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Di Maria S, Passannanti R, Poggialini F, Vagaggini C, Serafinelli A, Bianchi E, Governa P, Botta L, Maga G, Crespan E, Manetti F, Dreassi E, Musumeci F, Carbone A, Schenone S. Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in hepatocellular carcinoma. Eur J Med Chem 2024; 280:116929. [PMID: 39406114 DOI: 10.1016/j.ejmech.2024.116929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/10/2024] [Accepted: 09/29/2024] [Indexed: 11/25/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4-d]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the in-house pyrazolo[3,4-d]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, 7e showed an IC50 value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC50 = 2.47 μM). Furthermore, 7e exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that 7e deserves further investigation as a promising TKI in cancer therapies. Finally, 7e's ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed.
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Affiliation(s)
- Salvatore Di Maria
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Raffaele Passannanti
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Federica Poggialini
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Chiara Vagaggini
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Alessia Serafinelli
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Elena Bianchi
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy
| | - Paolo Governa
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Lorenzo Botta
- Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, I-53019, Castelnuovo Berardenga, Italy; Department of Ecological and Biological Sciences, University of Tuscia, Largo Dell'Universita Snc, I-01100, Viterbo, Italy
| | - Giovanni Maga
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy
| | - Emmanuele Crespan
- Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy
| | - Fabrizio Manetti
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, I-53019, Castelnuovo Berardenga, Italy
| | - Elena Dreassi
- Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy
| | - Francesca Musumeci
- Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132, Genoa, Italy.
| | - Anna Carbone
- Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132, Genoa, Italy.
| | - Silvia Schenone
- Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Largo Rosanna Benzi 10, 16132, Genoa, Italy
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Chen W, Zhang Z, Liu K, Jiang D, Sun X, Mao Y, Li S, Ye D. Circulating Copper and Liver Cancer. Biol Trace Elem Res 2023; 201:4649-4656. [PMID: 36633787 DOI: 10.1007/s12011-023-03554-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/02/2023] [Indexed: 01/13/2023]
Abstract
The association between circulating copper and the risk of liver cancer has been investigated by previous studies, while the findings were inconsistent. Thus, we aimed to evaluate the association between circulating copper and liver cancer by using meta-analysis and Mendelian randomization (MR). For meta-analysis, PubMed and Web of Science were searched to identify eligible studies published before April 4, 2022. Standardized mean difference (SMD) with 95% confidence interval (CI) in circulating copper level between liver cancer patients and controls were pooled. Furthermore, we selected genetic instruments for circulating copper from a genome-wide association study (GWAS) to conduct MR analysis. The summary statistics related to liver cancer were obtained from two large independent cohorts, UKBB and FinnGen, respectively. MR analysis was performed mainly by inverse-variance weighted (IVW) approach, followed by maximum-likelihood method as sensitivity analysis. In meta-analysis of eight studies, circulating copper was found to be higher in liver cancer patients (SMD: 1.65; 95% CI: 0.65 to 2.65) with high heterogeneity (I2 = 96.40%, P = 0.001). However, inconsistent findings were observed among subgroups with high evidence. In MR analysis, genetically predicted circulating copper was not significantly associated with the risk of liver cancer by IVW in UKBB (OR: 1.38; 95% CI: 0.72 to 2.65) and FinnGen (OR: 1.10; 95% CI: 0.69 to 1.73) separately, and the pooled results produced similar results (OR: 1.18, 95% CI: 0.81 to 1.72). Moreover, non-significant finding was confirmed by using maximum-likelihood method. There is no sufficient evidence to demonstrate that high levels of circulating copper increase the risks of liver cancer.
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Affiliation(s)
- Weiwei Chen
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China
| | - Zhiwei Zhang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Ke Liu
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China
| | - Die Jiang
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China
| | - Xiaohui Sun
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China
| | - Yingying Mao
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China.
| | - Ding Ye
- School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China.
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Demir AB, Baris E, Kaner UB, Alotaibi H, Atabey N, Koc A. Toll-interacting protein may affect doxorubicin resistance in hepatocellular carcinoma cell lines. Mol Biol Rep 2023; 50:8551-8563. [PMID: 37644370 DOI: 10.1007/s11033-023-08737-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Liver cancer is the third leading cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) is the most common type of liver cancer. Transarterial interventions are among the chemotherapeutic approaches used in hardly operable regions prior to transplantation, and in electrochemotherapy, where doxorubicin is used. However, the efficacy of treatment is affected by resistance mechanisms. Previously, we showed that overexpression of the CUE5 gene results in doxorubicin resistance in Saccharomyces cerevisiae (S. cerevisiae). In this study, the effect of Toll-interacting protein (TOLLIP), the human ortholog of CUE5, on doxorubicin resistance was evaluated in HCC cells to identify its possible role in increasing the efficacy of transarterial interventions. METHODS AND RESULTS The NIH Gene Expression Omnibus (GEO) and Oncomine datasets were analyzed for HCC cell lines with relatively low and high TOLLIP expression, and SNU449 and Hep3B cell lines were chosen, respectively. TOLLIP expression was increased by plasmid transfection and decreased by TOLLIP-siRNA in both cell lines and evaluated by RT-PCR and ELISA. Cell proliferation and viability were examined using xCELLigence and MTT assays after doxorubicin treatment, and growth inhibitory 50 (GI 50) concentrations were evaluated. Doxorubicin GI 50 concentrations decreased approximately 2-folds in both cell lines upon silencing TOLLIP after 48 h of drug treatment. CONCLUSIONS Our results showed for the first time that silencing TOLLIP in hepatocellular carcinoma cells may help sensitize these cells to doxorubicin and increase the efficacy of chemotherapeutic regimens where doxorubicin is used.
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Affiliation(s)
- Ayse Banu Demir
- Faculty of Medicine, Department of Medical Biology, Izmir University of Economics, Sakarya Street, No:156, Balcova, Izmir, 35330, Turkey.
| | - Elif Baris
- Faculty of Medicine, Department of Medical Pharmacology, Izmir University of Economics, Izmir, Turkey
| | - Umay Bengi Kaner
- Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
| | - Hani Alotaibi
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University Health Campus, Izmir, Turkey
- Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Nese Atabey
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Faculty of Medicine, Department of Medical Biology & Galen Research Center, Izmir Tinaztepe University, Izmir, Turkey
| | - Ahmet Koc
- Faculty of Medicine, Department of Medical Genetics, Inonu University, Malatya, Turkey
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Song J, Li H, Liu Y, Li X, Shi Q, Lei Q, Hu W, Huang S, Chen Z, He X. Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302425. [PMID: 37431681 PMCID: PMC10502857 DOI: 10.1002/advs.202302425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/16/2023] [Indexed: 07/12/2023]
Abstract
Aldolase A (ALDOA), a crucial glycolytic enzyme, is often aberrantly expressed in various types of cancer. Although ALDOA has been reported to play additional roles beyond its conventional enzymatic role, its nonmetabolic function and underlying mechanism in cancer progression remain elusive. Here, it is shown that ALDOA promotes liver cancer growth and metastasis by accelerating mRNA translation independent of its catalytic activity. Mechanistically, ALDOA interacted with insulin- like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to facilitate its binding to m6 A-modified eIF4G mRNA, thereby increasing eIF4G protein levels and subsequently enhancing overall protein biosynthesis in cells. Importantly, administration of GalNAc-conjugated siRNA targeting ALDOA effectively slows the tumor growth of orthotopic xenografts. Collectively, these findings uncover a previously unappreciated nonmetabolic function of ALDOA in modulating mRNA translation and highlight the potential of specifically targeting ALDOA as a prospective therapeutic strategy in liver cancer.
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Affiliation(s)
- Junjiao Song
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Hongquan Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Yanfang Liu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Xinrong Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Qili Shi
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Qun‐Ying Lei
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Weiguo Hu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Shenglin Huang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Zhiao Chen
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
- Key Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CenterFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Radiation OncologyFudan University Shanghai Cancer CenterFudan UniversityShanghai200032China
| | - Xianghuo He
- Fudan University Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
- Key Laboratory of Breast Cancer in ShanghaiFudan University Shanghai Cancer CenterFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Radiation OncologyFudan University Shanghai Cancer CenterFudan UniversityShanghai200032China
- Collaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing211166China
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Wu Y, Ou S, Liao X, Han C, Yang C, Qin W, Tan Y, Lao Q, Peng T, Ye X. Massive Hepatocellular Carcinoma with Situs Inversus Totalis Achieved a Complete Response Following Camrelizumab Plus Apatinib and Combined with Two-Stage Hepatectomy: A Case Report. Pharmgenomics Pers Med 2023; 16:111-120. [PMID: 36785780 PMCID: PMC9921441 DOI: 10.2147/pgpm.s376596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 11/18/2022] [Indexed: 02/10/2023] Open
Abstract
Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Two-stage hepatectomy (TSH) combined with translational therapy for hepatocellular carcinoma (HCC) with SIT has been rarely reported. We report a 41-year-old man with giant hepatocellular carcinoma (71 mm × 55 mm × 51 mm) whose future residual liver (FLR) and standard liver volume (SLV) ratio at first diagnosis was 37.4%. Preoperative volume assessment of portal vein ligation (PVL) revealed inadequate hypertrophy of FLR. After a multidisciplinary group discussion (MDT), the patient decided to follow conversion therapy. Three months later, ratio of the FLR/SLV increased from 37.4% to 71% after operation, which met the surgical requirements. Second hepatectomy, right lobectomy was successful. There was no recurrence after six months of follow-up. In our case, conversion therapy appears to be effective in maintaining residual liver hyperplasia, reducing tumor load, and preventing tumor progression in patients with large HCC during TSH.
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Affiliation(s)
- Yining Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Shenjian Ou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Yufeng Tan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Quan Lao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
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Poor Prognostic Biomarker KIAA1522 Is Associated with Immune Infiltrates in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2023; 2023:3538928. [PMID: 36761433 PMCID: PMC9904920 DOI: 10.1155/2023/3538928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/24/2022] [Accepted: 08/30/2022] [Indexed: 02/04/2023]
Abstract
Background The prognosis is poor for hepatocellular carcinoma (HCC), a tumor and cancer associated with inflammation that is common. New data showed that significant levels of KIAA1522 were expressed in HCC tissues and cell lines, suggesting that KIAA1522 may be a highly useful prognostic marker for HCC. However, its biochemical processes and impacts on the immune system go deeper. Objective To verify the significance of KIAA1522 in HCC and investigate its related carcinogenic mechanisms. Methods Studies examining the relationship between KIAA1522 expression and clinical-pathologic characteristics in HCC have been checked in the Cancer Genome Atlas (TCGA) database. A receiver operating characteristic (ROC) curve was used to assess the diagnostic efficacy of KIAA1522 in HCC. Western blot analysis was used to find the presence of the KIAA1522 protein in the tumor and paraneoplastic tissues of eight randomly chosen HCC patients. The GSVA program in R language was used to evaluate the relationship between KIAA1522 and immune cell infiltration in HCC. We searched the Search Tool for the Retrieval of Interacting Genes (STRING) database for interacting proteins connected to the expression of KIAA1522. Pathways were involved in the enrichment analysis of KIAA1522 to anticipate potential mechanisms through which KIAA1522 may affect immunological infiltration. Results Our study found that KIAA1522 was commonly elevated in HCC tumor tissues and that it also signaled a bad outcome. We found an inverse link between KIAA1522 and cytotoxic cells and an inverse relationship between KIAA1522 and Th2 cell infiltration. In STRING analysis, the top 5 coexpressed proteins of KIAA1522 were BAIAP2, NCK2, TSNAXIP1, POGK, and KLHL31. The effect of KIAA1522 on HCC may entail cell cycle alteration, an immunological response, and suppression of the PPAR signaling pathway. Conclusion High expression of KIAA1522 was linked to HCC immune cell infiltration, disease progression, and a poor prognosis.
