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Tang C, Tang C, Zhu X, Wang S, Yang Y, Miao Y, Zhao X, Jia L, Yang J, Su Y, Wang L, Wu C. Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma. Br J Pharmacol 2025; 182:1394-1409. [PMID: 39653061 DOI: 10.1111/bph.17413] [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: 04/02/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND AND PURPOSE As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC. EXPERIMENTAL APPROACH The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]). KEY RESULTS Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo. CONCLUSION AND IMPLICATIONS AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.
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MESH Headings
- Xenograft Model Antitumor Assays
- Organoids
- Tumor Cells, Cultured
- Primary Cell Culture
- Axin Protein/genetics
- Axin Protein/metabolism
- Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors
- Jumonji Domain-Containing Histone Demethylases/metabolism
- Wnt Proteins/metabolism
- Cyclin-Dependent Kinase Inhibitor p15/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Precision Medicine/methods
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Humans
- Animals
- Mice
- Genes, Tumor Suppressor
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/genetics
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Epigenesis, Genetic/drug effects
- Male
- Mice, Inbred BALB C
- RNA-Seq
- Loss of Function Mutation
- Down-Regulation
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Drug Synergism
- Adult
- Middle Aged
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Affiliation(s)
- Chengfang Tang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Chu Tang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Xuanchi Zhu
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Simeng Wang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Yuan Yang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Yu Miao
- Clinical Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoyao Zhao
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Lina Jia
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Jingyu Yang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Yang Su
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lihui Wang
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
| | - Chunfu Wu
- Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, China
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Guo H, Liu Y, Li X, Wang H, Mao D, Wei L, Ye X, Qu D, Huo J, Chen Y. Magnetic Metal-Organic Framework-Based Nanoplatform with Platelet Membrane Coating as a Synergistic Programmed Cell Death Protein 1 Inhibitor against Hepatocellular Carcinoma. ACS NANO 2023; 17:23829-23849. [PMID: 37991391 PMCID: PMC10722610 DOI: 10.1021/acsnano.3c07885] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/23/2023]
Abstract
Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC). However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function. In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment. We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33.77 wt %) and good immune escape. Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs. In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84.15% and prolonged the survival time of mice. Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.
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Affiliation(s)
- Hong Guo
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Yuping Liu
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
- Jiangsu
Clinical Innovation Center of Digestive Cancer of Traditional Chinese
Medicine, Nanjing 210028, China
| | - Xia Li
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Hong Wang
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Dengxuan Mao
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Liangyin Wei
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Xietao Ye
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Ding Qu
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Multi-component
of Traditional Chinese Medicine and Microecology Researh Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Jiege Huo
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu
Clinical Innovation Center of Digestive Cancer of Traditional Chinese
Medicine, Nanjing 210028, China
| | - Yan Chen
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu
Clinical Innovation Center of Digestive Cancer of Traditional Chinese
Medicine, Nanjing 210028, China
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Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022; 400:1345-1362. [PMID: 36084663 DOI: 10.1016/s0140-6736(22)01200-4] [Citation(s) in RCA: 1133] [Impact Index Per Article: 377.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/31/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is one of the most common cancers worldwide and represents a major global health-care challenge. Although viral hepatitis and alcohol remain important risk factors, non-alcoholic fatty liver disease is rapidly becoming a dominant cause of hepatocellular carcinoma. A broad range of treatment options are available for patients with hepatocellular carcinoma, including liver transplantation, surgical resection, percutaneous ablation, and radiation, as well as transarterial and systemic therapies. As such, clinical decision making requires a multidisciplinary team that longitudinally adapts the individual treatment strategy according to the patient's tumour stage, liver function, and performance status. With the approval of new first-line agents and second-line agents, as well as the establishment of immune checkpoint inhibitor-based therapies as standard of care, the treatment landscape of advanced hepatocellular carcinoma is more diversified than ever. Consequently, the outlook for patients with hepatocellular carcinoma has improved. However, the optimal sequencing of drugs remains to be defined, and predictive biomarkers are urgently needed to inform treatment selection. In this Seminar, we present an update on the causes, diagnosis, molecular classification, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, ON, Canada
