Discover Oncology
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2025
·Vol. 16
·期 1
·1-10
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IF 2.9
Gong Qineng,Zhu Tianyu,Zhang Linlin,Wu Hui,Miao Yang,Hu Ye
Hepatocellular carcinoma (HCC) is a predominant form of liver cancer and one of the leading causes of cancer-related death globally. Therefore, there is an urgent need for innovative therapeutic strategies that target the molecular mechanisms underlying HCC progression and metastasis, aiming to improve treatment efficacy and patient survival. The natural product celastrol (Cel) has demonstrated inhibitory effects in various cancer cell lines. However, its clinical application has been hindered by high toxicity and a low safety threshold. Metal-free quantum dots (QDs), AgInS 2 (AIS QDs) not only eliminate toxic risks associated with heavy metals but also exhibit high biocompatibility in the biomedical field. By developing AIS QD@Cel, an AIS QDs nano-delivery system for Cel, the cell selectivity and inhibitory effects of Cel on HCC were enhanced. Fourier-transform infrared spectroscopy (FTIR) analysis revealed that AIS QDs can interact with Cel via amide bonds. The encapsulation rate of AIS QDs to Cel reached 27.5%. AIS QD@Cel eliminated toxicity on 293T and enhanced inhibition on HCC cells by over 10 times. Furthermore, the western blotting and flow cytometry experiments showed that AIS QD@Cel promoted apoptosis and autophagy signal pathway. Finally, transcriptome sequencing revealed that AIS QD@Cel effect on HCC by regulating gene expression involved in critical signaling pathways that are implicated in the progression of cancer. This strategy holds the potential to increase safety threshold and clinical applicability of Cel, offering significant clinical value for the treatment of HCC patients.
研究领域:
肿瘤学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Ruibing Wu,Hengye Yuan,Yuehua Wang,Xianggang Gou,Wanhua Hou,Zhongzheng Zhou,Xinran Wang,Xiuling Deng,Changshan Wang,Haisheng Wang,Jia Yan
Background: Norcantharidin (NCTD), a bioactive compound derived from traditional Chinese medicine, has demonstrated promising anticancer activity against multiple malignancies, particularly hepatocellular carcinoma (HCC). However, its epigenetic regulatory mechanisms and associated transcriptional consequences remain poorly characterized.Methods: In this study, we integrated biochemical assays with a panel of cellular analyses assessing cell viability, proliferation, colony formation, and migratory capacity to investigate NCTD’s therapeutic potential in HCC progression. Potential molecular targets of NCTD were systematically identified through integrated network pharmacology approaches. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) was performed to quantify H3K27me3 enrichment level at the TOP2A locus in NCTD-treated HCC cells. Molecular docking simulations were employed to examine structural interactions between NCTD and EZH2 (enhancer of zeste homolog 2), while co-immunoprecipitation assays were further conducted to validate protein-protein interactions between EZH2 and protein phosphatase 1 (PP1).Results: We identified topoisomerase IIα (TOP2A) as a critical molecular target mediating NCTD’s anti-HCC effects. Functional characterization revealed that NCTD significantly attenuated HCC cell proliferation and induced G2/M phase cell cycle arrest through disruption of the TOP2A-p53 signaling axis. Mechanistic investigations demonstrated that NCTD epigenetically suppresses TOP2A transcription via PRC2 (Polycomb Repressive Complex 2)-mediated deposition of the repressive histone mark H3K27me3 at the TOP2A promoter. Structural biology analyses confirmed direct binding of NCTD to EZH2 protein, consequently impairing PP1-mediated dephosphorylation and enhancing PRC2 complex stability.Conclusion: Our findings establish that NCTD exerts anticancer effects in HCC through epigenetic silencing of TOP2A. This work not only elucidates a novel pharmacoepigenetic mechanism underlying NCTD’s antitumor activity but also provides translational rationale for developing PRC2-targeted therapeutic strategies in HCC management.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Turkish Journal of Gastroenterology
·
2025
·Vol. 36
·期 7
·431
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IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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药理学
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转化医学
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DOI
PubMed
高影响因子
Biology Direct
·
2024
·Vol. 19
·期 1
·1-17
·
IF 5.7
Liu Shiwei,Yuan Fukang,Dong Hui,Zhang Jiaqi,Mao Xinyu,Liu Yangsui,Li Huansong
Background Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, and the lack of effective biomarkers for early detection leads to poor therapeutic outcomes. Prostaglandin E Synthase 3 (PTGES3) is a putative prognostic marker in many solid tumors; however, its expression and biological functions in HCC have not been determined. The proteolysis-targeting chimera (PROTAC) is an established technology for targeted protein degradation. Compared to the small-molecule PROTAC, the peptide PROTAC (p-PROTAC) utilizes peptides bound to target proteins to mediate the ubiquitination and degradation of undruggable proteins. This study aimed to use the PROTAC technology to develop a PTGES3 degrader liposome complex containing a PTGES3-binding peptide and the E3 ubiquitin ligase ligand pomalidomide for regulating cell function and provide a novel pathway for treating HCC. Results In this study, we demonstrated that PTGES3 is highly expressed in HCC at the transcriptional and protein levels; furthermore, PTGES3 was identified as a novel drug target that could potentially treat HCC. Hence, we developed PTGES3-PROTACs by adjusting the ligand ratio to optimize the efficacy of degradation agents. The results revealed that PTGES3-PROTAC effectively degraded PTGES3 protein and strongly weakened the HCC malignant phenotype in vitro and in vivo. Conclusions Our findings revealed that the highly selective PTGES3 proteolysis is a potential therapeutic strategy for HCC, and PTGES3 degraders PTGES3-PROTACs can be developed as safe and effective drugs for HCC treatment. Graphical abstract
