Journal of Hepatocellular Carcinoma最新文献

{"title":"Gamma-Glutamyl Transpeptidase to Neutrophil Ratio: Prognostic Indicator for Hepatocellular Carcinoma Patients Post-Curative Resection [Response to Letter].","authors":"Xueqin Shen, Xiaoping Niu","doi":"10.2147/JHC.S509528","DOIUrl":"10.2147/JHC.S509528","url":null,"abstract":"","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2481-2482"},"PeriodicalIF":4.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles and Mechanisms of Ferroptosis in Sorafenib Resistance for Hepatocellular Carcinoma.","authors":"Ruyuan Liu, Huanyu Cui, Di Li, Xuefeng Guo, Zhengbao Zhang, Shengkui Tan, Xiaonian Zhu","doi":"10.2147/JHC.S500084","DOIUrl":"10.2147/JHC.S500084","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most prevalent malignant tumor, characterized by a poor prognosis. In recent decades, both the incidence and mortality rates of HCC have risen sharply. Sorafenib has emerged as the first conventional drug approved by the US Food and Drug Administration for first-line treatment in advanced HCC patients due to its favorable safety profile. However, its effectiveness is severely hindered by acquired drug resistance, which leads to only approximately 30% of HCC patients benefited from sorafenib therapy. Sorafenib resistance involves various mechanisms that inhibit cellular uptake of iron and reactive oxygen species (ROS). Consequently, ferroptosis a novel form of cell death contingent upon the accumulation of intracellular iron and ROS plays a critical role in mediating sorafenib resistance through the Hippo YAP pathway or Keap1-Nrf2 system. This review aimed to comprehensively elucidate the mechanisms underlying sorafenib resistance in HCC, particularly focusing on ferroptosis and its pathways, to provide valuable insights into targeting ferroptosis or its pathways for sorafenib-resistant HCC treatment.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2493-2504"},"PeriodicalIF":4.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALBI Grade Analyses of TACE Combined with Anti-Angiogenesis Therapies Plus PD-1 Inhibitors versus Anti-Angiogenesis Therapies Plus PD-1 Inhibitors in Advanced HCC.","authors":"Xin Hong, Di Hu, Wen-Jie Zhou, Xiu-De Wang, Li-Hua Huang, Tian-An Huang, Yi-Wei Guan, Jingyu Qian, Wen-Bin Ding","doi":"10.2147/JHC.S485867","DOIUrl":"10.2147/JHC.S485867","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the baseline albumin-bilirubin (ALBI) grade's role in advanced hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) plus anti-angiogenesis therapies and PD-1 inhibitors (TACE+TP) versus anti-angiogenesis therapies and PD-1 inhibitors (TP).</p><p><strong>Methods: </strong>This multicenter retrospective study enrolled advanced HCC undergoing TACE+TP or TP from January 2019 to June 2023 at three hospitals in China. The primary outcomes were time to progression of the ALBI grade and change in ALBI score between the initial baseline and the final assessment point available, the secondary outcomes consisted of overall survival (OS) as well as progression-free survival (PFS).</p><p><strong>Results: </strong>One hundred and eighty-three patients were ultimately enrolled in this study for analysis, of whom 44 were categorized as having an ALBI grade 1 (TACE+TP, n = 23; TP, n = 21) and 139 were classified as ALBI grade 2 (n = 77; n = 62). Time to progression of the ALBI grade, indicating liver function deterioration, was comparable between the TACE+TP and TP groups (median, 11.2 vs 19.3 months; P = 0.353). Change in ALBI score between the initial baseline and the final assessment point available was comparable among the two groups (difference in least squares mean, 0.084). Irrespective of the initial ALBI grade, patients in TACE+TP group exhibited a significant enhancement in OS and displayed a promising trend towards better PFS.</p><p><strong>Conclusion: </strong>TACE+TP had no negative influence on liver function and enhanced survival regardless of baseline ALBI grade when compared to TP in advanced HCC patients.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2505-2514"},"PeriodicalIF":4.