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Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121803. [PMID: 36557005 PMCID: PMC9785216 DOI: 10.3390/medicina58121803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.
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Radu ER, Semenescu A, Voicu SI. Recent Advances in Stimuli-Responsive Doxorubicin Delivery Systems for Liver Cancer Therapy. Polymers (Basel) 2022; 14:5249. [PMID: 36501642 PMCID: PMC9738136 DOI: 10.3390/polym14235249] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems' responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy.
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Affiliation(s)
- Elena Ruxandra Radu
- Department of Analytical Chemistry and Environmental Engineering, University Politehnica of Bucharest, 011061 Bucharest, Romania
- Advanced Polymers Materials Group, University Politehnica of Bucharest, 011061 Bucharest, Romania
| | - Augustin Semenescu
- Faculty of Materials Science, University Politehnica of Bucharest, Splaiul Independentei 313, 060042 Bucharest, Romania
- Academy of Romanian Scientists, Splaiul Independentei 54, 030167 Bucharest, Romania
| | - Stefan Ioan Voicu
- Department of Analytical Chemistry and Environmental Engineering, University Politehnica of Bucharest, 011061 Bucharest, Romania
- Advanced Polymers Materials Group, University Politehnica of Bucharest, 011061 Bucharest, Romania
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Alshammari GM. Cytotoxic effects of Lavandula angustifolia seed extracts on the viability of Huh-7 and Chang liver cells. PLoS One 2022; 17:e0267499. [PMID: 35446915 PMCID: PMC9022791 DOI: 10.1371/journal.pone.0267499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/08/2022] [Indexed: 11/18/2022] Open
Abstract
Flowering plants are valuable in numerous ways, including food/feed supply for living organisms, fuel production, and medicinal uses. Several plant extracts/products are used to treat variety of serious ailments in human and animals. Lavandula angustifolia is a flowering plant that possesses anti-inflammatory and anti-depressive medicinal properties. Cancer is a deadly disorder affecting millions of people globally. It affects several human organs, including liver, stomach, and lungs. Several researchers are doing efforts to eliminate the disease around the globe. In this study, Chang and Huh-7 liver cell lines were utilized as human normal hepatocyte model and innovation to mimic the liver environment. Cytotoxicity of L. angustifolia seed extracts was investigated at two different concentrations (50% and 100%) against Chang and Huh-7 liver cell lines by colorimetric assay which is used to assess cell metabolic activities. The Chang and Huh-7 liver cell lines were treated with L. angustifolia seeds extracts (50% and 100%) and incubated for 24 and 48 hours under standard conditions (37°C, 5% CO2). The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay was employed to quantify cell survival. Seed extracts of L. angustifolia exerted varied cytotoxic effects depending on the concentration and treatment duration. The results indicated that L. angustifolia seed extracts with 100% concentration exhibited the highest cytotoxicity against Huh-7 and Chang liver cell lines. In conclusion, L. angustifolia seed extracts exhibited cytotoxic activity which can be enhanced based on the concentration and treatment duration. The findings of the current study are critical for the development of novel herbal-based therapies for fatal disorders such as liver cancer. However, more investigations are required to reveal cytotoxicity mechanisms of L. angustifolia seed extracts.
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Affiliation(s)
- Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia
- * E-mail:
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Wang W, Wang F, Chen Q, Ouyang S, Iwamoto Y, Han X, Lin L, Hu H, Tong R, Chen YW. Phase Attention Model for Prediction of Early Recurrence of Hepatocellular Carcinoma With Multi-Phase CT Images and Clinical Data. FRONTIERS IN RADIOLOGY 2022; 2:856460. [PMID: 37492657 PMCID: PMC10365106 DOI: 10.3389/fradi.2022.856460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/24/2022] [Indexed: 07/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer that produces a high mortality rate. It is one of the most common malignancies worldwide, especially in Asia, Africa, and southern Europe. Although surgical resection is an effective treatment, patients with HCC are at risk of recurrence after surgery. Preoperative early recurrence prediction for patients with liver cancer can help physicians develop treatment plans and will enable physicians to guide patients in postoperative follow-up. However, the conventional clinical data based methods ignore the imaging information of patients. Certain studies have used radiomic models for early recurrence prediction in HCC patients with good results, and the medical images of patients have been shown to be effective in predicting the recurrence of HCC. In recent years, deep learning models have demonstrated the potential to outperform the radiomics-based models. In this paper, we propose a prediction model based on deep learning that contains intra-phase attention and inter-phase attention. Intra-phase attention focuses on important information of different channels and space in the same phase, whereas inter-phase attention focuses on important information between different phases. We also propose a fusion model to combine the image features with clinical data. Our experiment results prove that our fusion model has superior performance over the models that use clinical data only or the CT image only. Our model achieved a prediction accuracy of 81.2%, and the area under the curve was 0.869.
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Affiliation(s)
- Weibin Wang
- Graduate School of Information Science and Engineering, Ritsumeikan University, Kusatsu, Japan
| | - Fang Wang
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Qingqing Chen
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Shuyi Ouyang
- College of Computer Science and Technology, Zhejiang University, Hangzhou, China
| | - Yutaro Iwamoto
- Graduate School of Information Science and Engineering, Ritsumeikan University, Kusatsu, Japan
| | - Xianhua Han
- Graduate School of Information Science and Engineering, Yamaguchi University, Yamaguchi-shi, Japan
| | - Lanfen Lin
- College of Computer Science and Technology, Zhejiang University, Hangzhou, China
| | - Hongjie Hu
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Ruofeng Tong
- College of Computer Science and Technology, Zhejiang University, Hangzhou, China
- Zhejiang Lab, Research Center for Healthcare Data Science, Hangzhou, China
| | - Yen-Wei Chen
- Graduate School of Information Science and Engineering, Ritsumeikan University, Kusatsu, Japan
- College of Computer Science and Technology, Zhejiang University, Hangzhou, China
- Zhejiang Lab, Research Center for Healthcare Data Science, Hangzhou, China
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11
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Yttrium-90 radioembolization for unresectable hepatocellular carcinoma: predictive modeling strategies to anticipate tumor response and improve patient selection. Eur Radiol 2022; 32:4687-4698. [PMID: 35230518 PMCID: PMC9213379 DOI: 10.1007/s00330-022-08585-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 12/24/2022]
Abstract
Objectives This study aims to better characterize potential responders of Y-90-radioembolization at baseline through analysis of clinical variables and contrast enhanced (CE) MRI tumor volumetry in order to adjust therapeutic regimens early on and to improve treatment outcomes. Methods Fifty-eight HCC patients who underwent Y-90-radioembolization at our center between 10/2008 and 02/2017 were retrospectively included. Pre- and post-treatment target lesion volumes were measured as total tumor volume (TTV) and enhancing tumor volume (ETV). Survival analysis was performed with Cox regression models to evaluate 65% ETV reduction as surrogate endpoint for treatment efficacy. Univariable and multivariable logistic regression analyses were used to evaluate the combination of baseline clinical variables and tumor volumetry as predictors of ≥ 65% ETV reduction. Results Mean patients’ age was 66 (SD 8.7) years, and 12 were female (21%). Sixty-seven percent of patients suffered from liver cirrhosis. Median survival was 11 months. A threshold of ≥ 65% in ETV reduction allowed for a significant (p = 0.04) separation of the survival curves with a median survival of 11 months in non-responders and 17 months in responders. Administered activity per tumor volume did predict neither survival nor ETV reduction. A baseline ETV/TTV ratio greater than 50% was the most important predictor of arterial devascularization (odds ratio 6.3) in a statistically significant (p = 0.001) multivariable logistic regression model. The effect size was strong with a Cohen’s f of 0.89. Conclusion We present a novel approach to identify promising candidates for Y-90 radioembolization at pre-treatment baseline MRI using tumor volumetry and clinical baseline variables. Key Points • A decrease of 65% enhancing tumor volume (ETV) on follow-up imaging 2–3 months after Y-90 radioembolization of HCC enables the early prediction of significantly improved median overall survival (11 months vs. 17 months, p = 0.04). • Said decrease in vascularization is predictable at baseline: an ETV greater than 50% is the most important variable in a multivariable logistic regression model that predicts responders at a high level of significance (p = 0.001) with an area under the curve of 87%. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-022-08585-x.
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12
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Ding L, Zhang P, Huang X, Yang K, Liu X, Yu Z. Intracellular Reduction-Responsive Molecular Targeted Nanomedicine for Hepatocellular Carcinoma Therapy. Front Pharmacol 2022; 12:809125. [PMID: 35082681 PMCID: PMC8784786 DOI: 10.3389/fphar.2021.809125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/30/2021] [Indexed: 01/20/2023] Open
Abstract
The stimuli-responsive polymer-based platform for controlled drug delivery has gained increasing attention in treating hepatocellular carcinoma (HCC) owing to the fascinating biocompatibility and biodegradability, improved antitumor efficacy, and negligible side effects recently. Herein, a disulfide bond-contained polypeptide nanogel, methoxy poly(ethylene glycol)-poly(l-phenylalanine-co-l-cystine) [mPEG-P(LP-co-LC)] nanogel, which could be responsive to the intracellular reduction microenvironments, was developed to deliver lenvatinib (LEN), an inhibitor of multiple receptor tyrosine kinases, for HCC therapy. The lenvatinib-loaded nanogel (NG/LEN) displayed concise drug delivery under the stimulus of glutathione in the cancer cells. Furthermore, the intracellular reduction-responsive nanomedicine NG/LEN showed excellent antitumor effect and almost no side effects toward both subcutaneous and orthotopic HCC tumor-allografted mice in comparison to free drug. The excellent tumor-inhibition efficacy with negligible side effects demonstrated the potential of NG/LEN for clinical molecular targeted therapy of gastrointestinal carcinoma in the future.