| | - Riad Salem
- Department of Radiology, Northwestern University, Chicago, IL, USA
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Wang Y, Liu Y, Zhang T, Guan G, Mao T, Liu H, Zhang J, Lu F, Chen X. LncCDCA3L inhibits cell proliferation via a novel RNA structure-based crosstalk with CDCA3 in hepatocellular carcinoma. Liver Int 2022; 42:1432-1446. [PMID: 35230745 DOI: 10.1111/liv.15225] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 11/25/2021] [Accepted: 01/25/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS The molecular mechanisms underlying hepatocellular carcinoma (HCC) remain poorly understood. In this study, we investigated cell division cycle-associated 3 (CDCA3) expression status and characterized a CDCA3-related long non-coding RNA (lncRNA) in HCC. METHODS RT-qPCR and western blot were used to determine CDCA3 expression level in HCC clinical specimens. 5' and 3'-RACE, RNAscope, RNA pull-down, CRISPR/Cas9-based RNA immunoprecipitation (CRIP) and site-directed mutation experiments were used to characterize lncCDCA3L and investigate its function target. Chi-square test and Kaplan-Meier analysis were used to assess lncCDCA3L clinical significance. The effects of lncCDCA3L on HCC development were assessed by overexpression in vitro and in vivo. RESULTS In this study, we found CDCA3 was a potential oncogenic factor in HCC and characterized the lncCDCA3L, which could inhibit CDCA3. LncCDCA3L is significantly downregulated in HCC and its expression level is associated with tumour size and can act as an independent risk factor affecting postoperative survival time in HCC patients. Mechanistically, lncCDCA3L can repress CDCA3 protein level and inhibit hepatocarcinogenesis by directly binding to CDCA3 mRNA at 1423-1455 region via a novel manner based on a hairpin structure motif. CONCLUSIONS Our study collectively unveiled the molecular mechanisms of how lncCDCA3L repressed the tumourigenic properties of HCC cells and exhibited a tumour suppressor character in HCC in a CDCA3-dependent manner. The findings here support lncCDCA3L can be used as a candidate prognostic biomarker for HCC patients.
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Affiliation(s)
- Yongfeng Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China.,Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yongzhen Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China.,Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
| | - Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
| | - Guiwen Guan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
| | - Tianhao Mao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
| | - Hui Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
| | - Jing Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China.,Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, P.R. China
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5
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An J, Oh M, Kim SY, Oh YJ, Oh B, Oh JH, Kim W, Jung JH, Kim HI, Kim JS, Sung CO, Shim JH. PET-Based Radiogenomics Supports mTOR Pathway Targeting for Hepatocellular Carcinoma. Clin Cancer Res 2022; 28:1821-1831. [PMID: 35191466 DOI: 10.1158/1078-0432.ccr-21-3208] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/22/2021] [Accepted: 02/09/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE This work aimed to explore in depth the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets based on this imaging-genomic surrogate. EXPERIMENTAL DESIGN We used RNA sequencing and whole-exome sequencing data obtained from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging as a discovery cohort. The primary radiogenomic results were validated with transcriptomes from a second cohort of 81 patients with more advanced tumors. All patients were allocated to an FDG-avid or FDG-non-avid group according to the PET findings. We also screened potential drug candidates targeting FDG-avid HCCs in vitro and in vivo. RESULTS High FDG avidity conferred worse recurrence-free survival after HCC resection. Whole transcriptome analysis revealed upregulation of mTOR pathway signals in the FDG-avid tumors, together with higher abundance of associated mutations. These clinical and genomic findings were replicated in the validation set. A molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses in the public-access datasets of two cohorts. Treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control in both the hyperglycolytic HCC cell lines and xenograft mouse models. CONCLUSIONS Our PET-based radiogenomic analysis indicates that mTOR pathway genes are markedly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in precision care of patients with HCC.
