.Major treatments include liver transplantation,resection,and chemotherapy,but the 5-year recurrence rate remains high.Late diagnosis often prevents surgical intervention,contributing to poor patient survival rates.Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones.Enhancer of zeste homolog 2(EZH2),a key regulator of cell cycle progression,is frequently upregulated in HCC and is associated with advanced stages and poor prognosis,making it a potential biomarker.Additionally,signal transducer and activator of transcription 3,which binds to EZH2,affects disease staging and outcomes.Targeting EZH2 presents a promising therapeutic strategy.On the other hand,abnormal lipid metabolism is a hallmark of HCC and impacts prognosis.Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes,suggesting its potential as a biomarker.Other genes such as guanine monophosphate synthase,cell division cycle associated 5,and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC,offering potential as biomarkers and therapeutic targets.

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

Mechanisms and therapeutic strategies to combat the recurrence and progression of hepatocellular carcinoma after thermal ablation

Thermal ablation(TA),including radiofrequency ablation(RFA)and microwave ablation(MWA),has become the main treatment for early-stage hepatocellular carcinoma(HCC)due to advantages such as safety and minimal invasiveness.However,HCC is prone to local recurrence,with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition(EMT)and remodeling of the tumor microenvironment(TME).According to many studies,various components of the TME undergo complex changes after TA,such as the recruitment of innate and adaptive immune cells,the release of tumor-associated antigens(TAAs)and various cytokines,the formation of a hypoxic microenvironment,and tumor angiogenesis.Changes in the TME after TA can partly enhance the anti-tumor immune response;however,this response is weak to kill the tumor completely.Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions,leading to tumor recurrence and progression.How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear.Thus,in this review,we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.

Early diagnosis and therapeutic strategies for hepatocellular carcinoma:From bench to bedside

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.

Alendronate and FTI-277 combination as a possible therapeutic approach for hepatocellular carcinoma:An in vitro study

Background： An important product of mevalonate pathway is downstream synthesis of isoprenoid unitsthat has long been implicated in development and progression of tumor. It has been speculated thatinhibition of protein prenylation might be therapeutically beneficial. The objective of current study wasto evaluate antitumor potential of a novel therapeutic combination of mevalonate pathway inhibitors, FTI-277 and alendronate. We also examined differentially expressed proteins in response to treatment usingproteomics approach.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

Unlocking the diagnostic potential of vascular endothelial growth factor and interleukin-17: Advancing early detection strategies for hepatocellular carcinoma

Tian et al investigated the diagnostic value of serum vascular endothelial growth factor(VEGF)and interleukin-17(IL-17)in primary hepatocellular carcinoma(PHC).Their retrospective study,published in the World Journal of Gastrointestinal Surgery,revealed that the serum levels of VEGF and IL-17 are significantly elevated in PHC patients compared with healthy controls.These biomarkers are closely associated with pathological features such as tumor metastasis and clinical tumor node metastasis stage.A receiver operating characteristic analysis further confirmed the diagnostic efficacy thereof,suggesting that VEGF and IL-17 could serve as valuable tools for early detection and treatment guidance.This study underscores the potential of integrating these biomarkers into clinical practice to increase diagnostic accuracy and improve patient management in PHC.

Combined transarterial chemoembolization and tislelizumab for patients with unresectable hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)often presents as unresectable,necessitating effective treatment modalities.Combining transarterial chemoembolization(TACE)with immunotherapy and targeted therapy has shown promise,yet real-world evidence is needed.AIM To investigate effectiveness and safety of TACE with tislelizumab±targeted therapy for unresectable HCC in real-world setting.METHODS This retrospective study included patients with unresectable HCC receiving combined treatment of TACE and tislelizumab.The clinical outcomes included progression-free survival(PFS),overall survival(OS),objective response rate(ORR),and disease control rate(DCR).All patients were evaluated according to the mRECIST criteria.The adverse event(AE)was also assessed.RESULTS In this study of 56 patients with median follow-up of 10.9 months,7 had previous immunotherapy.Tislelizumab was administered before TACE in 21(37.50%)and after in 35(62.50%)patients,with 91.07%receiving concurrent targeted therapy.Median PFS was 14.0(95%CI:7.0-18.00)months,and OS was 28(95%CI:2.94-53.05)months.Patients with prior immunotherapy had shorter PFS(6 vs.18 months,P=0.006).Overall ORR and DCR were 82.14%and 87.50%.Grade≥3 treatment-related AEs included increased alanine aminotransferase(8.93%),aspartate aminotransferase(10.71%),and total bilirubin(3.57%).CONCLUSION The combination of TACE and tislelizumab,with or without targeted therapy,demonstrated promising efficacy and safety in unresectable HCC,especially in immunotherapy-naive patients,warranting further prospective validation studies.