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Affiliation(s)
- Lei Ding
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xu Huang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Kunmeng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xingkai Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Zhenxiang Yu
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
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Liu F, Zhu XT, Li Y, Wang CJ, Fu JL, Hui J, Xiao Y, Liu L, Yan R, Li XF, Liu Y. Magnesium demethylcantharidate inhibits hepatocellular carcinoma cell invasion and metastasis via activation transcription factor FOXO1. Eur J Pharmacol 2021; 911:174558. [PMID: 34634308 DOI: 10.1016/j.ejphar.2021.174558] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/30/2021] [Accepted: 10/06/2021] [Indexed: 11/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, develops rapidly and has a high mortality rate. Relapsed metastasis is the most important factor affecting prognosis and is also the main cause of death for patients with HCC. Cantharidin is a kind of folk medicine for malignant tumors in China. Because of its cytotoxicity, the application of cantharidin is very limited. Magnesium demethylcantharidate (MDC) is a derivative of cantharidin independently developed by our laboratory. Our results show that MDC has anticancer activity and exhibited lower toxicity than cantharidin. However, whether MDC affects the invasion and metastasis of HCC cells and the underlying molecular mechanisms remain obscure. Transwell and Matrigel assays showed that MDC could effectively inhibit the invasion and metastasis of the HCC cell lines SMMC-7721 and SK-Hep1 in a dose-dependent manner. Moreover, MDC significantly inhibited the expression of invasion and metastasis related proteins MMP-2 and MMP-9. In addition, our study found that MDC inhibited the invasion and metastasis of HCC cell lines SMMC-7721 and SK-Hep1 by activating transcription factor FOXO1. Interestingly, the combination of MDC and sorafenib significantly inhibited the invasion and metastasis of HCC cell lines SMMC-7721 and SK-Hep1 compared with the single drug treatment via the activated transcription factor FOXO1. Our work revealed that MDC obviously inhibited the invasion and metastasis of HCC cells, and suggested that MDC could be a potential candidate molecule against the invasion and metastasis of HCC.
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Affiliation(s)
- Fang Liu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Xin-Ting Zhu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China; Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China
| | - Yi Li
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Chen-Jing Wang
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Jia-Li Fu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Jing Hui
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China; Life Sciences Institute, Zunyi Medical University, Zunyi, 563000, China
| | - Yi Xiao
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China; Life Sciences Institute, Zunyi Medical University, Zunyi, 563000, China
| | - Liu Liu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Rong Yan
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Xiao-Fei Li
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China
| | - Yun Liu
- College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China; Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi, 563000, China; Life Sciences Institute, Zunyi Medical University, Zunyi, 563000, China.
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Kurhe Y, Caputo M, Cansby E, Xia Y, Kumari S, Anand SK, Howell BW, Marschall HU, Mahlapuu M. Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic Pathways. Cell Mol Gastroenterol Hepatol 2021; 13:405-423. [PMID: 34624527 PMCID: PMC8688184 DOI: 10.1016/j.jcmgh.2021.09.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, nonalcoholic steatohepatitis (NASH) has been recognized as a major catalyst for HCC. Thus, additional research is critically needed to identify mechanisms involved in NASH-induced hepatocarcinogenesis, to advance the prevention and treatment of NASH-driven HCC. Because the sterile 20-type kinase serine/threonine kinase 25 (STK25) exacerbates NASH-related phenotypes, we investigated its role in HCC development and aggravation in this study. METHODS Hepatocarcinogenesis was induced in the context of NASH in Stk25 knockout and wild-type mice by combining chemical procarcinogens and a dietary challenge. In the first cohort, a single injection of diethylnitrosamine was combined with a high-fat diet-feeding. In the second cohort, chronic administration of carbon tetrachloride was combined with a choline-deficient L-amino-acid-defined diet. To study the cell-autonomous mode of action of STK25, we silenced this target in the human hepatocarcinoma cell line HepG2 by small interfering RNA. RESULTS In both mouse models of NASH-driven HCC, the livers from Stk25-/- mice showed a markedly lower tumor burden compared with wild-type controls. We also found that genetic depletion of STK25 in mice suppressed liver tumor growth through reduced hepatocellular apoptosis and decreased compensatory proliferation, by a mechanism that involves protection against hepatic lipotoxicity and inactivation of STAT3, ERK1/2, and p38 signaling. Consistently, silencing of STK25 suppressed proliferation, apoptosis, migration, and invasion in HepG2 cells, which was accompanied by lower expression of the markers of epithelial-mesenchymal transition and autophagic flux. CONCLUSIONS This study provides evidence that antagonizing STK25 signaling hinders the development of NASH-related HCC and provides an impetus for further analysis of STK25 as a therapeutic target for NASH-induced HCC treatment in human beings.
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Affiliation(s)
- Yeshwant Kurhe
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mara Caputo
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Emmelie Cansby
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ying Xia
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sima Kumari
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sumit Kumar Anand
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Brian W Howell
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Margit Mahlapuu
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
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Alrfooh A, Patel A, Laroia S. Transarterial Radioembolization Agents: a Review of the Radionuclide Agents and the Carriers. Nucl Med Mol Imaging 2021; 55:162-172. [PMID: 34422126 PMCID: PMC8322227 DOI: 10.1007/s13139-021-00709-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/16/2021] [Accepted: 06/29/2021] [Indexed: 11/30/2022] Open
Abstract
Liver tumors, both primary and secondary to metastatic disease, remain a major challenge, with an increasing incidence. In this context, taking advantage of the dual blood supply of the liver, and the fact that liver tumors derive majority of their blood supply from the hepatic artery, intraarterial therapies are gaining popularity. Intraarterial liver-directed therapy (IALDT) is the option when the surgery is not feasible due to the number of metastases or for other reasons. Transarterial radioembolization (TARE) is a specific type of IALDT, where a carrier particle/microsphere is labeled with a radioactive substance and then is injected into hepatic artery for therapeutic purposes. As this field is rapidly evolving, with multiple agents being investigated and being introduced into clinical practice, it is hard for the practitioners and researchers to encompass all the available information concisely. This article aims to present a comprehensive review of the prominent TARE technologies.
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Affiliation(s)
- Aysheh Alrfooh
- University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA
| | - Aditi Patel
- Department of Radiology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA
| | - Sandeep Laroia
- Department of Radiology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA
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16
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Kim H, Lee JY, Park SJ, Kwag E, Koo O, Shin JH. ZNF746/PARIS promotes the occurrence of hepatocellular carcinoma. Biochem Biophys Res Commun 2021; 563:98-104. [PMID: 34062393 DOI: 10.1016/j.bbrc.2021.05.051] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/16/2021] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer to cause liver cancer related deaths worldwide. Zinc finger protein 746 (ZNF746), initially identified as a Parkin-interacting substrate (PARIS), acts as a transcriptional repressor of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in Parkinson's disease. As recent studies reported that PARIS is associated with cancer onset, we investigated whether PARIS is associated with HCC. We found an increase in insoluble parkin and PARIS accumulation in the liver of diethylnitrosamine (DEN)-injected mice, leading to the downregulation of PGC-1α and nuclear respiratory factor 1 (NRF1). Interestingly, the occurrence of DEN-induced tumors was significantly alleviated in the livers of DEN-injected PARIS knockout mice compared to DEN-injected wild-type mice, suggesting that PARIS is involved in DEN-induced hepatocellular tumorigenesis. Moreover, H2O2-treated Chang liver cells showed accumulation of PARIS and downregulation of PGC-1α and NRF1. Thus, these results suggest that PARIS upregulation by oncogenic stresses can promote cancer progression by suppressing the transcriptional level of PGC-1α, and the modulation of PARIS can be a promising therapeutic target for HCC.
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Affiliation(s)
- Hanna Kim
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
| | - Ji-Yeong Lee
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
| | - Soo Jeong Park
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
| | - Eunsang Kwag
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
| | - Okjae Koo
- Laboratory Animal Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea
| | - Joo-Ho Shin
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, South Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 06351, South Korea.
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Munakarmi S, Shrestha J, Shin HB, Lee GH, Jeong YJ. 3,3'-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells 2021; 10:cells10051178. [PMID: 34066056 PMCID: PMC8151225 DOI: 10.3390/cells10051178] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR.
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Affiliation(s)
- Suvesh Munakarmi
- Laboratory of Liver Regeneration, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Juna Shrestha
- Alka Hospital Private Limited, Jwalakhel, Kathmandu 446010, Nepal;
| | - Hyun-Beak Shin
- Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Geum-Hwa Lee
- Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Yeon-Jun Jeong
- Laboratory of Liver Regeneration, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea;
- Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea;
- Correspondence:
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Schaller E, Ma A, Gosch LC, Klefenz A, Schaller D, Goehringer N, Kaps L, Schuppan D, Volkamer A, Schobert R, Biersack B, Nitzsche B, Höpfner M. New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells. Int J Mol Sci 2021; 22:2243. [PMID: 33668139 PMCID: PMC7956560 DOI: 10.3390/ijms22052243] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 12/12/2022] Open
Abstract
New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.
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Affiliation(s)
- Eva Schaller
- Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany; (E.S.); (R.S.)
| | - Andi Ma
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (A.M.); (L.C.G.); (N.G.); (B.N.); (M.H.)
| | - Lisa Chiara Gosch
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (A.M.); (L.C.G.); (N.G.); (B.N.); (M.H.)
- In Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (D.S.); (A.V.)
| | - Adrian Klefenz
- Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; (A.K.); (L.K.); (D.S.)
| | - David Schaller
- In Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (D.S.); (A.V.)
| | - Nils Goehringer
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (A.M.); (L.C.G.); (N.G.); (B.N.); (M.H.)
| | - Leonard Kaps
- Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; (A.K.); (L.K.); (D.S.)
| | - Detlef Schuppan
- Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; (A.K.); (L.K.); (D.S.)
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
| | - Andrea Volkamer
- In Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (D.S.); (A.V.)
| | - Rainer Schobert
- Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany; (E.S.); (R.S.)
| | - Bernhard Biersack
- Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany; (E.S.); (R.S.)
| | - Bianca Nitzsche
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (A.M.); (L.C.G.); (N.G.); (B.N.); (M.H.)
| | - Michael Höpfner
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (A.M.); (L.C.G.); (N.G.); (B.N.); (M.H.)
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Fang Z, Wu L, Dai H, Hu P, Wang B, Han Q, Xu Y, Lv S, Zhu Y, Gan M, Zhou W, Zhang W. The role of vesicular overexpressed in cancer pro-survival protein 1 in hepatocellular carcinoma proliferation. Cancer Biomark 2021; 28:9-20. [PMID: 32083568 DOI: 10.3233/cbm-190574] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recently, hepatocellular carcinoma (HCC) has been ranked as the second leading cause of cancer-associated death. However, the underlying molecular mechanisms of HCC progression remain unclear. Vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) could be upregulated in a quantity of human cancers, including squamous cell carcinoma (SCC), gastric cancer, and glioblastoma. However, the precise functional mechanism of VOPP1 in HCC remains poorly understood. The present study aimed to investigate the role of VOPP1 in HCC proliferation. METHODS Immunohistochemistry (IHC), Western blot and Reverse-transcription polymerase chain reaction (RT-PCR) were used to analyze the protein and mRNA expressions of VOPP1, mitogen-activated protein kinase (MAPK) 14, ribosomal protein S6 kinase β1 (RPS6KB1), cylindromatosis (CYLD) and Twist family bHLH transcription factor 1 (TWIST1). The cell proliferation and apoptosis were tested using Celigo cell imaging analyzer and annexin V-APC apoptosis detection kit respectively. Colony formation and tumor xenograft assays were performed to understand their roles in tumorigenicity. RESULTS The expression of VOPP1 in HCC samples was higher than that in adjacent noncancerous tissues by immunohistochemistry. In addition, the down-regulation of VOPP1 using shRNA inhibited cell proliferation and tumour growth, and induced cell apoptosis in vitro and in vivo. Furthermore, VOPP1 silencing increased the expression of MAPK14 and RPS6KB1, indicating that the MAPK and mTOR signalling pathways might be involved in VOPP1-mediated cancer cell proliferation. CONCLUSION The present data indicate that VOPP1 may play an important role in the progression of HCC by targeting the MAPK and mTOR signalling pathways, and that VOPP1 may potentially be a candidate as a novel molecular target for HCC therapy.