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Affiliation(s)
- Jihyun An
- Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Gyeonggi, Republic of Korea
| | - Minyoung Oh
- Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seog-Young Kim
- Convergence Medicine Research Center, Asan Medical Center, Seoul, Republic of Korea
- Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yoo-Jin Oh
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Bora Oh
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Ji-Hye Oh
- Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Wonkyung Kim
- Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jin Hwa Jung
- Convergence Medicine Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Ha Il Kim
- Gastroenterology, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Jae-Seung Kim
- Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chang Ohk Sung
- Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Generation of in situ CRISPR-mediated primary and metastatic cancer from monkey liver. Signal Transduct Target Ther 2021; 6:411. [PMID: 34857736 PMCID: PMC8640017 DOI: 10.1038/s41392-021-00799-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Non-human primates (NHPs) represent the most valuable animals for drug discovery. However, the current main challenge remains that the NHP has not yet been used to develop an efficient translational medicine platform simulating human diseases, such as cancer. This study generated an in situ gene-editing approach to induce efficient loss-of-function mutations of Pten and p53 genes for rapid modeling primary and metastatic liver tumors using the CRISPR/Cas9 in the adult cynomolgus monkey. Under ultrasound guidance, the CRISPR/Cas9 was injected into the cynomolgus monkey liver through the intrahepatic portal vein. The results showed that the ultrasound-guided CRISPR/Cas9 resulted in indels of the Pten and p53 genes in seven out of eight monkeys. The best mutation efficiencies for Pten and p53 were up to 74.71% and 74.68%, respectively. Furthermore, the morbidity of primary and extensively metastatic (lung, spleen, lymph nodes) hepatoma in CRISPR-treated monkeys was 87.5%. The ultrasound-guided CRISPR system could have great potential to successfully pursue the desired target genes, thereby reducing possible side effects associated with hitting non-specific off-target genes, and significantly increasing more efficiency as well as higher specificity of in situ gene editing in vivo, which holds promise as a powerful, yet feasible tool, to edit disease genes to build corresponding human disease models in adult NHPs and to greatly accelerate the discovery of new drugs and save economic costs.
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Song X, Wang TX, Zhu XN, Tan SK. Immunological and prognostic significance of CBX2 expression in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2021; 29:1118-1129. [DOI: 10.11569/wcjd.v29.i19.1118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The number of cases of hepatocellular carcinoma (HCC), the sixth most common malignancy and the third leading cause of cancer death worldwide, has risen from 1.6 to 4.6 per 100000 people worldwide over the past 30 years. Guangxi has a high incidence of HCC in China, and its death rate ranks first in the spectrum of causes of tumor death in Guangxi, accounting for about 40% of all deaths from malignant tumors. Exploring the role of chromobox homolog 2 (CBX2) in HCC immunity will provide potential value for the treatment of this malignancy.
AIM To investigate the expression of CBX2 and analyze its immunological and prognostic significance in HCC.
METHODS The expression of CBX2 in 75 cases of HCC and matched non-tumor tissues was detected by tissue microarray and immunohistochemistry. The relationship of CBX2 expression with the clinicopathologic features of HCC and survival prognosis was analyzed. Then, the differential expression of CBX2 between HCC and normal tissues was verified in The Cancer Genomic Atlas (TCGA). Next, we explored the association between CBX2 expression and immunocyte infiltration, determined the relationship between CBX2 expression and immunosuppressors and immunostimulators, and identified the immune events that CBX2 was involved in through relevant GO and KEGG pathway enrichment analyses. A multi-gene risk prediction model was developed using a COX regression model, thereby generating a risk score that is an independent predictor of survival prognosis. ROC analysis was performed to assess the predictive accuracy of the risk score. Finally, a prognostic model with a calibration curve was constructed to predict the patients' survival probability at 3 and 5 years.
RESULTS The positive expression of CBX2 in HCC tissue was 66.7% (50/75), which was significantly higher than that in matched non-tumor tissues (25.3% (19/75); P < 0.01). The expression of CBX2 was associated with TNM stage and AFP status (P < 0.05). The survival time of patients in the CBX2 positive group was significantly lower than that of the CBX2 negative group, suggesting that CBX2 positive expression may be related to the prognosis of HCC patients. TCGA database verification reached the same conclusion. The expression of CBX2 was positively correlated with the infiltration levels of T helper 2 cells. CBX2 was identified to be associated with 10 immunosuppressors and 23 immunostimulators, and enriched analysis of related GO and KEGG pathways showed that CBX2 was associated with immune events such as intestinal immune network for immunoglobulin A production, cytokine-cytokine receptor interactions, cell adhesion molecules, and rheumatoid arthritis.
CONCLUSION CBX2 positive expression may be a prognostic risk factor in HCC patients. Our findings provide evidence for the role of CBX2 in tumor immunity in HCC, suggesting that CBX2 may be a potential immunoprognostic marker for HCC.
