Cell Reports Medicine
·
2025
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IF 10.6
Shuai Yang,Xinyao Qiu,Yingcheng Yang,Jing Wu,Shan Wang,Bo Zheng,Jianmin Wu,Tao Zhou,Yangqianwen Zhang,Mixue Bai,Shuowu Liu,Zihan Zhao,Yani Zhang,Yixian Wang,Jinxia Bao,Mengye Wu,Dongdong Xue,Meiyu Bao,Ji Hu,Siyun Shen,Hongyang Wang,Lei Chen
Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206 + macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.
研究领域:
肿瘤学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Guirong Zheng,Ruirui Zhao,Aixiao Xu,Zhichun Shen,Xian Chen,Jingwei Shao
Combination with chemotherapeutic drug and gene therapy has been proven highly effective in suppressing tumor progression. Hence, an asialoglycoprotein receptor (ASGPR)-targeting nanodrug delivery system based on mesoporous silica (MSN) nanocarrier for co-delivery of sorafenib (SO) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) to hepatocellular carcinoma (HCC) was successfully designed and synthesized. The structure of nanoparticles was characterized by IR, particle size, zeta potential and N2 adsorption-desorption. The nanoparticles were further evaluated for drug release, cellular uptake, transfection, cell cytotoxicity and cell cycle against HepG2 and Huh7 cells. In vitro testing demonstrated that MSN-LA delivery system could not only induce S cell cycle arrest, enhance the cytotoxicity and improve the tumor target of SO and siVEGF, but also enhance the siVEGF transfection efficiency in ASGPR-overexpressing Huh7 cells. Overall, the MSN-LA delivery system can be a promising drug carrier which could further enhance the anti-cancer efficacy of SO and siVEGF via the active targeting property of LA .
研究领域:
药剂学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Molecular Therapy-Nucleic Acids
·
2023
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IF 8.8
Yufei Pan,Jing Guan,Yujing Gao,Yuejie Zhu,Huantong Li,Hua Guo,Qianyi He,Zhu Guan,Zhenjun Yang
Antisense oligonucleotides (ASOs) are a class of therapeutics targeting mRNAs or genes that have attracted much attention. However, effective delivery and optimal accumulation in target tissues in vivo are still challenging issues. CT102 is an ASO that targets IGF1R mRNA and induces cell apoptosis. Herein, a detailed exploration of the tissue distribution of ASOs delivered by liposomes was carried out. A formulation that resulted in increased hepatic accumulation was identified based on multiple intermolecular interactions between DCP (cytidinyl/cationic lipid DNCA/CLD and DSPE-PEG) and oligonucleotides, including hydrogen bonding, π-π stacking, and electrostatic interactions. The structurally optimized CT102s present a novel strategy for the treatment of hepatocellular carcinoma. The gapmer CT102 MOE5 and conjugate Glu-CT102 MOE5 showed superior antiproliferation and IGF1R mRNA suppression effects at 100 nM in vitro and achieved greater efficacy at a lower dose and administration frequency in vivo . Combined transcriptome and proteome analyses revealed that additional associated targets and functional regulations might simultaneously exist in ASO therapy. These results showed that a combination of lipid encapsulation and structural optimization in the delivery of oligonucleotide drugs has favorable prospects for clinical application.
研究领域:
分子生物学
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肿瘤学
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药物递送系统
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DOI
PubMed
高影响因子
SAUDI PHARMACEUTICAL JOURNAL
·
2024
·
IF 3
Yao Yao,Qian Zhao,Feng Xu,Tingting Yao
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Sorafenib (Sf) is currently the first-line treatment for HCC. However, due to the side effects and unsatisfied efficiency of Sf, it is urgent to combine different therapeutic agents to inhibit HCC progression and increase the therapeutic efficacy. Here, our study constructed a Sf and KIAA1199-siRNA co-loaded liposome Sf-Lp-KIAA, which was prepared by electrostatic interaction of KIAA1199-siRNA and Sf loaded liposome (Sf-Lp). The particle size, zeta potential, the in vitro cumulative release was investigated. The physical and chemical properties were characterized, and the inhibition of HepG2 growth and metastasis in vitro was investigated. The cellular uptake of the co-loaded liposome was significantly higher than that of free siRNA, and the drug/siRNA could be co-delivered to the target cells. Sf-Lp-KIAA could significantly inhibit the growth, migration, invasion and down-regulate KIAA1199 expression of HepG2 cells in vitro than that of single Sf treated group. In addition, the co-delivery liposome accumulated in the HepG2 subcutaneous tumor model and suppress tumor growth after systemic administration without induce obvious toxicity. The present study implied that the co-delivery of Sf and KIAA1199-siRNA through the co-loaded liposomes exerted synergistic antitumor effects on HCC, which would lay a foundation for HCC therapy in the future.