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Affiliation(s)
- Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Linjun Wu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Haojiang Dai
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Peng Hu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Binfeng Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Qiuyue Han
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yongfu Xu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shangdong Lv
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu Zhu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Meifu Gan
- Department of Pathology, Enze Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
| | - Weijie Zhou
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenlong Zhang
- Department of Hepatobiliary Surgery, Enze Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
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20
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Zuo Q, He J, Zhang S, Wang H, Jin G, Jin H, Cheng Z, Tao X, Yu C, Li B, Yang C, Wang S, Lv Y, Zhao F, Yao M, Cong W, Wang C, Qin W. PPARγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPARγ-Dependent WNT/β-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis. Hepatology 2021; 73:644-660. [PMID: 32298475 DOI: 10.1002/hep.31280] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 01/23/2020] [Accepted: 04/03/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. APPROACH AND RESULTS In this study, we observed that PGC1α was down-regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/β-catenin pathway, and inhibition of the WNT/β-catenin pathway was induced by activation of PPARγ. CONCLUSIONS Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/β-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.
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Affiliation(s)
- Qiaozhu Zuo
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jia He
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shu Zhang
- Liver Cancer InstituteZhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Fudan UniversityShanghaiChina
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Guangzhi Jin
- Department of PathologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhuoan Cheng
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Xuemei Tao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chengtao Yu
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Botai Li
- Shanghai Jiao Tong University School of Biomedical EngineeringShanghaiChina
| | - Chen Yang
- Shanghai Medical College of Fudan UniversityShanghaiChina
| | - Siying Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuanyuan Lv
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenming Cong
- Department of PathologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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21
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Zhang J, Hong Y, Xie P, Chen Y, Jiang L, Yang Z, Cao G, Chen Z, Liu X, Chen Y, Wu Y, Cai Z. Spatial Lipidomics Reveals Anticancer Mechanisms of Bufalin in Combination with Cinobufagin in Tumor-Bearing Mice. Front Pharmacol 2021; 11:593815. [PMID: 33597874 PMCID: PMC7883642 DOI: 10.3389/fphar.2020.593815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/30/2020] [Indexed: 01/31/2023] Open
Abstract
Bufalin (BFL) and cinobufagin (CBF) are the principal bioactive constituents of Chansu, a widely used traditional Chinese medicine (TCM). The synergistic effects of potential active components are responsible for the bioactivities of TCM. Our results showed that the cotreatment with BFL and CBF confers superior anticancer efficacy compared to monotreatment. To reveal the underlying mechanisms of their cotreatment, an integrated method composed of mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging was used to delineate the responses of tumor-bearing mice treated with BFL and CBF individually or in combination. The cotreatment with BFL and CBF modulated the sphingolipid metabolism and glycerophospholipid metabolism, and subsequently led to mitochondria-driven apoptosis and systemic disruption of biomembranes in tumor cells. Furthermore, we found that the disturbed lipid markers were mainly located in the non-necrotic tumor areas, the essential parts for the formation of solid tumor framework. Together, our findings revealed what occurred in tumor in response to the treatment of BFL and CBF, from lipids to enzymes, and thus provide insights into the critical role of lipid reprogramming in the satisfactory anticancer effect of BFL in combination with CBF.
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Affiliation(s)
- Jinghui Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yanjun Hong
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China.,Shenzhen Research Institute and Continuing Education, Hong Kong Baptist University, Shenzhen, China.,School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Peisi Xie
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Yang Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lilong Jiang
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China.,Shenzhen Research Institute and Continuing Education, Hong Kong Baptist University, Shenzhen, China
| | - Zhiyi Yang
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Guodong Cao
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Zhongjian Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xuesong Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yong Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yongjiang Wu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zongwei Cai
- Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
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22
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Yang P, Yang Y, Sun P, Tian Y, Gao F, Wang C, Zong T, Li M, Zhang Y, Yu T, Jiang Z. βII spectrin (SPTBN1): biological function and clinical potential in cancer and other diseases. Int J Biol Sci 2021; 17:32-49. [PMID: 33390831 PMCID: PMC7757025 DOI: 10.7150/ijbs.52375] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022] Open
Abstract
βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.
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Affiliation(s)
- Panyu Yang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yanyan Yang
- Department of Immunology, Basic Medicine School, Qingdao University, No. 308 Ningxia Road, Qingdao 266071, People's Republic of China
| | - Pin Sun
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yu Tian
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Fang Gao
- Department of Physical Medicine and Rehabiliation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Chen Wang
- Department of Physical Medicine and Rehabiliation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Tingyu Zong
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Min Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Ying Zhang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Tao Yu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.,Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Zhirong Jiang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
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23
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Hu B, Yang XB, Yang X, Sang XT. LncRNA CYTOR affects the proliferation, cell cycle and apoptosis of hepatocellular carcinoma cells by regulating the miR-125b-5p/KIAA1522 axis. Aging (Albany NY) 2020; 13:2626-2639. [PMID: 33318318 PMCID: PMC7880333 DOI: 10.18632/aging.202306] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 10/22/2020] [Indexed: 04/27/2023]
Abstract
We aimed to investigate whether lncRNA CYTOR could sponge miR-125b-5p to affect hepatocellular carcinoma (HCC) cells through targeting KIAA1522. The expression of CYTOR, miR-125b-5p and KIAA1522 in HCC cells was detected by Real-time quantitative polymerase chain reaction (RT-qPCR) analysis. KIAA1522 expression in HCC tissues was detected by immunohistochemistry. The proliferation, cell cycle and apoptosis of HCC cells after transfection were respectively detected by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, and related protein expression was determined by Western blot analysis. As a result, The Cancer Genome Atlas (TCGA) database indicated that expression of CYTOR and KIAA1522 was increased in HCC tissues and high expression of CYTOR and KIAA1522 was related to worse overall survival. MiR-125b-5p expression was decreased in HCC tissues, which was negatively correlated with the expression of CYTOR and KIAA1522. The proliferation and cell cycle of HCC cells were suppressed by CYTOR interference while promoted by miR-125b-5p interference and KIAA1522 overexpression. The apoptosis of HCC cells was promoted by CYTOR interference while inhibited by miR-125b-5p interference and KIAA1522 overexpression. In conclusion, CYTOR interference suppressed the proliferation and cell cycle, and promoted the apoptosis of HCC cells by regulating the miR-125b-5p/KIAA1522 axis.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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24
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Chen B, Liao Z, Qi Y, Zhang H, Su C, Liang H, Zhang B, Chen X. miR-631 Inhibits Intrahepatic Metastasis of Hepatocellular Carcinoma by Targeting PTPRE. Front Oncol 2020; 10:565266. [PMID: 33344226 PMCID: PMC7746836 DOI: 10.3389/fonc.2020.565266] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) have been reported to play critical roles in the pathological development of hepatocellular carcinoma (HCC), one of the most common cancers in the world. Our study aims to explore the expression, function and mechanism of miR-631 in HCC. Our findings are that expression of miR-631 is significantly down-regulated in HCC tissue compared with that in adjacent non-cancerous tissue, and low expression of miR-631 in HCC tissue is associated with cirrhosis, multiple tumors, incomplete tumor encapsulation, poor tumor differentiation, and high TNM stage. Our test results showed that miR-631 could inhibit migration, invasion, epithelial–mesenchymal transition (EMT) and intrahepatic metastasis of HCC. Receptor-type protein tyrosine phosphatase epsilon (PTPRE) as a downstream target of miR-631 could promote migration, invasion and EMT of HCC cells. Besides, the expression of PTPRE had a negative correlation with the expression of miR-631 both in vivo and in vitro, and increasing expression of PTPRE could reverse inhibitory effects of miR-631 in HCC cells. In sum, our study first demonstrated that miR-631 targeted PTPRE to inhibit intrahepatic metastasis in HCC. We gain insights from these findings into the mechanism of miRNAs regulation in HCC metastasis and further introduce a novel therapeutic target for HCC treatment.
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Affiliation(s)
- Bingqing Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Yongqiang Qi
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Chen Su
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Science and Technology Department of Hubei Province, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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25
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Zheng Y, Zhu M, Li M. Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2020; 146:2439-2446. [DOI: 10.1007/s00432-020-03331-6] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
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26
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Jin C, Yang W, Ran L, Zhang J, Zhu H. Feasibility of High-Intensity Focused Ultrasound for Hepatocellular Carcinoma after Stereotactic Body Radiation Therapy: Initial Experience. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:2744-2751. [PMID: 32747074 DOI: 10.1016/j.ultrasmedbio.2020.06.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 06/11/2023]
Abstract
The purpose of this initial clinical observation was to investigate the safety and effect of high-intensity focused ultrasound (HIFU) for patients with hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT). Twenty patients who had been treated with SBRT, with 24 local residuals, received HIFU ablation. The changes of periphery blood cell count and serum biochemistry were observed before HIFU and 1 week after. Contrast-enhanced magnetic resonance imaging before HIFU and 2 weeks after was performed to assess the effect of HIFU. All patients received follow-up. The mean ± standard deviation follow-up time was 19.3 ± 18.0 mo. The median survival time and 1-y survival rate were 21 mo and 76.2%. Seventeen residual lesions (70.8%) received complete ablation and seven received partial ablation, with a mean ablation ratio of 75.8% ± 18.2%. No significant differences were found in periphery blood cell counts or serum biochemistry 1 week after HIFU compared with before HIFU. No severe adverse reactions related to HIFU were observed. Thus, we believe that HIFU can safely and effectively ablate residual HCC after SBRT, which may be a feasible option for patients with HCC who have local residuals after SBRT.