Therapeutic potential of small interfering RNAs/micro interfering RNA in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the predominant form of primary liver cancer and represents the third leading cause of cancer-related death worldwide. Current available therapeutic approaches are poorly effective,especially for the advanced forms of the disease. In the last year,short double stranded RNA molecules termed small interfering RNAs(si RNAs) and micro interfering RNAs(mi RNA),emerged as interesting molecules with potential therapeutic value for HCC. The practical use of these molecules is however limited by the identification of optimal molecular targets and especially by the lack of effective and targeted HCC delivery systems. Here we focus our discussion on the most recent advances in the identification of si RNAs/mi RNAs molecular targets and on the development of suitable si RNA/mi RNAs delivery systems.

Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.

Application of ablative therapy for intrahepatic recurrent hepatocellular carcinoma following hepatectomy

The post-hepatectomy recurrence rate of hepatocellular carcinoma(HCC)is persistently high,affecting the prognosis of patients.An effective therapeutic option is crucial for achieving long-term survival in patients with postoperative recurrences.Local ablative therapy has been established as a treatment option for resectable and unresectable HCCs,and it is also a feasible approach for recurrent HCC(RHCC)due to less trauma,shorter operation times,fewer complications,and faster recovery.This review focused on ablation techniques,description of potential candidates,and therapeutic and prognostic implications of ablation for guiding its application in treating intrahepatic RHCC.

FXYD6： a novel therapeutic target toward hepatocellular carcinoma

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

Multimodality treatment in hepatocellular carcinoma patients with tumor thrombi in portal vein

AIM: To compare the therapeutic effect and significances of multimodality treatment for hepatocellular carcinoma (HCC) with tumor thrombi in portal vein (PVTT). METHODS: HCC patients (n=147) with tumor thrombi in the main portal vein or the first branch of portal vein were divided into four groups by the several therapeutic methods. There were conservative treatment group in 18 out of patients (group A); and hepatic artery ligation(HAL) and/or hepatic artery infusion (HAI) group in 18 patients (group B), in whom postoperative chemoembolization was done periodically; group of removal of HCC with PVTT in 79 (group C) and group of transcatheter hepatic arterial chemoembolization (TACE) or HAI and/or portal vein infusion (PVI) after operation in 32 (group D). RESULTS: The median survival period was 12 months in our series and the 1-,3-, and 5-year survival rates were 44.3%, 24.5% and 15.2%, respectively. The median survival times were 2, 5, 12 and 16 months in group A, B, C and D, respectively. The 1-, 3- and 5-year survival rates were 5.6%, 0% and 0% in group A; 22.2%, 5.6% and 0% in group B; 53.9%, 26.9% and 16.6% in group C; 79.3%, 38.9% and 26.8% in group D, respectively. Significant difference appeared in the survival rates among the groups (P 【 0.05). CONCLUSION: Hepatic resection with removal of tumor thrombi and HCC should increase the curative effects and be encouraged for the prolongation of life span and quality of life for HCC patients with PVTT, whereas the best therapeutic method for HCC with PVTT is with regional hepatic chemotherapy or chemoembolization after hepatic resection with removal of tumor thrombi.

Study on the Changes in Microvessel Density in Hepatocellular Carcinoma Following Transcatheter Arterial Chemoembolization

To study the changes in intratumoral microvessel density (MVD) in hepatocellular carcinoma (HCC) following transcatheter arterial chemoembolization (TACE), MVD in 42 HCC specimens histologically verified was studied by using immunohistochemical method. Of all the specimens, 20 were obtained from the patients treated with surgical resection alone, 22 from those with second stage surgical resection after TACE. The results showed that the MVD in HCC tissues was 53.4±21 9 in the TACE group and 27.6±9.2 in the single operating group, respectively, with the difference being significant between them ( P <0.001). It was suggested that TACE might contribute to angiogenesis of HCC, possibly due to anoxic stress and ischemia reperfusion injury.

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

The population of patients with hepatocellular carcinoma(HCC)overlaps to a high degree with those for chronic kidney disease(CKD)and end-stage renal disease(ESRD).The degrees of renal dysfunction vary,from the various stages of CKD to dialysis-dependent ESRD,which often affects the prognosis and treatment choice of patients with HCC.In addition,renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes.This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction.The possible mechanisms of CKD causing HCC involve uremia itself,long-term dialysis status,immunosuppressive agents for postrenal transplant status,and miscellaneous factors such as hormone alterations and dysbiosis.The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome.Finally,we categorized the risk factors that could lead to both HCC and CKD into four categories:Environmental toxins,viral hepatitis,metabolic syndrome,and vasoactive factors.Both CKD and ESRD have been reported to negatively affect HCC prognosis,but more research is warranted to confirm this.Furthermore,ESRD status itself ought not to prevent patients receiving aggressive treatments.This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment,treatment-related adverse renal effects,and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD.Such aggressive treatments include liver resection,simultaneous liver kidney transplantation,radiofrequency ablation,and transarterial chemoembolization.Finally,focusing on patients unable to receive active treatment,this study compiled information on the latest systemic pharmacological therapies,including targeted and immunotherapeutic drugs.Based on available clinical studies and Food and Drug Administration labels,this study details the drug indications,side effects,and dose adjustments for patients with renal dysfunction.It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.

