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Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells

Hepatobiliary & Pancreatic Diseases International 2020年第6期19卷 547-554页

作者： Yi-Ting Hu Zhe-Yue Shu Jing-Hua Jiang Qin-Fen Xie Shu-Sen Zheng Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalZhejiang Shuren UniversityShulan International Medical CollegeHangzhou 310022China Division of Hepatobiliary Pancreatic Surgery First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Jinhua Municipal Central HospitalJinhua 321000China

Background:sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma(HCC).However,resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of *** the activation of AKT/mTOR played a pivotal role in sorafenib resistance,we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC ***:The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell *** synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay *** induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western ***:sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells,which underscores the significance of AKT ***2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis ***2 successfully suppressed the sorafenib-activated mTORC2-AKT axis,leading to the dephosphorylation of Ser136 in BAD protein,and increased the expression of total BAD,which contributed to the apoptosis in sorafenibresistant HCC ***:In this study,Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenibresistant HCC cells,via the suppression of mTORC2-AKT-BAD *** results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.

关键词： Torin2 sorafenib resistance Hepatocellular carcinoma mTORC2-AKT-BAD pathway

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Microvesicles:the functional mediators in sorafenib resistance

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Cancer Drug resistance 2022年第3期5卷 749-761页

作者： Cong He Doulathunnisa Jaffar Ali Bo Sun Bei-Cheng Sun Zhong-Dang Xiao State Key Laboratory of Bioelectronics School of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096JiangsuChina Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008JiangsuChina

Overcoming drug resistance in cancer therapies remains challenging,and the tumor microenvironment plays an important part in ***(MVs)are functional natural carriers of cellular information,participate in intercellular communication,and dynamically regulate the tumor *** contribute to drug resistance by transferring functional molecules between ***,due to their specific cell or tissue targeting ability,MVs are considered as carriers for therapeutic molecules to reverse drug ***,in this mini-review,we aim to highlight the crucial role of MVs in cell-to-cell communication and therefore their diverse impact mainly on liver cancer progression and *** addition,we summarize the possible mechanisms for sorafenib resistance(one of the main hurdles in hepatocellular carcinoma treatments)and recent advances in using MVs to reverse sorafenib resistance in liver cancer *** the functional role of MVs in cancer therapy might provide a new aspect for developing precise novel therapeutics in the future.

关键词： Microvesicles(MVs) sorafenib resistance tumor microenvironment cancer therapy

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Silencing MFN2 Drives WNT/β-catenin Nucleation to Reduce sorafenib Sensitivity in Hepatocellular Carcinoma Cells

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Current Medical Science 2024年第4期44卷 789-798页

作者： Chai-ming ZENG Bin SHAO Yan-ping CHEN Gui-sheng DING Department of Geriatric Medicine Shengli Clinical Medical College of Fujian Medical UniversityFujian Key Laboratory of Geriatrics DiseasesFujian Provincial Center for GeriatricsFujian Provincial HospitalFuzhou350001China Department of Rehabilitation Shengli Clinical Medical College of Fujian Medical UniversityFujian Provincial HospitalFuzhou350001China Department of Gynecology Shengli Clinical Medical College of Fujian Medical UniversityFujian Provincial HospitalFuzhou350001China Department of Ultrasonography Shengli Clinical Medical College of Fujian Medical UniversityFujian Provincial HospitalFuzhou350001China

Objective Mitofusin-2(MFN2)is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular *** further elucidate the impact of MFN2,this study aimed to investigate its significance on hepatocellular carcinoma(HCC)cell function and its potential role in mediating *** This study investigated the effects of silencing and overexpressing MFN2 on the survival,proliferation,invasion and migration abilities,and sorafenib resistance of MHCC97-L HCC *** experiments were conducted using XAV939(aβ-catenin inhibitor)and HLY78(aβ-catenin activator)to further validate these *** Silencing MFN2 significantly promoted the survival and proliferation of MHCC97-L cells,enhanced their invasion and migration capacities,increased the IC50 of sorafenib,reduced the percentage of TUNEL-positive cells,and decreased the expression of proapoptotic ***,silencing MFN2 markedly induced the nuclear translocation ofβ-catenin,increasedβ-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail1 and Vimentin while inhibiting E-cadherin ***,overexpressing MFN2 reversed the effects observed in MHCC97-L cells mentioned *** results confirmed that silencing MFN2 activated theβ-catenin/epithelial-mesenchymal transition(EMT)pathway and reduced the sensitivity of cells to sorafenib,which could be reversed by XAV939 ***,overexpression of MFN2 inhibited theβ-catenin/EMT pathway and increased the sensitivity of cells to sorafenib,which could be altered by *** Low expression of MFN2 in HCC cells promotes the nuclear translocation ofβ-catenin,thereby activating the EMT pathway and mediating resistance to sorafenib.