研究领域:
肿瘤学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2025
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IF 4.1
Shuyuan Chang,Ayaka Tomii,Yunfei Zhou,Xun Yang,Yihong Dong,Jun Yan,Aodi Wu,Yumeng Wang,Qingxin Zhang,Hongxue Meng,Lei Yu,Wei Sun,Dabin Liu
Succinate is a crucial metabolite in the TCA cycle and contributes to cancer development. However, the role of exogenous succinate in hepatocellular carcinoma (HCC) is unclear. Here, we report that the concentration of succinate in HCC tissues is lower compared to adjacent normal tissues, as determined by spatial metabolomics and quantitative metabolomics analysis. Succinate supplementation exhibits an anti-tumorigenic effect, inhibiting cell proliferation and colony formation in liver cancer cells but not in non-tumor LO2 cells. Additionally, succinate supplementation significantly reduces tumor formation in xenograft nude mice models and carcinogen-induced WT mice models. The anti-tumorigenic function of succinate is mechanistically mediated by FN1-activated SQLE-related cholesterol biosynthesis. Our study demonstrates that exogenous succinate acts as a cholesterol biosynthesis inhibitor to suppress HCC both in vitro and in vivo , highlighting its potential therapeutic applications.
研究领域:
肿瘤学
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代谢组学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cancer Communications
·
2024
·
IF 20.1
Wei Mu,Pengfei Gu,Huating Li,Jinjin Zhou,Yulun Jian,Weiping Jia,Yang Ge
Background Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P-induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer-stroma communications for a toxicologically associated microenvironment. Method Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404-100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre-education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P-exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull-down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the “on-off” interaction of circRNA-miRNA pairs. We further developed an adeno-associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA-miRNA cascade. Results Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404-100Bap Exo. In the exosome-educated in vivo model, fibrosis factors and pro-inflammatory molecules of are up-regulated when injected with exosomes. Compared to non-exposed 7404 cells, circ_0011496 was up-regulated following B[a]P treatment and was mainly packaged into 7404-100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR-486-5p in recipient fibroblasts. The down-regulation of miR-486-5p converted fibroblast to cancer-associated fibroblast via regulating the downstream of Twinfilin-1 (TWF1) and matrix metalloproteinase-9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer-stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre-metastatic niche formation. Conclusion We demonstrated that B[a]P-induced tumor exosomes can deliver circ_0011496 to activate miR-486-5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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药理学
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毒理学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
·Vol. 17
·期 1
·750
·
IF 12.2
Luomeng Qian,Ping Chen,Bo Wang,Qing Zhang,Yuan Guo,Jie Cui,Ran Ding,Hongkai Zhang,Sihe Zhang
Sorafenib is a widely used targeting drug for hepatocellular carcinoma (HCC) patients; however, sorafenib resistance poses a significant clinical challenge. Hypoxia and extracellular vesicles (EVs) induce vasculogenic mimicry (VM) which is linked to sorafenib resistance in HCC. Migrasomes (Migs), the newly discovered large EVs, foster HCC malignant phenotypes by facilitating the intercellular transfer of functional molecules. Despite these advancements, the precise mechanism by which Migs cause sorafenib resistance is still unknown. In this study, we found that hypoxia upregulates the Migs release and CD147 expression on Migs surface, which is related to sorafenib resistance in HCC. Further investigations revealed that hypoxia-induced migrasomes (hypo-Migs) induce VM formation, thereby promoting sorafenib resistance in HCC. Notably, hypo-Migs are internalized into HCC cells through macropinocytosis, which depends on the expression of lysophosphatidic acid receptor 6 (LPAR6). Mechanistically, CD147-positive (CD147 + ) hypo-Migs activate the PI3K/AKT/TWIST1 signaling pathway, subsequently inducing VM formation and promoting sorafenib resistance. Importantly, dual blockade of CD147 + -hypo-Migs macropinocytosis and VM formation enhances the sorafenib-killing efficacy to HCC. Conclusively, our findings uncover a novel sorafenib resistance mechanism induced by CD147 + -hypo-Migs, and highlight dual-targeting of macropinocytosis and VM as a promising strategy to overcome the sorafenib resistance in HCC.