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Learning-Based Automatic Segmentation Combined with Radiomics to Predict Post-TACE Liver Failure in HCC Patients.","authors":"Shuai Li, Kaicai Liu, Chang Rong, Xiaoming Zheng, Bo Cao, Wei Guo, Xingwang Wu","doi":"10.2147/JHC.S499436","DOIUrl":"10.2147/JHC.S499436","url":null,"abstract":"<p><strong>Objective: </strong>To develop and validate a deep learning-based automatic segmentation model and combine with radiomics to predict post-TACE liver failure (PTLF) in hepatocellular carcinoma (HCC) patients.</p><p><strong>Methods: </strong>This was a retrospective study enrolled 210 TACE-trated HCC patients. Automatic segmentation model based on nnU-Net neural network was developed to segment medical images and assessed by the Dice similarity coefficient (DSC). The screened clinical and radiomics variables were separately used to developed clinical and radiomics predictive model, and were combined through multivariate logistic regression analysis to develop a combined predictive model. The area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were applied to compare the performance of the three predictive models.</p><p><strong>Results: </strong>The automatic segmentation model showed satisfactory segmentation performance with an average DSC of 83.05% for tumor segmentation and 92.72% for non-tumoral liver parenchyma segmentation. The international normalized ratio (INR) and albumin (ALB) was identified as clinically independent predictors for PTLF and used to develop clinical predictive model. Ten most valuable radiomics features, including 8 from non-tumoral liver parenchyma and 2 from tumor, were selected to develop radiomics predictive model and to calculate Radscore. The combined predictive model achieved the best and significantly improved predictive performance (AUC: 0.878) compared to the clinical predictive model (AUC: 0.785) and the radiomics predictive model (AUC: 0.815).</p><p><strong>Conclusion: </strong>This reliable combined predictive model can accurately predict PTLF in HCC patients, which can be a valuable reference for doctors in making suitable treatment plan.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2471-2480"},"PeriodicalIF":4.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Impact of CCA Components in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.","authors":"Zhu Zhu, Chun Yang, Mengsu Zeng, Changwu Zhou","doi":"10.2147/JHC.S491243","DOIUrl":"10.2147/JHC.S491243","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the differences of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) patients with a cholangiocarcinoma (CCA) component ≥ 30% or < 30% versus intrahepatic cholangiocarcinoma (iCCA) patients in recurrence-free survival (RFS) and overall survival (OS) prognoses.</p><p><strong>Methods: </strong>Patients with cHCC-CCA and iCCA after surgery were recruited. All cHCC-CCA patients were divided into two subgroups (CCA components ≥ 30% and < 30%). Then, Kaplan-Meier survival analysis and Cox regression analysis were used to investigate and compare the differences of cHCC-CCAs with a CCA component ≥ 30% or < 30% versus iCCAs in RFS and OS prognoses, respectively. The differences of MRI features between cHCC-CCAs with a CCA component ≥ 30% and < 30% were also compared.</p><p><strong>Results: </strong>One hundred sixty-four cHCC-CCAs and 146 iCCAs were enrolled. Compared with iCCAs, cHCC-CCAs with a CCA component < 30% had better OS prognosis (HR: 2.888, p = 0.045). However, Cox regression analysis revealed that cHCC-CCAs with a CCA component ≥ 30% had poorer RFS (HR: 0.503, p < 0.001) and OS (HR: 0.58, p = 0.033) prognoses than iCCAs. In addition, rim APHE (OR = 0.286, p < 0.001), targetoid diffusion restriction (OR = 0.316, p = 0.019), corona enhancement (OR = 0.481, p = 0.033), delayed enhancement (OR = 0.251, p = 0.001), and LR-M (OR = 1.586, p < 0.001) were significant factors associated with cHCC-CCAs with a CCA component ≥ 30%. Multivariable regression analyses showed that only LR-M (OR = 1.522, p = 0.042) was a significantly independent predictor for cHCC-CCAs with a CCA component ≥ 30%.