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Affiliation(s)
- Chengbing Jin
- Clinical Center for Tumor Therapy, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Wei Yang
- Institute of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Lifeng Ran
- Institute of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Jun Zhang
- Clinical Center for Tumor Therapy, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hui Zhu
- Clinical Center for Tumor Therapy, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, China
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27
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Saad ZM, Fouad Y, Ali LH, Hassanin TM. Clinical Significance of Annexin A4 as a Biomarker in the Early Diagnosis of Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2020; 21:2661-2665. [PMID: 32986366 PMCID: PMC7779427 DOI: 10.31557/apjcp.2020.21.9.2661] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 09/20/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most prevalent cancer worldwide. Early detection of HCC is crucial to improve prognosis and survival. Nearly 30 % of HCC patients present with normal serum alpha fetoprotein (AFP), which highlights the need for new biomarkers for HCC. Annexin A4 (ANXA4) is one of the annexin family with high expressions found in gastric, liver, lung, colorectal and ovarian cancers. AIM to evaluate the clinical significance of ANXA4 in the early diagnosis of HCC. METHODS Thirty patients with hepatitis C virus (HCV) related HCC were enrolled in this study. They were stage A according to Barcelona Clinic Liver Cancer (BCLC) staging and they were grade A or B according to Child Pugh Classification. Twenty patients with HCV-related liver cirrhosis and 20 healthy persons seronegative for both HCV and HBV served as control group. ANXA4 and AFP were measured in serum of all cases. RESULTS Serum ANXA4 level was significantly higher in HCC patients compared to patients with liver cirrhosis and healthy controls (188, IQR 42-428 and 23, IQR 24-33 and and 21, IQR 22-24 ng ̷ ml, respectively). By using the ROC curve, the area under the curve of ANXA4 was 0.972 and the best cut-off value was115 ng/ml, with sensitivity 95% and specificity 80%. CONCLUSION The serum level of ANXA4 might be a good biomarker for the early detection of HCC.
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Affiliation(s)
- Zienab M Saad
- Endemic Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt.
| | - Yasser Fouad
- Endemic Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt.
| | - Lamia H Ali
- Clinical Pathology Department, Faculty of Medicine, Minia University, Minia, Egypt.
| | - Taha M Hassanin
- Endemic Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt.
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28
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Lee S, Choi EJ, Cho EJ, Lee YB, Lee JH, Yu SJ, Yoon JH, Kim YJ. Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway. Clin Mol Hepatol 2020; 26:529-539. [PMID: 32829570 PMCID: PMC7641573 DOI: 10.3350/cmh.2019.0056n] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 06/10/2020] [Indexed: 12/17/2022] Open
Abstract
Background/Aims Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis due to the lack of effective systemic therapies. Epithelial-to-mesenchymal transition (EMT) is a pivotal event in tumor progression, during which cancer cells acquire invasive properties. In this study, we investigated the effects of phosphatidylinositol 3-kinase (PI3K) inhibitors, including LY294002 and idelalisib, on the EMT features of HCC cells in vitro. Methods Human HCC cell lines, including Huh-BAT and HepG2, were used in this study. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and cell cycle distributions were evaluated using a flow cytometer by propidium iodide staining. Immunofluorescence staining, quantitative real-time polymerase chain reaction, and immunoblotting were performed to detect EMT-associated changes. Results PI3K inhibitors suppressed the proliferation and invasion of HCC cells and deregulated the expression of EMT markers, as indicated by increased expression of E-cadherin, an epithelial marker, and decreased expression of N-cadherin, a mesenchymal marker, and Snail, a transcription factor implicated in EMT regulation. Furthermore, LY294002 and idelalisib inhibited the phosphorylation of GSK-3β and induced the nuclear translocation of GSK-3β, which corresponded to the downregulation of Snail and β-catenin expressions in Huh-BAT and HepG2 cells. Conclusions The inhibition of PI3K/Akt signaling decreases Snail expression by enhancing the nuclear translocation of GSK-3β, which suppresses EMT in HCC cells, suggesting the potential clinical application of PI3K inhibitors for HCC treatment.
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Affiliation(s)
- Seulki Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ji Choi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ju Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yun Bin Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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Salah Z, Abd El Azeem EM, Youssef HF, Gamal-Eldeen AM, Farrag AR, El-Meliegy E, Soliman B, Elhefnawi M. Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach. Curr Gene Ther 2020; 19:342-354. [PMID: 31701846 DOI: 10.2174/1566523219666191108103739] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 10/16/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. OBJECTIVE We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. METHODS In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. RESULTS ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. CONCLUSION Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.
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Affiliation(s)
- Zeinab Salah
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
| | - Eman M Abd El Azeem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hanan F Youssef
- Refractories, Ceramics and Building Materials Department, National Research Centre (NRC), Dokki, Cairo 12622, Egypt
| | - Amira M Gamal-Eldeen
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, Al Mutamarat Rd, Al Mathnah, At Taif 26521, Saudi Arabia
| | - Abdel R Farrag
- Pathology Department Medical Division Research, National Research Centre, Cairo, 12622, Dokki, Egypt
| | - Emad El-Meliegy
- Department of Biomaterials, National Research Centre, Cairo, Egypt
| | - Bangly Soliman
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
| | - Mahmoud Elhefnawi
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, Informatics and System Dept, National Research Centre (NRC), Cairo, Egypt
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Wang T, Jin H, Hu J, Li X, Ruan H, Xu H, Wei L, Dong W, Teng F, Gu J, Qin W, Luo X, Hao Y. COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:148. [PMID: 32746865 PMCID: PMC7398077 DOI: 10.1186/s13046-020-01650-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/21/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Collagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell behaviors. However, their roles in hepatocellular carcinoma (HCC) are poorly understood. METHODS In this study, we screened all 44 collagen members in HCC using whole transcriptome sequencing data from the public datasets, and collagen type IV alpha1 chain (COL4A1) was identified as most significantly differential expressed gene. Expression of COL4A1 was detected in HCC samples by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry (IHC). Finally, functions and potential mechanisms of COL4A1 were explored in HCC progression. RESULTS COL4A1 is the most significantly overexpressed collagen gene in HCC. Upregulation of COL4A1 facilitates the proliferation, migration and invasion of HCC cells through FAK-Src signaling. Expression of COL4A1 is upregulated by RUNX1 in HCC. HCC cells with high COL4A1 expression are sensitive to the treatment with FAK or Src inhibitor. CONCLUSION COL4A1 facilitates growth and metastasis in HCC via activation of FAK-Src signaling. High level of COL4A1 may be a potential biomarker for diagnosis and treatment with FAK or Src inhibitor for HCC.
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Affiliation(s)
- Ting Wang
- Shanghai Medical College of Fudan University, Shanghai, 200032, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Jingying Hu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Xi Li
- The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, 519000, People's Republic of China.,Changzheng Hospital, Navy Medical University, Shanghai, 200003, People's Republic of China
| | - Haoyu Ruan
- Shanghai Medical College of Fudan University, Shanghai, 200032, People's Republic of China
| | - Huili Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Lin Wei
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Weihua Dong
- Changzheng Hospital, Navy Medical University, Shanghai, 200003, People's Republic of China
| | - Fei Teng
- Changzheng Hospital, Navy Medical University, Shanghai, 200003, People's Republic of China
| | - Jianren Gu
- Shanghai Medical College of Fudan University, Shanghai, 200032, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China
| | - Xiaoying Luo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China.
| | - Yujun Hao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, People's Republic of China.
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Ding D, Huang H, Li Q, Yu W, Wang C, Ma H, Wu J, Dang Y, Yu L, Jiang W. NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2. Cell Death Discov 2020; 6:3. [PMID: 32123579 PMCID: PMC7026180 DOI: 10.1038/s41420-020-0236-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/19/2022] Open
Abstract
Nuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.
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Affiliation(s)
- Donglin Ding
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN USA
| | - Huixing Huang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Quanfu Li
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenbo Yu
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Chenji Wang
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Haijie Ma
- Laboratory of Cytobiology and Molecular Biology, The Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang China
| | - Jiaxue Wu
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Yongjun Dang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Long Yu
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Wei Jiang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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Elhefnawi M, Salah Z, Soliman B. The Promise of miRNA Replacement Therapy for Hepatocellular Carcinoma. Curr Gene Ther 2019; 19:290-304. [DOI: 10.2174/1566523219666191023101433] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/25/2019] [Accepted: 10/09/2019] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate
94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of
noncoding RNAs, which exhibit decreased or inhibited expression in the case of carcinogenesis.
Therefore, the replacement of these molecules leads to post-transcriptional regulation of tens to hundreds
of oncogenic targets and limiting the tumor. Interestingly, there is a group of tumor silencer
miRNAs that have been highlighted in HCC and herein, our review will discuss the prominent examples
of these miRs in terms of their efficient delivery using vectors, nano-delivery systems, their successful
models either in vitro or in vivo and pre-clinical trials. Collectively, tumor suppressor miRNAs
can act as novel therapeutics for HCC and more studies should be directed towards these promising
therapeutics.
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Affiliation(s)
- Mahmoud Elhefnawi
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Zeinab Salah
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
| | - Bangly Soliman
- Biomedical Informatics and Chemo-Informatics Group Leader, Centre of Excellence for Medical Research, National Research Centre (NRC), Cairo, Egypt
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Li S, Peng F, Ning Y, Jiang P, Peng J, Ding X, Zhang J, Jiang T, Xiang S. SNHG16 as the miRNA let-7b-5p sponge facilitates the G2/M and epithelial-mesenchymal transition by regulating CDC25B and HMGA2 expression in hepatocellular carcinoma. J Cell Biochem 2019; 121:2543-2558. [PMID: 31696971 DOI: 10.1002/jcb.29477] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022]
Abstract
Long noncoding RNAs (lncRNAs) play crucial roles in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of small nucleolar RNA host gene 16 (SNHG16) for regulating the cell cycle and epithelial to mesenchymal transition (EMT) remain elusive. In this study, SNHG16 expression profiles of HCC tissues or cell lines were compared with those of normal tissues or hepatocyte cell line. The effect of SNHG16 knockdown in HCC cell lines was investigated by using in vitro loss-of-function experiments and in vivo nude mouse experiments. The potential molecular regulatory mechanism of SNHG16 in HCC progression was investigated by using mechanistic experiments and rescue assays. The results revealed that SNHG16 was highly expressed in HCC tissues and cell lines, which predicted poor prognosis of HCC patients. On one hand, the downregulation of SNHG16 induced G2/M cell cycle arrest, inducing cell apoptosis and suppression of cell proliferation. On the other hand, it inhibited cell metastasis and EMT progression demonstrated by in vitro loss-of-function cell experiments. Besides, knockdown of SNHG16 increased the sensitivity of HCC cells to cisplatin. For the detailed mechanism, SNHG16 was demonstrated to act as a let-7b-5p sponge in HCC. SNHG16 facilitated the G2/M cell cycle transition by directly acting on the let-7b-5p/CDC25B/CDK1 axis, and promoted cell metastasis and EMT progression by regulating the let-7b-5p/HMGA2 axis in HCC. In addition, the mechanism of SNHG16 for regulating HCC cell proliferation and metastasis was further confirmed in vivo by mouse experiments. Furthermore, these results can provide new insights into HCC treatment and its molecular pathogenesis, which may enlighten the further research of the molecular pathogenesis of HCC.