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
高影响因子
Contrast Media & Molecular Imaging
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2018
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IF 2.934
Weiyue Li,Xiang Xiao,Xiaodan Li,Yikai Xu,Lichao Ma,Liuji Guo,Chenggong Yan,Yuankui Wu
Objective. To investigate the potential of L5 peptide-guided pretargeting approach to identify GPC3-expressing hepatocellular carcinoma (HCC) using ultrasmall superparamagnetic iron oxide (USPIO) as the MR probe. Methods. Immunofluorescence with carboxyfluorescein- (FAM-) labeled L5 peptide was performed in HepG2 cells. Polyethylene glycol-modified USPIO (PEG-USPIO) and its conjugation with streptavidin (SA-PEG-USPIO) were synthesized, and their hydrodynamic diameters, zeta potential, T2 relaxivity, and cytotoxicity were measured. In vitro and in vivo two-step pretargeting MR imaging was performed on HepG2 cells and tumor-bearing mice after the administration of biotinylated L5 peptide (first step), followed by SA-PEG-USPIO (second step). Prussian blue staining was performed to assess iron deposition in tumors. Results. The high specificity of L5 peptide for GPC3 was demonstrated. Generation of SA-PEG-USPIO nanoparticles with good biocompatibility (an average hydrodynamic diameter of 35.97 nm and a zeta potential of −7.91 mV), superparamagnetism (R2 = 0.1039 × 103 mM−1s−1), and low toxicity was achieved. The pretargeting group showed more enhancement than the nonpretargeting group both in vitro (60% vs 20%, ) and in vivo (32% vs 6%, ). Substantial iron deposition was only observed in HepG2 cells and tumors in the pretargeting group. Conclusion. L5 peptide-guided, two-step pretargeting approach with USPIO as the MR imaging probe is a lucrative strategy to specifically identify GPC3-expressing HCC.
研究领域:
医学影像学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Dandan Wu,Zongchao Zuo,Xinning Sun,Xin Li,Fangzhou Yin,Wu Yin
Long-chain fatty acyl-Coa ligase 4 (ACSL4) is an important enzyme that converts fatty acids to fatty acyl-Coa esters, there is increasing evidence for its role in carcinogenesis. However, the precise role of ACLS4 in hepatocellular carcinoma (HCC) is not clearly understood. In the present study, we provide evidence that ACSL4 expression was specifically elevated in HCC and is associated with poor clinical outcomes. ACSL4 significantly promotes the growth and metastasis of HCC both in vitro and in vivo . RNA sequencing and functional experiments showed that the effect of ACSL4 on HCC development was heavily dependent on PAK2. ACSL4 expression is well correlated with PAK2 in HCC, and ACSL4 even transcriptionally increased PAK2 gene expression mediated by Sp1. In addition, emodin, a naturally occurring anthraquinone derivative, inhibited HCC cell growth and tumor progression by targeting ACSL4. In summary, ACSL4 plays a novel oncogene in HCC development by regulating PAK2 transcription. Targeting ACSL4 could be useful in drug development and therapy for HCC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2024
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IF 4.5
Xue Zhang,Jiang Chen,Yuan Yin,Shijun Xiao,Rui Zhang,Haiyang Guo,Tong Yang,Tongyu Zhou,Siyan Zhang,Yang Yang,Caili Bi,Xiao-Jun Li
Targeted delivery of chemotherapeutic agents to the cancerous cells is of fundamental importance and the key step of the targeted delivery system design is to choice a specific receptor. Glypican-3 (GPC3) is a known cell membrane-associated oncofetal proteoglycan that is specifically up-regulated in the fast-growing hepatocarcinoma cells but rarely expressed in the normal healthy liver. Therefore, GPC3 may be a perfect targeting receptor for delivery treatment of hepatocellular carcinoma (HCC). In the present study, a GPC3 specific-targeting nanoliposomal drug delivery system was constructed with GPC3 targeting peptide (named as L5 peptide) modification and anticancer drug cantharidin encapsulation, which aims to realize cantharidin targeted treatment of liver cancer. In our study, nanoliposome specifically targeting GPC3 receptor was successfully constructed with particle size of 127.9 nm and a spherical shape. The targeted liposomes were stable under 4 °C or room temperature for almost 15 days. The drug release from L5-modified liposomes was controlled and delayed. Their targeted delivery properties were characterized by relatively more accumulation in the GPC3 highly expressed HepG2 cells than that of GPC3 lowly expressed Huh-7 cells. The competition results also indicated that the liposomes with L5 peptide modification could competitively bind to GPC3 receptor. Moreover, the liposomes showed colocalization with the lysosome after 3 h incubation. The L5-modified liposomal CTD had an augmented cell growth inhibition and tumor inhibition than that of the free CTD on HepG2 cells and GPC3 highly expressed tumor mice. Our study establishes a new strategy for improving HCC treatment and chemotherapeutic agent targeting delivery.