关键词： mitofusin-2 epithelial-mesenchymal transition sorafenib resistance apoptosis hepatocellular carcinoma

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Overexpression of RBM34 Promotes Tumor Progression and Correlates with Poor Prognosis of Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2023年第2期11卷 369-381页

作者： Wei Wang Rui Zhang Ning Feng Longzhen Zhang Nianli Liu Cancer Institute Xuzhou Medical UniversityXuzhouJiangsuChina Center of Clinical Oncology Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina Department of Radiation Oncology Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina

Background and Aims:Emerging evidence suggests that RNA-binding motif(RBM)proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor *** objective of this study was to investigate the role of RBM34,an RBM protein,in hepatocellular carcinoma(HCC).Methods:We first examined the expression of RBM34 across *** correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then *** enrichment analysis of RBM34-related differentially expressed genes(DEGs)was performed to explore its biological *** sequencing(RNA-seq)was applied to identify downstream genes and pathways affected upon RBM34 *** correlation of RBM34 with immune characteristics was also *** oncogenic function of RBM34 was examined in in vitro and in vivo ***:RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and ***34 was positively associated with tumor immune cell infiltration,biomarkers of immune cells,and immune checkpoint expression.A positive correlation was also observed between RBM34,T cell exhaustion,and regulatory T cell marker *** of RBM34 significantly inhibited cell proliferation,migration,and xenograft tumor growth,and sensitized HCC cells to sorafenib ***34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC ***:Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

关键词： RBM34 Hepatocellular carcinoma Oncogene sorafenib resistance Immune infiltration

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A biomimetic liver cancer on-a-chip reveals a critical role of LIPOCALIN-2 in promoting hepatocellular carcinoma progression

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4621-4637页

作者： Peiliang Shen Yuanyuan Jia Weijia Zhou Weiwei Zheng Yueyao Wu Suchen Qu Shiyu Du Siliang Wang Huilian Shi Jia Sun Xin Han Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of Medicine&Holistic Integrative MedicineJiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative MedicineNanjing University of Chinese MedicineNanjing 210023China Department of Pharmacy Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China Nanjing Medical Center for Clinical Pharmacy Nanjing 210008China Department of Infectious Diseases Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210023China

Hepatic stellate cells(HSCs)represent a significant component of hepatocellular carcinoma(HCC)microenvironments which play a critical role in tumor progression and drug ***-ona-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal *** we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC *** analysis revealed activated HSCs contributed to endothelial invasion,HCC drug resistance and natural killer(NK)cell *** array and RNA sequencing analysis were combined to indicate the iron-binding protein LIPOCALIN-2(LCN-2)as a key factor in remodeling tumor microenvironments in the ***-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model,including angiogenesis inhibition,sorafenib sensitivity promotion and NK-cell cytotoxicity *** together,the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.

关键词： HCC-on-a-chip model Hepatic stellate cells Tumor microenvironment Endothelial invasion sorafenib resistance NK cell Exhaustion LIPOCALIN-2 Personalized anti-cancer therapies

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CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment

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Bioactive Materials 2022年第11期7卷 147-161页

作者： Yuehua Wang Zhenjie Wang Fei Jia Qing Xu Zhilin Shu Junlin Deng Aimin Li Meng Yu Zhiqiang Yu Cancer Center Integrated Hospital of Traditional Chinese MedicineSouthern Medical University.Guangzhou510315PR China Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou510515PR China The People’s Hospital of Gaozhou Maoming525200PR China CAS Key Laboratory of Standardization and Measurement for Nanotechnology CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing100190PR China

Clinical sorafenib treatment could activate C-X-C receptor type 4(CXCR4)/stromal source factor-1α(SDF-1α)axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma(HCC),which further leads to progression,invasion,metastasis,and immunosuppression of tumors and in return causes resistance to sorafenib ***,a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane(PFH)-cored liposome,with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397(named PFH@LSLP)for sorafenib-resistant HCC *** PFH@LSLP was developed to overcome sorafenib resistance by syner-gistic effects of the following 3 roles:1)the O_(2)-saturated PFH core could alleviate the tumor hypoxia by O_(2) supply;2)the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib;3)PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs,further enhanced CD8^(+)T cell infiltration to reverse immunosuppression in *** performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft(PDX)model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation,resistance-related gene regulation,and immune-microenvironment modification.