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Affiliation(s)
- Shengguang Li
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, China.,Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Center of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou Institute of Systems Medicine, Suzhou, China
| | - Fujun Peng
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yichong Ning
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, China
| | - Peng Jiang
- Suzhou Geneworks Technology Co, Ltd, Suzhou, China
| | - Jian Peng
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaofeng Ding
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, China
| | - Jian Zhang
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, China
| | - Taijiao Jiang
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Center of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou Institute of Systems Medicine, Suzhou, China
| | - Shuanglin Xiang
- State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, China
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Xing S, Kan J, Su A, Liu QD, Wang K, Cai X, Dong J. The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma. Aging (Albany NY) 2019; 11:8474-8483. [PMID: 31584009 PMCID: PMC6814593 DOI: 10.18632/aging.102333] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 09/22/2019] [Indexed: 01/20/2023]
Abstract
INTRODUCTION We aimed to characterize the expression of major facilitator superfamily domain-containing protein 2A (MFSD2A) in hepatocellular carcinoma (HCC) patients and analyze its prognostic value. RESULTS Immunohistochemistry revealed that low expression of MFSD2A was present in 37 of 79 cases (46.84%), which was significantly correlated with poor histological differentiation (P = 0.012). The plasma MFSD2A level in HCC patients was significantly lower than in healthy controls (P = 0.0079) and controls with chronic hepatitis B virus (HBV) infection (P = 0.0430). Moreover, patients with lower MFSD2A expression had shorter survival than higher expression (P = 0.021). Multivariate analysis revealed that MFSD2A was an independent prognostic predictor for HCC patients (P = 0.027). CONCLUSION The current study indicate MFSD2A may be an optimal diagnostic and prognostic biomarker for HCC. METHODS First, we examined MFSD2A expression in 24 paired HCC and nontumorous tissues by real-time quantitative PCR (RT-qPCR). Second, the protein levels of MFSD2A in 11 paired HCC and nontumorous tissues were investigated by western blotting (WB). Moreover, MFSD2A protein expression was evaluated by immunohistochemistry in 79 HCC patients. In addition, we detected the plasma level of MFSD2A in HCC patients and healthy individuals and investigated the relationship between MFSD2A expression and clinicopathological parameters or prognosis of HCC patients.
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Affiliation(s)
- Shan Xing
- Department of Laboratory, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Jun Kan
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Aishan Su
- Department of GCP Center, Nanfang Hospital of Southern Medical University, Guangzhou 510515, P.R. China
| | - Qiao-Dan Liu
- Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519001, Guangdong Province, China
| | - Kailin Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Pharmaceutical University, Guangzhou 510062, China
| | - Xiuyu Cai
- Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Jun Dong
- Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
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Qi X, Schepers E, Avella D, Kimchi ET, Kaifi JT, Staveley-O'Carroll KF, Li G. An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis. J Vis Exp 2019. [PMID: 31566616 DOI: 10.3791/59368] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The absence of a clinically relevant animal model addressing the typical immune characteristics of hepatocellular cancer (HCC) has significantly impeded elucidation of the underlying mechanisms and development of innovative immunotherapeutic strategies. To develop an ideal animal model recapitulating human HCC, immunocompetent male C57BL/6J mice first receive a carbon tetrachloride (CCl4) injection to induce liver fibrosis, then receive histologically-normal oncogenic hepatocytes from young male SV40 T antigen (TAg)-transgenic mice (MTD2) by intra-splenic (ISPL) inoculation. Androgen generated in recipient male mice at puberty initiates TAg expression under control of a liver-specific promoter. As a result, the transferred hepatocytes become cancer cells and form tumor masses in the setting of liver fibrosis/cirrhosis. This novel model mimics human HCC initiation and progression in the context of liver fibrosis/cirrhosis and reflects the most typical features of human HCC including immune dysfunction.
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Affiliation(s)
- Xiaoqiang Qi
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia; Molecular Microbiology and Immunology, University of Missouri-Columbia
| | - Emily Schepers
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia
| | - Diego Avella
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia
| | - Eric T Kimchi
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia
| | - Jussuf T Kaifi
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia
| | - Kevin F Staveley-O'Carroll
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia;
| | - Guangfu Li
- Department of Surgery, University of Missouri-Columbia; Ellis Fischel Cancer Center, University of Missouri-Columbia; Molecular Microbiology and Immunology, University of Missouri-Columbia;
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Shi J, Sun J, Liu C, Chai Z, Wang N, Zhang H, Cheng S. All-trans-retinoic acid (ATRA) plus oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) versus FOLFOX alone as palliative chemotherapy in patients with advanced hepatocellular carcinoma and extrahepatic metastasis: study protocol for a randomized controlled trial. Trials 2019; 20:245. [PMID: 31036040 PMCID: PMC6489221 DOI: 10.1186/s13063-019-3349-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 04/03/2019] [Indexed: 12/20/2022] Open
Abstract
Background Among patients with hepatocellular carcinoma (HCC), 85% of patients have an advanced disease stage at diagnosis and curative therapies cannot be performed. Prognosis has been quite poor as until recently there was no proven effective chemotherapy. Our group found that all-trans-retinoic acid (ATRA) could improve the efficacy of platinum in HCC in vivo and in vitro, thus we wish to validate the efficiency of ATRA in clinical practice. Methods This is a double-blinded, 1:1 randomized, controlled, multicenter clinical trial. Three hundred and sixty-eight patients with HCC and extrahepatic metastases will receive palliative chemotherapy at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University and Fujian Provincial Cancer Hospital. Subjects will be randomly assigned to one of the two arms, either ATRA + oxaliplatin + 5-fluorouracil/leucovorin (FOLFOX4) or FOLFOX4 alone. ATRA 20 mg will be given orally three times/day for 3 days prior to the initiation of FOLFOX4. ATRA will be discontinued at the end of FOLFOX4. Discussion Overall survival rate is the primary endpoint. Secondary endpoints are time to progression according to the modified response evaluation criteria in solid tumors (mRECIST) criteria, acute and chronic adverse events, and quality of life. Trial registration Chinese Clinical Trial Registry, ChiCTR-IIR-17012916. Registered on 9 October 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3349-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Rd No.225, Shanghai, 200438, China
| | - Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Rd No.225, Shanghai, 200438, China
| | - Chang Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Rd No.225, Shanghai, 200438, China
| | - Zongtao Chai
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Rd No.225, Shanghai, 200438, China
| | - Nanya Wang
- Department of Cancer Center, First Hospital of Jilin University, Xinmin Rd No71, Changchun, 130021, Jilin Province, China
| | - Hui Zhang
- Department of Surgery of Hepato-Biliary & Pancreatic Tumor, Fujian Provincial Cancer Hospital, Fuma Rd No.420, Fuzhou, 350011, Fujian Province, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Changhai Rd No.225, Shanghai, 200438, China.
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Wang Q, Zhang P, Li Z, Feng X, Lv C, Zhang H, Xiao H, Ding J, Chen X. Evaluation of Polymer Nanoformulations in Hepatoma Therapy by Established Rodent Models. Theranostics 2019; 9:1426-1452. [PMID: 30867842 PMCID: PMC6401493 DOI: 10.7150/thno.31683] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/08/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatoma is one of the most severe malignancies usually with poor prognosis, and many patients are insensitive to the existing therapeutic agents, including the drugs for chemotherapy and molecular targeted therapy. Currently, researchers are committed to developing the advanced formulations with controlled drug delivery to improve the efficacy of hepatoma therapy. Numerous inoculated, induced, and genetically engineered hepatoma rodent models are now available for formulation screening. However, animal models of hepatoma cannot accurately represent human hepatoma in terms of histological characteristics, metastatic pathways, and post-treatment responses. Therefore, advanced animal hepatoma models with comparable pathogenesis and pathological features are in urgent need in the further studies. Moreover, the development of nanomedicines has renewed hope for chemotherapy and molecular targeted therapy of advanced hepatoma. As one kind of advanced formulations, the polymer-based nanoformulated drugs have many advantages over the traditional ones, such as improved tumor selectivity and treatment efficacy, and reduced systemic side effects. In this article, the construction of rodent hepatoma model and much information about the current development of polymer nanomedicines were reviewed in order to provide a basis for the development of advanced formulations with clinical therapeutic potential for hepatoma.
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Affiliation(s)
- Qilong Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Zhongmin Li
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Xiangru Feng
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Chengyue Lv
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Huaiyu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
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Campos M, Candelária I, Papanikolaou N, Simão A, Ferreira C, Manikis GC, Caseiro-Alves F. Perfusion Magnetic Resonance as a Biomarker for Sorafenib-Treated Advanced Hepatocellular Carcinoma: A Pilot Study. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:260-267. [PMID: 31328140 DOI: 10.1159/000493351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/27/2018] [Indexed: 12/12/2022]
Abstract
Background Sorafenib is the currently recommended therapy in patients with advanced hepatocellular carcinoma (HCC). Among the several biomarkers available for the evaluation of the therapeutic response and prognosis, there is perfusion magnetic resonance imaging (p-MRI) that, through measurement of the vascular permeability unit (ktrans), may retrieve useful information regarding the microvascular properties of focal liver lesions. The aim of this study was to evaluate the impact of sorafenib therapy in patients with advanced HCC using the p-MRI technique. Materials and Methods In this retrospective study, 27 patients with the diagnosis of advanced HCC were included for palliative therapy using sorafenib. MRI of the liver was performed before the beginning of the oral therapy (T0), after 3 (T3), and after 6 months (T6). Dynamic acquisitions of the tumor (n = 50, during the first 2 min after contrast injection) were obtained in the coronal plane and were used to compute the parametric perfusion maps, acquiring the ktrans value using the extended Tofts pharmacokinetic model. Results The value of ktrans obtained at T0 was significantly different from the value of ktrans obtained at T6 (p = 0.028). There were no significant differences between T0 and T3 (p = 0.115) or a correlation between ktrans at T0 and the size of the lesion (p = 0.376). The ktrans value at T0 in patients with progression-free survival (PFS) > 6 months was not significantly different from the ktrans value in patients with PFS ≤6 months (p = 0.113). The ktrans value at T0 was not significantly different between patients who were previously submitted to chemoembolization and those who were not submitted (p = 0.587). Conclusion In this pilot study, the ktrans value may serve as a biomarker of tumor response to antiangiogenic therapy, but only 6 months after its initiation. Clinical outcomes such as PFS were not predicted before the initiation of treatment.