</p><p><strong>Conclusion: </strong>cHCC-CCAs with a CCA component ≥ 30% had worse prognoses than iCCAs. Therefore, we suggest that the postoperative treatment of cHCC-CCAs with a CCA component ≥ 30% can be based on the treatment strategy for iCCAs.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2483-2492"},"PeriodicalIF":4.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicenter Study on Transarterial Chemoembolization Combined with Radiofrequency Ablation for Early-Stage Hepatocellular Carcinoma: Primary versus Recurrent HCC.","authors":"Yu-Tang Chen, Bo-Wen-Tao Chen, Jun-Ming Xu, Xiao-Cui You, Yi Tang, Shao-Jie Wu, Zhu-Ting Fang","doi":"10.2147/JHC.S497956","DOIUrl":"10.2147/JHC.S497956","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the efficacy of transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) for both primary and recurrent early-stage hepatocellular carcinoma (HCC) and to analyze the significant prognostic factors.</p><p><strong>Patients and methods: </strong>Data from patients with early-stage primary or recurrent HCC who underwent TACE plus RFA between August 2019 and May 2024 were collected from three major general hospitals. 158 patients were divided into a primary group and a recurrent group on the basis of their baseline characteristics. Compared the objective response rate (ORR), 1-, 3-, and 5-year progression-free survival (PFS) rates, 1-, 3-, and 5-year overall survival (OS) rates, and complication rate between the two groups. Multivariate analyses were used to evaluate the factors influencing PFS and OS.</p><p><strong>Results: </strong>One hundred fifty-eight patients were enrolled. The ORRs of the primary and recurrent groups were 98.2% and 95.1%, respectively, with no statistically significant difference (χ²= 2.032, <i>Ρ</i> = 0.362). The primary group having a significantly longer PFS time than the recurrent group (<i>Ρ</i> < 0.001). However, there was no significant difference in the 1-, 3-, and 5-year OS rates between the two groups (<i>Ρ</i> = 0.218). Multivariate analysis revealed that primary or recurrent HCC and the Child‒Pugh score were significant prognostic factors for PFS, whereas the serum albumin level was a significant prognostic factor for OS.</p><p><strong>Conclusion: </strong>TACE plus RFA has similar clinical efficacy and safety for both primary and recurrent early HCC. Compared with patients with primary HCC, those with recurrent disease had significantly shorter PFS times.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2441-2452"},"PeriodicalIF":4.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPIH Expression Correlates with Tumor Aggressiveness and Immune Dysregulation in Hepatocellular Carcinoma.","authors":"Jiaxin Bei, Zihao Sun, Rongdang Fu, Xinkun Huang, Jiabai Huang, Yongyou Luo, Yihu Li, Ye Chen, Zhisheng Wei","doi":"10.2147/JHC.S492420","DOIUrl":"10.2147/JHC.S492420","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatocellular Carcinoma (HCC) features a complex pathophysiology and unpredictable immunosuppressive microenvironment, which limit the effectiveness of traditional therapies and lead to poor patient outcomes. Understanding the immune characteristics of HCC is essential for elucidating the immune microenvironment and developing more effective treatments. This study investigates the role of Peptidyl-prolyl isomerase H (PPIH) in HCC by analyzing its expression, prognosis, methylation levels, and relationship with immune cell infiltration.</p><p><strong>Methods: </strong>We utilized bulk sequencing and clinical data from UCSC Xena and the GTEx database for preprocessing and subsequent differential expression analysis of PPIH in tumor and adjacent normal tissues, evaluating prognostic parameters like overall survival and disease-free interval between low and high PPIH expression groups. Immune infiltration was analyzed via CIBERSORT and ssGSEA, while DNA methylation and somatic mutation analyses were performed using MExpress and \"maftools\", respectively, alongside in vitro and in vivo experiments to assess PPIH's functional roles.