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DOI
PubMed
高影响因子
Cell Reports
·
2025
·Vol. 44
·期 12
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IF 6.9
Yunfei Zhou,Xinxin Yang,Jianwen Xu,Yidi Wu,Yin Fu,Yihong Dong,Xun Yang,Qiang Fu,Chenxu Guo,Yunjing Hou,Shuyuan Chang,Jun Yan,Ju Ran,Yumeng Wang,Qingxin Zhang,Tomii Ayaka,Lei Yu,Feng Geng,Liuyang Zhao,Xiaoyang Hu,Shuijie Li,Hongxue Meng,Dabin Liu
Dysregulated cholesterol synthesis fuels cancer progression, but its precise role in hepatocellular carcinoma (HCC) remains unclear. Here, we identify elevated acetylation of 24-dehydrocholesterol reductase (DHCR24) at Lys254 as a hallmark of HCC. Both total DHCR24 and its K254 acetylation independently predict poor patient survival. Acetylation stabilizes DHCR24, sustaining hepatic cholesterol synthesis and promoting tumorigenesis. Mechanistically, DHCR24 acetylation enhances 7-ketocholesterol accumulation, which upregulates p62 and drives HCC growth in vitro and in vivo . Pharmacologic inhibition of DHCR24 expression and acetylation with the US Food and Drug Administration (FDA)-approved drug irbesartan suppresses cell proliferation and reduces tumor burden in xenograft and carcinogen-induced mouse models. Reduced p62 expression parallels the antitumor effects. These findings define DHCR24 acetylation as a metabolic switch linking sterol synthesis to oncogenesis and highlight the DHCR24-7-ketocholesterol-p62 axis as a therapeutic target for HCC.
研究领域:
癌症生物学
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分子肿瘤学
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代谢调控
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肝脏病学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Jin-Xin Huang,Wei-Hua Zhang,Ye-Ming Wu,Jian-Yu Hu,Huan Long,Hai-Dong Zhu,Jian-Qiong Zhang,Gao-Jun Teng,Fei Xiong
Drug-eluting bead transcatheter arterial chemoembolization (D-TACE) is one of the first-line treatment for intermediate hepatocellular carcinoma (HCC). However, the dual hypoxia microenvironment, due to inherent tumor hypoxia and TACE-induced hypoxia, triggers drug resistance in HCC. To address this challenge, the study develops multicavitary microspheres capable of encapsulating oxygen and harnessing magnetic hyperthermia to enhance oxygen permeability. The novel multicavitary oxygen-encapsulated magnetothermal drug-eluting microspheres (OTD-Ms) effectively reduce hypoxia-related proteins (HIF-1α, VEGF-A) and drug resistance (P-gp) both in vitro and in vivo. Moreover, these microspheres demonstrate improved TACE efficacy and enhance survival rates in a rabbit VX-2 tumor model, suggesting their potential for HCC treatment.
研究领域:
肿瘤学
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介入放射学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Xin Yang,Guang-Yuan Ma,Xiao-Qiang Li,Na Tang,Yang Sun,Xiao-Wei Hao,Ke-Han Wu,Yu-Bo Wang,Wen Tian,Xin Fan,Zezhi Li,Caixia Feng,Xu Chao,Yu-Fan Wang,Yao Liu,Di Li,Wei Cao
Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of ALDOA strikingly decreased HCC development in vivo . Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.
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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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2025
·Vol. 192
·期 8
·1-17
·
IF 5.3
Liang Jintao,Li Canru,Zhou Yu,Fan Lingling,Liu Lin,Liang Jianlu,Tan Xiaohong,Zhou Zhide,Li Guiyin
Golgi protein 73 (GP73) is highly expressed in hepatocellular carcinoma (HCC) and considered a sensitive serum biomarker for HCC diagnosis. Herein, a label-free electrochemical aptasensor for ultrasensitive detection GP73 based on nitrogen-doped reduced graphene oxide-ferrocene-platinum@palladium nanoparticles (NRGO-Fc-Pt@Pd NPs) was constructed. The NRGO-Fc-Pt@Pd NPs offered excellent conductivity, biocompatibility, and large surface area, serving as both an electrode modifier and a redox probe due to Fc's good electroactivity. GP73 aptamer (GP73 Apt ) was covalently bound with the NRGO-Fc-Pt@Pd NPs to form the signal probe. When GP73 specifically bound to GP73 Apt to form GP73-GP73 Apt complex and fell off from the electrode, it leads to an increased Fc(Fe(II)/Fe(III)) peak current in differential pulse voltammetry (DPV) due to the enhancing of the sensing interface's electroactivity. Under optimized conditions, the label-free electrochemical aptasensor demonstrated a linear relationship with GP73 concentration in the range 1.0 ng/mL-300 ng/mL, with R 2 of 0.99594 and a limit of detection (LOD) of 0.3524 ng/mL. In addition, the aptasensor showed good specificity, reproducibility, and stability. Furthermore, the developed aptasensor was applied to detect the GP73 in actual serum samples with good recoveries (97.85%-107.48%) and relative standard deviations (RSDs) (0.37%–7.85%) via the spiked recovery method. All the results may provide a new approach for HCC clinical detection. Graphical
研究领域:
生物医学工程
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肿瘤学
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分析化学
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纳米材料
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2018
·Vol. 365
·期 2
·398-407
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IF 3.706
Jie Gao,Zhao Wang,Gao-Ju Wang,Hong-Xin Zhang,Na Gao,Jie Wang,Cai-E. Wang,Zhao Chang,Yan Fang,Yun-Fei Zhang,Jun Zhou,Han Jin,Hai-Ling Qiao
Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.
研究领域:
肿瘤学
·
药理学
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毒理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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