Protocol of Interventional Treatment for Hepatocellular Carcinoma

To establish a reasonable protocol for interventional treatment ofhcpatocellular carcinoma (HCC). Methods: The data of 1000 HCC patients treated by different kinds ofinterventional treatments were reviewed with their results of biochemistry, imaging, pathology andsurvival rate evaluated. The values as well as the pros and cons of these various kinds ofinterventional treatments were compared in order to find an optimal protocol. Results:Segmental-transcatheter oil chemoembolization (S-TOCE) could more effectively eradicate the tumoryet inflicting less damage on the noncancerous hepatic tissue and giving much higher survival ratethan the conventional transcatheter oil chemoembolization (C-TOCE). Precutaneous ethanol injection(PEI) in combination with chemoembolization could eliminate the residual tumor and significantlyincrease the survival rate without damaging the noncancerous hepatic tissue. The living quality orsurvival rate could be improved by choosing different ways of interventional treatments to cut downthe complications. Conclusion: The selection of different interventional treatments should bo doneaccording to the size and type of HCC. Active management is indicated for different complicationspresenting along with HCC.

Histopathological study of hepatocellular carcinoma after transcatheter hepatic arterial embolization

AIMS To study the histopathological changes in hepatocellular carcinoma (HCC) after transcatheter arterial embolization (TAE). METHODS Histopathological analysis was made in 39 cases of liver neoplasms after TAE and 11 cases of liver neoplasms after digital selective angiography (DSA), including pathological type, histological grade, necrotic degree, capsule, times of treatment, injured vessel and lymphocyte infiltration. RESULTS Six cases with 100% necrosis, 14 cases with 30% 95% necrosis, 19 cases with 0% 5% necrosis after TAE and 11 cases without necrosis after DSA were found histologically. The necrosis was related to the pathological type, capsule, injured vessels, but not to the histological grade, time of treatment and lymphocyte infiltration of the liver neoplasms. CONCLUSIONS TAE is an effective therapy for the late stage HCC. The encapsulated HCC is a preferable indicator for TAE.

Hepatocellular Carcinoma with Tumor Thrombus in Portal Vein: Finding in Ultrasonography, Computed Tomography, Angiography and Chemoembolization

Transcatheter hepatic artery chemoembolization (TACE) was performed in 41 patients with hepatocellular carcinoma (HCC) accompanied with portal tumor thrombus (PTT). The primary tumors and the PTTs had been detected with ultrasonography (US), computed tomography (CT) and digital subtraction angiography (DSA) before TACE. The purpose of this article is to compare the sensitivity of these methods. Eighty cases of HCC without PTT detected by DSA during the same period were studied as a control group. The PTTs were found in 37 of 41 (90.2%) cases with DSA, whereas the detection rate was 81.1% with US and 41.0% with CT. The internal left lobe of liver was invaded by tumor in 23 of 41 (56.1%) patients with PTT, but it is only 26.3% in the control group (P<001). The primary tumor located in the internal left lobe was significantly smaller than that in the right lobe (P<001). No serious dysfunction of the liver occurred during the treatment. It is concluded that DSA and US are more sensitive than CT to the detection of PTT, that tumor in the internal left lobe of the liver more easily invades the portal vein, and that TACE should be performed as actively as possible even if the portal vein has been invaded.

Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less as first-line treatment

AIM:To evaluate long-term outcomes of radiofrequency(RF) ablation as first-line therapy for single hepatocellular carcinoma(HCC) ≤ 3 cm and to determine survival and prognostic factors.METHODS:We included all 184 patients who underwent RF ablation as a first-line treatment for single HCC ≤ 3 cm between April 2005 and December 2013.According to the criteria of Livraghi,the 184 patients were divided into two groups:those suitable for surgical resection(84 cases) and those unsuitable for surgical resection(100 cases).The primary endpoints were the overall survival(OS) rate and safety;the secondary endpoints were primary technique effectiveness and recurrence rate.RESULTS:There were 19(10.3%) cases of ablation related minor complications.The complete tumor ablation rate after one RF session was 97.8%(180/184).The rate of local tumor progression,extrahepatic metastases and intrahepatic distant recurrence were 4.9%(9/184),9.8%(18/184) and 37.5%(69/184),respectively.In the 184 patients,the 1-,3-,and 5-year OS rates were 99.5%,81.0%,and 62.5%,respectively.The 1-,3-,and 5-year OS rates were 100%,86.9%,and 71.4%,respectively,in those suitable for surgical resection and 99.0%,76.0%,and 55.0%,respectively,in those unsuitable for surgical resection(P = 0.021).On univariate and multivariate analyses,poorer OS was associated with Child-Pugh B class and portal hypertension(P < 0.05).CONCLUSION:RF ablation is a safe and effective treatment for single HCC ≤ 3 cm.The OS rate of patients suitable for surgical resection was similar to those reported in surgical series.