研究领域:
肿瘤学
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药剂学
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DOI
高影响因子
Portal Hypertension & Cirrhosis
·
2024
·Vol. 3
·期 2
·86-95
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IF 0
Kaibo Yang,Kunjin Wu,Zitong Lei,Tong Liu,Xing Zhang,Jing Li,Kun Yang,Qiuting Peng,Ting Lin,Chang Liu,Kai Qu
Aim Tumor budding (TB) has excellent prognostic value in many solid tumors, but there is little research on it in hepatocellular carcinoma (HCC). This study assessed the prognostic value of TB in patients with HCC who received hepatectomy. Methods This retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University, between 2016 and 2018. TB was evaluated on hematoxylin- and eosin-stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference. t -tests, Chi-squared tests, and rank-sum tests were used to correlate the extent of TB with clinicopathological parameters. Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method. Results The positive detection rate of TB was 45.2% (95/210) in 210 patients with HCC. Patients positive for TB always exhibit lower tumor differentiation, higher hepatitis B virus DNA levels, and more severe liver fibrosis. Multivariate Cox analysis identified TB (hazard ratio [HR]: 2.232, 95% confidence interval [CI]: 1.479–3.368, p < 0.001) as an independent prognostic factor for patients' recurrence-free survival (RFS), similar to tumor size (HR: 1.070, 95% CI: 1.070–1.142, p = 0.042) and satellite nodule (HR: 2.266, 95% CI: 1.298–3.956, p = 0.004). Kaplan–Meier analysis also demonstrated that TB-positive patients had a significantly worse RFS. Interestingly, subgroup analysis revealed that among HCC patients with negative microvascular invasion (MVI), TB was also strongly associated with RFS (HR: 3.206, 95% CI: 1.667–6.168, p < 0.001). These findings suggest that TB may serve as a supplemental prognostic biomarker for HCC-negative MVI. Conclusions TB is an adverse prognostic biomarker for HCC, particularly in patients negative for MVI. TB evaluation should be considered in the postoperative pathological examination of HCC in clinical practice. Graphical This study assessed tumor budding (TB) in hepatocellular carcinoma patients. TB refers to the detachment of tumor cells from the primary tumor mass, infiltrating the adjacent matrix and forming separate clusters. It may represent two distinct pathological features compared to microvascular invasion, which involves the invasion of tumor cells into microvessels. ECM: extracellular matrix. Key points Significant findings of the study This single-center study found that tumor budding (TB) positivity was significantly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). What this study adds TB could serve as a potential supplemental prognostic biomarker for HCC with negative microvascular invasion.
研究领域:
病理学
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肿瘤学
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外科学
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DOI
Journal of Hematology & Oncology
·
2020
·Vol. 13
·期 1
·1-20
·
IF 11.059
Zuo Xueliang,Chen Zhiqiang,Gao Wen,Zhang Yao,Wang Jinguo,Wang Junfeng,Cao Ming,Cai Juan,Wu Jindao,Wang Xuehao
Background Long non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear.Methods Differentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pull-down, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration.Results We identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N6-methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy.Conclusion sOur results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.