关键词： Hepatocellular carcinoma sorafenib resistance Hypoxia relief Immunotherapy Tumor targeting regulation

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Radiomics signature:A potential biomarker forβ-arrestin1 phosphorylation prediction in hepatocellular carcinoma

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World Journal of Gastroenterology 2022年第14期28卷 1479-1493页

作者： Feng Che Qing Xu Qian Li Zi-Xing Huang Cai-Wei Yang Li Ye Wang Yi Wei Yu-Jun Shi Bin Song Department of Radiology West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina Institute of Clinical Pathology West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina Department of Research and Development Shanghai United Imaging Intelligence Co.LtdShanghai 200232China

BACKGROUND The phosphorylation status ofβ-arrestin1 influences its function as a signal strongly related to sorafenib *** retrospective study aimed to develop and validate radiomics-based models for predictingβ-arrestin1 phosphorylation in hepatocellular carcinoma(HCC)using whole-lesion radiomics and visual imaging features on preoperative contrast-enhanced computed tomography(CT)*** To develop and validate radiomics-based models for predictingβ-arrestin1 phosphorylation in HCC using radiomics with contrast-enhanced *** Ninety-nine HCC patients(training cohort:n=69;validation cohort:n=30)receiving systemic sorafenib treatment after surgery were enrolled in this retrospective ***-dimensional whole-lesion regions of interest were manually delineated along the tumor margins on portal venous CT *** features were generated and selected to build a radiomics score using logistic regression *** features were evaluated by two radiologists *** these features were combined to establish clinico-radiological(CR)and clinico-radiological-radiomics(CRR)models by using multivariable logistic regression *** diagnostic performance and clinical usefulness of the models were measured by receiver operating characteristic and decision curves,and the area under the curve(AUC)was *** association with prognosis was evaluated using the Kaplan-Meier *** Four radiomics features were selected to construct the radiomics *** the multivariate analysis,alanine aminotransferase level,tumor size and tumor margin on portal venous phase images were found to be significant independent factors for predictingβ-arrestin1 phosphorylation-positive HCC and were included in the CR *** CRR model integrating the radiomics score with clinico-radiological risk factors showed better discriminative performance(AUC=0.898,95%CI,0.820 to 0.977)than the CR model(AUC=0.794,95%CI,0.686 to 0.901;P=0.011),wit

关键词： Hepatocellular carcinoma sorafenib resistance β-Arrestin1 phosphorylation Radiomics Computed tomography Overall survival

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Physcion increases the sensitivity of hepatocellular carcinoma to sorafenib through miRNA-370/PIM1 axis-regulated glycolysis

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World Journal of Gastrointestinal Oncology 2023年第8期15卷 1400-1411页

作者： Xiao-Ping Pan Bu-Ren Jiya Feng Wang Zhu Lan Department of Interventional Radiology Inner Mongolia International Mongolian HospitalHohhot 016000Inner Mongolia Autonomous RegionChina Graduate School Inner Mongolia Medical UniversityHohhot 016000Inner Mongolia Autonomous RegionChina

BACKGROUND resistance to sorafenib has become a challenge in clinical treatment of hepatocellular carcinoma(HCC).Physcion is a common bioactive anthraquinone that has potential as an anticancer *** To study the effect of physcion on sensitizing HCC cells to *** sorafenib-resistant HCC cells were established and treated with sorafenib and/or *** cell viability,proliferation and apoptosis were measured by cell counting kit-8,colony formation,flow cytometry,and in vivo xenograft *** uptake,lactate acid production,extracellular acidification rate(ECAR),and oxygen consumption rate(OCR)were measured to analyze *** of glycolysis-related regulators was assessed by western *** The addition of physcion significantly enhanced the antitumor effects of sorafenib on sorafenib-resistant HCC cells,manifested by enhanced apoptosis and suppressed cell *** glucose uptake,lactate acid production,and ECAR were elevated,and OCR was suppressed by physcion *** level of PIM1 was elevated and miR-370 was suppressed in sorafenib-resistant HCC cells compared with the parental cells,which was suppressed by physcion *** of miR-370 notably reversed the effects of physcion on sorafenib-resistant HCC *** Our data indicated that physcion enhanced the sensitivity of HCC cells to sorafenib by enhancing miR-370 to suppress PIM1-promoted glycolysis.