</p><p><strong>Results: </strong>Our findings indicated that PPIH is significantly upregulated in various cancer types, correlating with poor patient prognosis, increased somatic mutations, and altered gene methylation patterns. High PPIH levels were linked to enhanced T regulatory (Treg) cell infiltration and a decline in Th17 cell populations, impacting vital pathways related to DNA damage repair and tumor proliferation. Furthermore, PPIH knockdown in vitro led to reduced cell viability, proliferation, and invasion while promoting apoptosis. In vivo, PPIH knockdown repressed tumor growth and modified the immune microenvironment by attenuating Th17 cell infiltration and potentially increasing Treg cell accumulation.</p><p><strong>Conclusion: </strong>This study emphasizes PPIH's critical role in HCC progression by facilitating tumor growth and survival while modulating the immune landscape, thereby positioning PPIH as a potential therapeutic target for HCC management.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2453-2470"},"PeriodicalIF":4.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxymatrine Inhibits PD-L1 by Downregulating IFN-γ to Promote Ferroptosis and Enhance Anti-PD-L1 Efficacy in Liver Cancer.","authors":"Yixi Nong, Houji Qin, Liyan Wei, Xi Wei, Jiannan Lv, Xiaoyi Huang, Biaoliang Wu","doi":"10.2147/JHC.S492582","DOIUrl":"10.2147/JHC.S492582","url":null,"abstract":"<p><strong>Purpose: </strong>Oxymatrine has potent anti-cancer activity, but its exact mechanism in liver cancer remains elusive. The present study was designated to explore oxymatrine's effect and the potential mechanism on Programmed cell death-ligand 1 (PD-L1) expression and ferroptosis in liver cancer.</p><p><strong>Methods: </strong>Oxymatrine's influence on PD-L1 expression and ferroptosis-related proteins in liver cancer cells was explored in vitro and in vivo utilizing Western blotting, qRT-PCR, immunofluorescence, ELISA, H&E staining, immunohistochemistry, as well as detection of Fe²⁺, ROS, and MDA.</p><p><strong>Results: </strong>The in-vivo results showed that xenotransplanted tumor mice with drug interventions (oxymatrine, anti-PD-L1, and combination groups) exhibited inhibited tumor growth compared to control mice. Relative to anti-PD-L1 administration alone, the combined treatment inhibited tumor growth more significantly, along with reduced interferon-γ (IFN-γ) expression in peripheral blood and remarkably increased tumor immune lymphocyte (CD4⁺ T and CD8⁺ T) infiltration in cancer tissues. Meanwhile, PD-L1, xCT, and GPX4 protein levels in the combination group were significantly downregulated. According to the in vitro results, IFN-γ promoted PD-L1, xCT, and GPX4 protein levels in liver cancer cell lines. Oxymatrine reversed IFN-γ-induced upregulation of PD-L1 expression; moreover, it downregulated xCT and GPX4 protein levels in liver cancer cells and promoted intracellular Fe²⁺, ROS, and MDA levels.</p><p><strong>Conclusion: </strong>Oxymatrine promotes tumor immune response and ferroptosis in liver cancer by downregulating IFN-γ and synergistically enhances the inhibitory effect of anti-PD-L1 on liver cancer.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2427-2440"},"PeriodicalIF":4.2,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Outcomes of Laparoscopic Anatomical versus Non-Anatomical Liver Resection for Hepatocellular Carcinoma.","authors":"Songyao Leng, Li Cao, Xingru Wang, Jian Chen, Xiaojun Wang, Yong Cao, Xuesong Li, Shuguo Zheng, Feng Tian, Jianwei Li","doi":"10.2147/JHC.S483014","DOIUrl":"10.2147/JHC.S483014","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to investigate the long-term outcomes between laparoscopic anatomical liver resection (LAR) and laparoscopic non-anatomical liver resection (LNAR) in patients with hepatocellular carcinoma (HCC).</p><p><strong>Methods: </strong>In this single-center retrospective cohort study, 1773 patients, from January 2009 to December 2017, were assessed for inclusion. After exclusions, 661 patients were included: 304 patients received LAR and 357 patients received LNAR. Propensity score matching (PSM) with 1:1 ratio was used to eliminate the selection bias between LAR and LNAR groups. The Kaplan-Meier and Cox models were used for survival analysis.