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Affiliation(s)
- Marta Campos
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
| | - Isabel Candelária
- Medical Imaging Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Local Healthcare Unit, Castelo Branco, Portugal
| | | | - Adélia Simão
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.,Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Carlos Ferreira
- Coimbra Institute for Biomedical Imaging and Translational Research, Coimbra, Portugal.,Institute of Nuclear Sciences Applied to Health, Universidade de Coimbra, Coimbra, Portugal
| | - Georgios C Manikis
- Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece
| | - Filipe Caseiro-Alves
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.,Medical Imaging Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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40
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Xue C, Ren Z, Hu X, He Y, Sun R, Li J, Cui G, Yu Z. The successful treatment for cardiac tamponade during radiofrequency ablation of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2019; 18:90-92. [PMID: 30579735 DOI: 10.1016/j.hbpd.2018.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 12/03/2018] [Indexed: 02/05/2023]
Affiliation(s)
- Chen Xue
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhigang Ren
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xiaobo Hu
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yuting He
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Ranran Sun
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Juan Li
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Guangying Cui
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zujiang Yu
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, China; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Schobert I, Chapiro J, Nezami N, Hamm CA, Gebauer B, Lin M, Pollak J, Saperstein L, Schlachter T, Savic LJ. Quantitative Imaging Biomarkers for 90Y Distribution on Bremsstrahlung SPECT After Resin-Based Radioembolization. J Nucl Med 2019; 60:1066-1072. [PMID: 30655331 DOI: 10.2967/jnumed.118.219691] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 12/19/2018] [Indexed: 12/27/2022] Open
Abstract
Our purpose was to identify baseline imaging features in patients with liver cancer that correlate with 90Y distribution on postprocedural SPECT and predict tumor response to transarterial radioembolization (TARE). Methods: This retrospective study was approved by the institutional review board and included 38 patients with hepatocellular carcinoma (HCC) (n = 23; 18/23 men; mean age, 62.39 ± 8.62 y; 34 dominant tumors) and non-HCC hepatic malignancies (n = 15; 9/15 men; mean age, 61.13 ± 11.51 y; 24 dominant tumors) who underwent 40 resin-based TARE treatments (August 2012 to January 2018). Multiphasic contrast-enhanced MRI or CT was obtained before and Bremsstrahlung SPECT within 2 h after TARE. Total tumor volume (cm3) and enhancing tumor volume (ETV [cm3] and % of total tumor volume), and total and enhancing tumor burden (%), were volumetrically assessed on baseline imaging. Up to 2 dominant tumors per treated lobe were analyzed. After multimodal image registration of baseline imaging and SPECT/CT, 90Y distribution was quantified on SPECT as tumor-to-normal-liver ratio (TNR). Response was assessed according to RECIST1.1 and quantitative European Association for the Study of the Liver criteria. Clinical parameters were also assessed. Statistical tests included Mann-Whitney U, Pearson correlation, and linear regression. Results: In HCC patients, high baseline ETV% significantly correlated with high TNR on SPECT, demonstrating greater 90Y uptake in the tumor relative to the liver parenchyma (P < 0.001). In non-HCC patients, a correlation between ETV% and TNR was observed as well (P = 0.039). Follow-up imaging for response assessments within 1-4 mo after TARE was available for 23 patients with 25 treatments. The change of ETV% significantly correlated with TNR in HCC (P = 0.039) but not in non-HCC patients (P = 0.886). Additionally, Child-Pugh class B patients demonstrated significantly more 90Y deposition in nontumorous liver than Child-Pugh A patients (P = 0.021). Conclusion: This study identified ETV% as a quantifiable imaging biomarker on preprocedural MRI and CT to predict 90Y distribution on postprocedural SPECT in HCC and non-HCC. However, the relationship between the preferential uptake of 90Y to the tumor and tumor response after radioembolization could be validated only for HCC.
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Affiliation(s)
- Isabel Schobert
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany; and
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Nariman Nezami
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Charlie A Hamm
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany; and
| | - Bernhard Gebauer
- Institute of Radiology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany; and
| | - MingDe Lin
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Visage Imaging Inc., San Diego, California
| | - Jeffrey Pollak
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Lawrence Saperstein
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Todd Schlachter
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
| | - Lynn J Savic
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.,Institute of Radiology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany; and
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Zhao Z, Zhong L, He K, Qiu C, Li Z, Zhao L, Gong J. Cholesterol attenuated the progression of DEN-induced hepatocellular carcinoma via inhibiting SCAP mediated fatty acid de novo synthesis. Biochem Biophys Res Commun 2019; 509:855-861. [PMID: 30638930 DOI: 10.1016/j.bbrc.2018.12.181] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 12/29/2018] [Indexed: 01/06/2023]
Abstract
Worldwide, hepatocellular carcinoma (HCC) remains a top instigator of cancer mortality. Previous clinical studies have revealed that low serum cholesterol predicts a poor outcome in HCC patients, but the potential role of cholesterol in the progression of HCC remains controversial. In the present study,we tested the influence of cholesterol on the progression of DEN-induced HCC by feeding mice with a high cholesterol diet (HCD) and by depriving cholesterol with atorvastatin, a widely used inhibitor of the mevalonate pathway. We found that HCD induced more and larger liver tumors and an increased occurrence of lung metastasis in DEN-injected mice. These effects could be prevented by cholesterol deprivation with atorvastatin. In vitro, cholesterol loading repressed the proliferation, migration, and the invasion of SK hep1 cells, which was additionally prevented by cholesterol deprivation. Both in vivo and in vitro, cholesterol loading decreased the expression of Sterol regulatory element-binding protein cleavage-activating protein (SCAP), the translocation of sterol regulatory element-binding protein1 (SREBP1) to the nucleolus, and the genetic expression of FAS and ACC-1. Over-expression of SCAP in cholesterol-loaded SK hep1 cells promoted the nuclear translocation of SREBP1 and the expression of FAS and ACC-1, which promoted the proliferation, migration, and the invasion of SK hep1 cells. Knockdown of SCAP also restrained the cholesterol deletion-mediated up-regulation of fatty acid de novo synthesis in SK hep1 cells, inhibiting the atorvastatin-mediated proliferation, migration, and invasion of SK hep1 cells. In conclusion, cholesterol inhibited the progression of HCC through restraining SCAP-mediated fatty acid de novo synthesis.
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Affiliation(s)
- Zhibo Zhao
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China
| | - Li Zhong
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Kun He
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China
| | - Chan Qiu
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China
| | - Zhi Li
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China.
| | - Jianping Gong
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital & Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) of Chongqing Medical University, 40016, Chongqing, China.
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Bouvry C, Palard X, Edeline J, Ardisson V, Loyer P, Garin E, Lepareur N. Transarterial Radioembolization (TARE) Agents beyond 90Y-Microspheres. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1435302. [PMID: 30687734 PMCID: PMC6330886 DOI: 10.1155/2018/1435302] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022]
Abstract
Liver malignancies, either primary tumours (mainly hepatocellular carcinoma and cholangiocarcinoma) or secondary hepatic metastases, are a major cause of death, with an increasing incidence. Among them, hepatocellular carcinoma (HCC) presents with a dark prognosis because of underlying liver diseases and an often late diagnosis. A curative surgical treatment can therefore only be proposed in 20 to 30% of the patients. However, new treatment options for intermediate to advanced stages, such as internal radionuclide therapy, seem particularly attractive. Transarterial radioembolization (TARE), which consists in the use of intra-arterial injection of a radiolabelled embolising agent, has led to very promising results. TARE with 90Y-loaded microspheres is now becoming an established procedure to treat liver tumours, with two commercially available products (namely, SIR-Sphere® and TheraSphere®). However, this technology remains expensive and is thus not available everywhere. The aim of this review is to describe TARE alternative technologies currently developed and investigated in clinical trials, with special emphasis on HCC.
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Affiliation(s)
- C. Bouvry
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
- Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, 35000 Rennes, France
| | - X. Palard
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
- Univ Rennes, Inserm, LTSI (Laboratoire Traitement du Signal et de l'Image), UMR_S 1099, 35000 Rennes, France
| | - J. Edeline
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
- Univ Rennes, Inra, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR_A 1341, UMR_S 1241, 35000 Rennes, France
| | - V. Ardisson
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
| | - P. Loyer
- Univ Rennes, Inra, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR_A 1341, UMR_S 1241, 35000 Rennes, France
| | - E. Garin
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
- Univ Rennes, Inra, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR_A 1341, UMR_S 1241, 35000 Rennes, France
| | - N. Lepareur
- Comprehensive Cancer Centre Eugène Marquis, 35042 Rennes, France
- Univ Rennes, Inra, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR_A 1341, UMR_S 1241, 35000 Rennes, France
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Maimaitiming A, Zhou X, Ma X, Huang Y, Wang Q, Deng R, Ren Y, Chai X, Zhang P. Clinicopathological and Prognostic Value of Plasma CD24 Level in Hepatocellular Carcinoma. J INVEST SURG 2018; 33:536-541. [PMID: 30543135 DOI: 10.1080/08941939.2018.1535009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Purpose: CD24 is overexpressed in hepatocellular carcinoma (HCC) tumor tissues and in the highly metastatic HCC cell lines. However, plasma CD24 level in HCC patients and the correlation of plasma CD24 level with clinicopathological factors and prognosis of HCC patients still remain unclear. Materials and Methods: Enzyme-linked immunosorbent assay was used to detect plasma CD24 level in 86 HCC patients, 35 healthy subjects, 26 patients with liver cirrhosis and 23 patients with chronic hepatitis. The relationship between plasma CD24 level with clinicopathological characteristics in HCC patients was assessed using the Mann-Whitney U test. Patient survival between groups was evaluated by the Kaplan-Meier method and the log-rank test, prognostic factors being analyzed by the Cox regression model. Results: Our present study demonstrated that plasma CD24 level in HCC patients was significantly higher than that in the controls. CD24 was significantly associated with tumor differentiation, but was not correlated with other clinicopathologic parameters including gender, age, tumor size, tumor number, capsulation status, HBsAg status, tumor node metastasis stage, ALT, AFP, and GGT level. CD24 might be a prognostic predictor for overall survival and recurrence-free survival. Conclusions: Plasma CD24 level was significantly higher in HCC patients than that in the controls. Plasma CD24 level was associated with tumor differentiation. The HCC patients with high plasma CD24 level had unfavorable prognosis. CD24 might be a prognostic biomarker for HCC in the future.
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Affiliation(s)
- Abuduaiheti Maimaitiming
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing Zhou
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianxiong Ma
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongming Huang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingbo Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yahui Ren
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinqun Chai
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pei Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jin GZ, Zhang Y, Cong WM, Wu X, Wang X, Wu S, Wang S, Zhou W, Yuan S, Gao H, Yu G, Yang W. Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking. PLoS Biol 2018; 16:e2006483. [PMID: 30335765 PMCID: PMC6193743 DOI: 10.1371/journal.pbio.2006483] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 09/14/2018] [Indexed: 12/13/2022] Open
Abstract
Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults. Sorafenib is the only clinically approved systemic drug for patients with advanced HCC. Identification of novel targets and biomarkers will provide new therapeutic strategies for advanced HCC and better prognostic prediction. Phosphoglucomutase (PGM) is an evolutionarily conserved enzyme that regulates one of the most important pathways in glucose metabolis—catalyzing the bidirectional interconversion of glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P). In this study, we identify PGM1 as a metabolic tumor suppressor. Its expression allocates more glucose to glycogenesis, which reduces the glycolytic intermediates for biosynthesis, thereby impairing HCC progression. We delineate the mechanism of PGM1 down-regulation in HCC, finding that forkhead box protein J2 (FOXJ2) loss releases cellular nucleic acid-binding protein (CNBP) to bind to and modify the DNA structure of PGM1 promoter, thereby inhibiting PGM1 expression. Immunohistochemical analyses of human HCC tumors indicate that low FOXJ2 and PGM1 expression correlates with the malignancy and poor progression of human HCC. These results also suggest that the activation of residual PGM1 may impair HCC development through switching glycolysis to glycogenesis.