关键词： Hepatocellular carcinoma sorafenib resistance Physcion Glycolysis PIM1

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LINC00662 affects the sensitivity of hepatocellular carcinoma cells to sorafenib drug by regulating miR-106a-5p/CAV1 axis

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Journal of Hainan Medical University 2023年第11期29卷 8-14页

作者： CHEN Bo‑cen LIANG Na YAN Dong‑jing CHEN Tong XIAO Man CAI Wang‑wei Key Laboratory of Biochemistry and Molecular Biology Hainan Medical UniversityHaikou 571199China

Objective:To investigate the mechanism of long non-coding RNA-LINC00662 on induction of sorafenib resistance in hepatocellular carcinoma(HCC)***:HCC cells(HepG2,HCCLM3),sorafenib-resistant hepatocellular carcinoma cells HCC-SR(HepG2-SR,HCCLM3-SR)were investigated by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)and Western blot was used to detect LINC00662,miR-106a-5p and cavitin-1(CAV1)expression in each group of cells.106a-5p and cavitin-1(CAV1)expression levels were measured by RT-qPCR and Western *** si-LINC00662 and miR-106a-5p mimics were transfected with HCC-SR cells,respectively,and cell sensitivity to sorafenib drug was detected by cell activity kit(CCK-8).And the targeting relationship between LINC00662 and miR-106a-5p,miR-106a-5p and CAV1 was further determined by dual luciferase reporter assay,RT-qPCR,and Western ***:The relative expression of LINC00662 and CAV1 was significantly increased and miR-106a-5p expression was significantly decreased in HCC-SR cells(Psorafenib drug(Presistance of sorafenib in HCC *** with LINC00662 expression can inhibit sorafenib resistance and increase sorafenib drug sensitivity in HCC cells.

关键词： LINC00662 Liver cancer sorafenib resistance miR-106a-5p CAV1

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Identification of novel immune ferroptosis-specific genes associated with prognostic features in hepatocellular carcinoma

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Cancer Advances 2023年第20期6卷 1-10页

作者： Xiao-Bin Fan Feng-Feng Song Wen-Xing Li Xian-Ying Fan Yan-Wei Hu Ming Li Hua Gao Yan-Jun Lian Department of General Surgery Xingtai Third HospitalXingtai 054099China The Second Division of General Surgery People's Hospital of BinzhouShandong 256600China Department of General Surgery The Second Hospital of Shanxi Medical UniversityShanxi 030001China Department of Thoracic Surgery Zhongshan Hospital of Fudan UniversityShanghai 200032China Cancer Center Zhongshan Hospital of Fudan UniversityShanghai 200032China Department of General Surgery The First Hospital of Xinjiang Medical UniversityXinjiang 830054China

Background:As the most common iron metabolism and storage organ,the specific regulatory mechanism and prognostic relevance of hepatocellular carcinoma(HCc)need further ***:We aimed to perform a multi-omics integration and a ferroptosis-associated signature of ***:Gene Expression Omnibus was searched for available data with ferroptosis inducers,and three independent datasets(GSE104462,GSE112384,and GSE142591)were ***-omic data with available clinical information of TCGA-LIHC and CHCC were retrieved from the Cancer Genome Atlas(TCGA,http://***/)and iProX database(***,IPx0000937000).Integrated multi-omics analyses revealed the difference among biological functions,the activation status of key signaling pathways,tumor microenvironment,and sorafenib resistance in ***-sample gene set enrichment analysis(ssGSEA)identified a novel panel associated with clinical and molecular attributes,including survival,immune microenvironment,sorafenib resistance,genetic profile,liver-specific proteome,and ***:We performed a multi-omics integrationfor ferroptosis-associated characterization of HCC using paired tumor and adjacent liver tissues from 370 samples of *** proposed a novel panel including twelve genes that could reflect the prognosis and capacity of ferroptosis(ATAD2,DTL,DUT,E2F2,GINS2,FOXK1,MCM4,MCM5,MTHFD1,PHF19,POLA1,THOC6).Samples with high ferroptosis prognostic scores suggested significantly inferior survival(P=0.0028),a lower degree of ferroptosis(P<0.001),and greater ferroptosis induction capacity(P<0.001).Conclusion:The score in our study revealed the inherent state and further potential of ferroptosis in tumor cells,which also distinct features in tumor metabolism,microenvironment,clinical phenotype,and potential therapeutics.

关键词： hepatocellular carcinoma ferroptosis multi-omics prognosis sorafenib resistance

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