</p><p><strong>Results: </strong>After PSM, 250 patients were in LAR or LNAR group, respectively. The overall survival (OS) had no significant difference between LAR and LNAR by Kaplan-Meier analysis. While, LAR had better disease-free survival (DFS) compared with LNAR (Log-rank P=0.035). The cumulative 5-year DFS rates were 48% for LAR, and 38% for LNAR. By Cox analysis, LAR was an independent risk factor of DFS (HR=1.308, P=0.030). In subgroup analysis for tumor size ≤ 5 cm, 207 patients were in LAR or LNAR subgroup after PSM. LAR had better DFS compared with LNAR (Log-rank P=0.033). LAR was an independent risk factor of DFS (HR=1.333, P=0.036). The cumulative 5-year DFS rates were 50% for LAR, and 39% for LNAR. In another subgroup analysis for tumor size > 5 cm, 43 patients were in LAR or LNAR subgroup after PSM. The DFS had no significant difference between LAR and LNAR (Log-rank P=0.912).</p><p><strong>Conclusion: </strong>LAR is preferred for HCC patients with tumor size ≤5cm compared with LNAR because of the better DFS. For patients with tumor size >5cm, LAR and LNAR might be alternative procedures with comparable long-term outcomes.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2413-2425"},"PeriodicalIF":4.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"m⁶A-Methylated NUTM2B-AS1 Promotes Hepatocellular Carcinoma Stemness Feature via Epigenetically Activating <i>BMPR1A</i> Transcription.","authors":"Wenchuan Li, Min Zeng, Yuanjia Ning, Rongzhou Lu, Yunyu Wei, Zuoming Xu, Huamei Wei, Jian Pu","doi":"10.2147/JHC.S480522","DOIUrl":"10.2147/JHC.S480522","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Oncofetal proteins are the optimal diagnostic biomarkers and therapeutic targets for HCC. As the most abundant modification in RNA, N⁶-methyladenosine (m⁶A) has been reported to be involved in HCC initiation and progression. However, whether m⁶A has oncofetal characteristics remains unknown.</p><p><strong>Methods: </strong>Gene expression in HCC tissues and cells was detected using qPCR. The level of m⁶A methylation was determined using methylated RNA immunoprecipitation assay. The biological roles of NUTM2B-AS1 in HCC were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, and spheroid formation assays. The mechanisms underlying the roles of NUTM2B-AS1 were explored using RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), and assay for transposase-accessible chromatin (ATAC).</p><p><strong>Results: </strong>NUTM2B-AS1 was identified as a novel oncofetal long noncoding RNA that was upregulated in the fetal liver and HCC and silenced in adult liver tissues. METTL3 and METTL16 induce m⁶A hypermethylation of NUTM2B-AS1. The m⁶A methylation levels of NUTM2B-AS1 exhibit oncofetal characteristics. m⁶A methylation upregulates NUTM2B-AS1 expression by increasing NUTM2B-AS1 transcript stability. m⁶A-methylated NUTM2B-AS1 promotes HCC cell proliferation and stemness via epigenetically activating <i>BMPR1A</i> expression. NUTM2B-AS1 specifically binds to <i>BMPR1A</i> promoter. m⁶A-methylated NUTM2B-AS1 is recognized by the m⁶A reader YTHDC2, which further binds to the H3K4 methyltransferase MLL1. m⁶A-methylated NUTM2B-AS1 recruits YTHDC2 and MLL1 to <i>BMPR1A</i> promoter, leading to increased H3K4me3 and chromatin accessibility at <i>BMPR1A</i> promoter. Functional rescue assays suggest that BMPR1A is a critical mediator of the oncogenic role of m⁶A-methylated NUTM2B-AS1 in HCC.</p><p><strong>Conclusion: </strong>METTL3- and METTL16-mediated m⁶A methylation of NUTM2B-AS1 is a novel oncofetal molecular event in HCC that promotes HCC stemness via epigenetically activating <i>BMPR1A</i> transcription.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"11 ","pages":"2393-2411"},"PeriodicalIF":4.2,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11624692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}