研究领域:
肿瘤学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2025
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IF 3.5
Zilin Li,Yan Wang,Jiahui Hu,Jingyang Du,Huizong Nie,Yiling Xi,Yue Huang,Kexin Wang,Kaixuan Zhang,Qiuran Xu,Liyan Cheng,Dongsheng Huang,Linglan Tu
Background Hepatocellular carcinoma (HCC) is a significant malignant tumor that is typically diagnosed late and has a poor prognosis. USP28 (Ubiquitin-specific protease 28), a deubiquitinating enzyme within the ubiquitin-specific proteases (USPs) family, plays a pivotal role in various biological processes, especially in cancer progression. However, its functions and molecular mechanisms in HCC are still unknown. Methods We first analyzed the expression level of USP28 in HCC tissues relative to normal tissues using TCGA database. This was further validated by qRT-PCR and Western Blot. To investigate the function of USP28 in HCC, CCK-8 assay, clone formation assay and Transwell assay were performed in control and USP28 knockdown or overexpressed HCC cells. To explore potential downstream targets of USP28, we used IP-MS analysis. The interaction between USP28 and KRT1 was confirmed by immunoprecipitation and immunofluorescence staining. Finally, we evaluated the in vivo effects of USP28 on HCC growth and metastasis using a ectopic tumor-bearing mouse model. Results The expression of USP28 in HCC tissues was significantly higher than that in normal tissues, and its high expression was associated with poor prognosis. Functional experiments showed that down-regulation of USP28 expression effectively inhibited the proliferation, migration and invasion of HCC cells, while overexpression of USP28 produced the opposite effect. Mechanistic investigations demonstrated that USP28 interacted with KRT1 and exerted deubiquitination on KRT1, thereby maintaining the stability of KRT1. Further studies revealed that USP28 knockdown resulted in decreased IFITM3 expression, which inhibited HCC cell proliferation. In addition, USP28 knockdown combined with sorafenib inhibited tumor growth and metastasis in tumor xenograft mice model. Conclusions Our study confirmed the carcinogenic effects of USP28 by stabilizing KRT1 expression and promoting IFITM3. USP28 small molecule inhibitors can inhibit the proliferation of hepatocellular carcinoma cells and enhance the sensitivity of hepatocellular carcinoma cell lines to sorafenib. This provides a theoretical basis for USP28 to be a new clinical method to alleviate sorafenib resistance.
研究领域:
肿瘤学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2025
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IF 5.5
Mei Luo,Yuelian Wang,Xiaodong Liu,Lin Liu,Li Zhu,Guo Chen,Qing Ye,Chengshi He,Xujue Xiao,Jike Li
Among the spectrum of digestive system cancers, hepatocellular carcinoma (HCC) poses a particularly formidable challenge due to its poor prognosis. Geniposide, an iridoid glucoside extracted from the fruit of Gardenia jasminoides Ellis, exhibits a diverse array of biological activities. The goal of this study is to delineate the specific roles and underlying mechanisms of geniposide on the progression of HCC. Cell viability, apoptosis and migration of Huh7 and HepG2 cells were, respectively, assessed via CCK-8, flow cytometry and trans-well assays. The level of reactive oxygen species (ROS) was assessed with a dihydroethidium (DHE) probe. The measurement of mitochondrial membrane potential (MMP) was conducted using JC-1 staining. Ferroptosis-related markers were evaluated by Western Blot assay. Transcriptome sequencing was performed in HCC cells both treated and untreated with geniposide. In vivo experiments were applied with the subcutaneous xenograft tumor model. In vitro experiments revealed that geniposide exerted a concentration-dependent suppression on cell viability and migration, concurrently eliciting apoptosis in HCC cells. Ferroptosis was identified as the main form of geniposide-induced cell death in HCC. Geniposide promoted the iron ions levels, ROS accumulation, and the expression of ferroptosis markers, which were partially reversed by the addition of deferoxamine (DFO, ferroptosis inhibitor). Intersection analysis was applied between upregulated genes of HCC cells and ferroptosis-related genes. DUOX1 was proven to be involved in geniposide-mediated roles in HCC. In vivo experiments further clarified the suppressive effects of geniposide on tumors. Geniposide treatment increased intracellular iron ions and induced ferroptosis in HCC. Geniposide attenuated tumor progression and oxidative stress via DUOX1-mediated ferroptosis.
研究领域:
生物医学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
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2020
·
IF 2.014
Yue YANG,Yan LIAO,Yan-Ping GUI,Li ZHAO,Lu-Bo GUO
Adriamycin resistance in HCC seriously hinders the treatment of patients, it is necessary to investigate the mechanisms. Autophagy is involved in adriamycin resistance and JNK2 is related to autophagy. However, whether JNK2 inducing drug resistance though autophagy is unknown. GL-V9, a new synthesized flavonoid derivative, has been proved of its anti-tumor effects. The aim of the study is to explore the role of JNK2-related autophagy on adriamycin-induced drug resistance and the effects of GL-V9 on reversing adriamycin resistance. We concluded that JNK2 played an important role in drug resistance induced by adriamycin. The high expression of JNK2 activated protective autophagy in Hep G2-DOXR cells under non-stress condition, which protected cells from drug attacking. Furthermore, we found that GL-V9 reversed adriamycin resistance by blocking the JNK2-related protective autophagy in HCC.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）