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Affiliation(s)
- Guang-Zhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yajuan Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xueyuan Wu
- Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China
| | - Xiongjun Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Siyang Wu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Siyao Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hong Gao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Guanzhen Yu
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- * E-mail: (GY); (WY)
| | - Weiwei Yang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- * E-mail: (GY); (WY)
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Nakashima Y, Nahar S, Miyagi-Shiohira C, Kinjo T, Toyoda Z, Kobayashi N, Saitoh I, Watanabe M, Fujita J, Noguchi H. A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of the Proteins Secreted by Human Adipose-Derived Mesenchymal Stem Cells. Cell Transplant 2018; 27:1469-1494. [PMID: 30226075 PMCID: PMC6180722 DOI: 10.1177/0963689718795096] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Liquid chromatography using a tandem mass spectrometer (LC-MS/MS) is a method of
proteomic analysis. A shotgun analysis by LC-MS/MS comprehensively identifies proteins
from tissues and cells with high resolution. The hepatic function of mice with acute
hepatitis following the intraperitoneal administration of CCL4 was improved by the tail
vein administration of the culture conditional medium (CM) of human mesenchymal stem cells
from adipose tissue (hMSC-AT). In this study, a secreted protein expression analysis of
hMSC-AT was performed using LC-MS/MS; 128 proteins were identified. LC-MS/MS showed that
106 new functional proteins and 22 proteins (FINC, PAI1, POSTN, PGS2, TIMP1, AMPN, CFAH,
VIME, PEDF, SPRC, LEG1, ITGBL, ENOA, CSPG2, CLUS, IBP4, IBP7, PGS1, IBP2, STC2, CTHR1,
CD9) were previously reported in hMSC-AT-CMs. In addition, various proteins associated
with growth (SAP, SEM7A, PTK7); immune system processes (CO1A2, CO1A1, CATB, TSP1, GAS6,
PTX3, C1 S, SEM7A, G3P, PXDN, SRCRL, CD248, SPON2, ENPP2, CD109, CFAB, CATL1, MFAP5, MIF,
CXCL5, ADAM9, CATK); and reproduction (MMP2, CATB, FBLN1, SAP, MFGM, GDN, CYTC) were
identified in hMSC-AT-CMs. These results indicate that a comprehensive expression analysis
of proteins by LC-MS/MS is useful for investigating new factors associated with cellular
components, biological processes, and molecular functions.
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Affiliation(s)
- Yoshiki Nakashima
- 1 Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Saifun Nahar
- 2 Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Chika Miyagi-Shiohira
- 1 Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Takao Kinjo
- 3 Department of Basic Laboratory Sciences, School of Health Sciences in Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Zensei Toyoda
- 3 Department of Basic Laboratory Sciences, School of Health Sciences in Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
| | | | - Issei Saitoh
- 5 Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Masami Watanabe
- 6 Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Jiro Fujita
- 2 Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Hirofumi Noguchi
- 1 Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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Mashaly AH, Anwar R, Ebrahim MA, Eissa LA, El Shishtawy MM. Diagnostic and Prognostic Value of Talin-1 and Midkine as Tumor Markers in Hepatocellular Carcinoma in Egyptian Patients. Asian Pac J Cancer Prev 2018; 19:1503-1508. [PMID: 29936723 PMCID: PMC6103586 DOI: 10.22034/apjcp.2018.19.6.1503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 05/06/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a main cause of cancer death all over the world. Treatment and outcome of HCC based on its early diagnosis. This study was conducted to estimate the role of talin-1 and midkine in combination with total antioxidant capacity (TAC) as tumor markers in HCC patients. Methods: Serum levels of talin-1 and midkine were measured in 90 Egyptian subjects including 44 patients with HCC, 31patients with cirrhosis and 15 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. While a colorimetric method was used for measurement of TAC. Results: Serum talin-1 in HCC patients was significantly lower than that in patients with cirrhosis (P<0.001) and normal control (P<0.001). In addition, increased invasion and metastasis correlated with reduced talin-1 level. Serum midkine in HCC patients was significantly higher compared to cirrhotic patients (P<0.001) and normal control (P<0.001). Midkine at a cut off value of 1683 pg/ml showed a sensitivity of (81.82%) and specificity of (83.87%). While alpha-fetoprotein (AFP) at a cut off value of 200 ng/ml had a sensitivity of (52.27%), while specificity was (96.77%). Midkine was positive in 80.9% of HCC patients with negative AFP. Serum TAC was significantly decreased in HCC patients when compared with control group (P<0.001). Conclusion: Talin-1 may be implicated in the carcinogenesis and metastasis of HCC and can be used as a useful tumor marker for HCC. Midkine may be a potential diagnostic marker for HCC and may be used in addition to AFP to increase the sensitivity of HCC detection.
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Affiliation(s)
- Aya H Mashaly
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. ,
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Yang L, Qiu J, Xiao Y, Hu X, Liu Q, Chen L, Huang W, Li X, Li L, Zhang J, Ding X, Xiang S. AP-2β inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition. Theranostics 2018; 8:3707-3721. [PMID: 30026878 PMCID: PMC6037033 DOI: 10.7150/thno.25166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/18/2018] [Indexed: 12/14/2022] Open
Abstract
Transcription factor AP-2β plays an important role in human cancer, but its clinical significance in hepatocellular carcinogenesis is largely unknown. Methods: AP-2β expression was detected in human hepatocellular cancer (HCC) tissues and cell lines. The effects of AP-2β on HCC proliferation, migration, invasion, tumor formation and metastasis were evaluated by MTT, colony formation and transwell assays in vitro and mouse experiments in vivo. The association between AP-2β and miR-27a/EMT markers in HCC cell lines and tissues was analyzed. Results: AP-2β expression was decreased in HCC tissues and cell lines. Reduced expression of AP-2β was significantly associated with more advanced tumor stages and larger tumor sizes. The overexpression of AP-2β reduced HCC proliferation, migration, invasion, tumor formation and metastasis in vitro and in vivo. Additionally, AP-2β overexpression increased the sensitivity of HCC cells to cisplatin. Moreover, AP-2β modulates the levels of EMT markers through Slug and Snail in HCC cell lines and tissues. Furthermore, oncogenic miR-27a inhibits AP-2β expression by binding to the AP-2β 3′ untranslated region (UTR) and reverses the tumor suppressive role of AP-2β. Conclusion: These results suggested that AP-2β is lowly expressed in HCC by inhibiting EMT signaling to regulate HCC cell growth and migration. Therefore, AP-2β in the novel miR-27a/AP-2β/Slug/EMT regulatory axis enhances the chemotherapeutic drug sensitivity of HCC and might represent a potential target for evaluating the treatment and prognosis of human HCC.
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γ-Glutamylcysteine synthetase (γ-GCS) as a target for overcoming chemo- and radio-resistance of human hepatocellular carcinoma cells. Life Sci 2018; 198:25-31. [PMID: 29549912 DOI: 10.1016/j.lfs.2018.02.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 02/09/2018] [Accepted: 02/10/2018] [Indexed: 11/20/2022]
Abstract
AIMS This study uncovered that the genetically endowed intracellular glutathione contents (iGSH) regulated by the catalytic subunit of γ‑glutamylcysteine synthetase heavy chain (γ‑GCSh) as a prime target for overcoming both the inherited and stimuli-activated chemo- and radio-resistance of hepatocellular carcinoma (HCC) cells. MAIN METHODS Reactive oxygen species (ROS) production and mitochondrial membrane potential (Δψm) were determined by the probe-based flow cytometry. The TUNEL assay was used as an index of radio-sensitivity and the MTT assay was used as an index of chemo-sensitivity against various anti-cancer agents. iGSH and γ‑GCSh activity were measured by HPLC methods. γ‑GCSh-overexpressing GCS30 cell line was established by tetracycline-controlled Tet-OFF gene expression system in SK-Hep-1 cells. KEY FINDINGS The relative radio-sensitivities of a panel of five HCC cells were found to be correlated negatively with both the contents of iGSH and their corresponding γ‑GCSh activities with an order of abundance being Hep G2 > Hep 3B > J5 > Mahlavu > SK-Hep-1, respectively. Similarly, the cytotoxicity response patterns of these HCC cells against arsenic trioxide (ATO), a ROS-producing anti-cancer drug, were exactly identical to the order of ranking instigated by the radiotherapy (RT) treatment. Next, γ‑GCSh-overexpressing GCS30 cells were found to possess excellent ability to profoundly mitigate both the drop of Δψm and apoptotic TUNEL-positive cell population engendered by ATO, cisplatin, doxorubicin, and RT treatments. SIGNIFICANCE Our data unequivocally demonstrate that γ‑GCSh may represent a prime target for overcoming anti-cancer drugs and RT resistance for HCC cells.
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50
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Li YC, Yang CS, Zhou WL, Li HS, Han YJ, Wang QS, Wu HB. Low glucose metabolism in hepatocellular carcinoma with GPC3 expression. World J Gastroenterol 2018; 24:494-503. [PMID: 29398870 PMCID: PMC5787784 DOI: 10.3748/wjg.v24.i4.494] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/20/2017] [Accepted: 12/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between glucose metabolism and glypican-3 (GPC3) expression in hepatocellular carcinoma (HCC).
METHODS Immunohistochemical staining of pathological samples for GPC3 and glucose transporter 1 (GLUT1), and whole-body 18F-FDG PET/CT for measuring tumour glucose uptake were performed in 55 newly diagnosed HCC patients. The maximum standard uptake value (SUVmax) and tumour-to-non-tumourous liver uptake (T/NT) ratio were used to quantify 18F-FDG uptake. In vitro18F-FDG uptake assay of GPC3-expressing HepG2 and non-GPC3-expressing RH7777 cells was used to examine the effect of GPC3 in cellular glucose metabolism. The relationships between GPC3 expression and 18F-FDG uptake, GLUT1 expression, tumour differentiation, and other clinical indicators were analysed using Spearman rank correlation, univariate and multiple logistic regression analyses.
RESULTS Positive GPC3 expression was observed in 67.3% of HCC patients, including 75.0% of those with well or moderately differentiated HCC and 36.4% of those with poorly differentiated HCC. There was an inverse relationship between GPC3 expression and SUVmax (Spearman correlation coefficient = -0.281, P = 0.038) and a positive relationship between GLUT1 expression and SUVmax (Spearman correlation coefficient = 0.681, P < 0.001) in patients with HCC. Univariate analysis showed that two glucose metabolic parameters (SUVmax and T/NT ratio), tumour differentiation, lymph node metastasis, and TNM stage were all significantly associated with GPC3 expression (P < 0.05), whereas GLUT1 expression, sex, age, tumour size, intrahepatic lesion number, and distant metastasis showed no statistical association (P > 0.05). Further multivariate analysis revealed that only the T/N ratio was significantly correlated with GPC3 expression in patients with HCC (P < 0.05). In vitro assay revealed that the uptake of 18F-FDG in GPC3-expressing HepG2 cells was significantly lower than that of non-GPC3-expressing RH7777 cells (t = -20.352, P < 0.001).
CONCLUSION The present study demonstrated that GPC3 expression is inversely associated with glucose metabolism, suggesting that GPC3 may play a role in regulating glucose metabolism in HCC.
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Affiliation(s)
- You-Cai Li
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Chuan-Sheng Yang
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Wen-Lan Zhou
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hong-Sheng Li
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yan-Jiang Han
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Quan-Shi Wang
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hu-Bing Wu
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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