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Affiliation(s)
- Xin Song
- School of Public Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Tian-Xian Wang
- School of Public Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Nian Zhu
- School of Public Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Kui Tan
- School of Public Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
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Ma YS, Wu TM, Qian B, Liu YS, Ding H, Fan MM, Liu JB, Yu F, Wang HM, Shi Y, Gu LP, Li L, Tian LL, Wang PY, Wang GR, Wu ZJ, Zou QF, Ling CC, Fu D. KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation. J Cell Mol Med 2021; 25:4040-4052. [PMID: 33621431 PMCID: PMC8051710 DOI: 10.1111/jcmm.16371] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 01/17/2021] [Accepted: 02/01/2021] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP‐qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR‐433, while dual luciferase assay was carried out to confirm the targeting relationship between miR‐433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo‐tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A‐miR‐433‐FXYD3‐PI3K‐AKT axis in the progression of HCC after loss‐ and gain‐function assays. KDM5A p‐p85 and p‐AKT were highly expressed but miR‐433 was down‐regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR‐433 by demethylating H3K4me3 on its promoterregion. miR‐433 negatively targeted FXYD3. Depleting miR‐433 or re‐expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down‐regulated miR‐433 and up‐regulated FXYD3‐PI3K‐AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3‐PI3K‐AKT axis to enhance angiogenesis in HCC by suppressing miR‐433.
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Affiliation(s)
- Yu-Shui Ma
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China.,Cancer Institute, Nantong Tumor Hospital, Nantong, China
| | - Ting-Miao Wu
- Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bin Qian
- Department of General Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Yu-Shan Liu
- Department of Pathology, Nantong Tumor Hospital, Nantong, China
| | - Hua Ding
- Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China
| | - Ming-Ming Fan
- Department of Biliary Surgery IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ji-Bin Liu
- Cancer Institute, Nantong Tumor Hospital, Nantong, China
| | - Fei Yu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui-Min Wang
- Cancer Institute, Nantong Tumor Hospital, Nantong, China
| | - Yi Shi
- Cancer Institute, Nantong Tumor Hospital, Nantong, China
| | - Li-Peng Gu
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liu Li
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lin-Lin Tian
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Pei-Yao Wang
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gao-Ren Wang
- Department of Radiotherapy, Nantong Tumor Hospital, Nantong, China
| | - Zhi-Jun Wu
- Department of Oncology, Nantong Second People's Hospital, Nantong, China
| | - Qi-Fei Zou
- Department of Biliary Surgery IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Chang-Chun Ling
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China
| | - Da Fu
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei, China
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9
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Yu J, Chen GG, Lai PBS. Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies. Med Res Rev 2020; 41:507-524. [PMID: 33026703 DOI: 10.1002/med.21738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/27/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.
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Affiliation(s)
- Jianqing Yu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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10
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Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling. Br J Cancer 2020; 123:1145-1153. [PMID: 32624579 PMCID: PMC7525442 DOI: 10.1038/s41416-020-0971-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 06/01/2020] [Accepted: 06/17/2020] [Indexed: 12/24/2022] Open
Abstract
Background Wisteria floribunda agglutinin (WFA)+ Mac-2-binding protein (M2BPGi) is a novel serum marker for liver fibrosis. Although an elevated serum level of M2BPGi can predict development of hepatocellular carcinoma (HCC), the effect of M2BPGi on HCC remains unclear. There are no reports about the association of M2BPGi with HCC aggressiveness. We aimed to clarify the significance of M2BPGi in HCC. Methods The protein expression of M2BPGi and galectin-3, a ligand of M2BP, and the mRNA expression of M2BP were evaluated in surgically resected human HCC samples. M2BPGi-regulating signals in HCC cells were investigated using transcriptome analysis. The effects of M2BPGi on HCC properties and galectin-3/mTOR signaling were evaluated. Results M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC. Conclusions M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway.
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11
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Cai Z, Chen G, Zeng Y, Dong X, Li Z, Huang Y, Xin F, Qiu L, Xu H, Zhang W, Su X, Liu X, Liu J. Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma. Clin Cancer Res 2019; 25:5284-5294. [PMID: 31217202 DOI: 10.1158/1078-0432.ccr-18-3477] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/27/2019] [Accepted: 06/07/2019] [Indexed: 01/27/2023]
Abstract
PURPOSE Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. EXPERIMENTAL DESIGN We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers. RESULTS All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapse-free survival (P = 0.001) and overall survival (P = 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection. CONCLUSIONS We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.
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MESH Headings
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Circulating Tumor DNA/blood
- Circulating Tumor DNA/genetics
- Follow-Up Studies
- High-Throughput Nucleotide Sequencing/methods
- Humans
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Mutation
- Neoplasm Metastasis
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Prognosis
- Survival Rate
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Affiliation(s)
- Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Geng Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Xiuqing Dong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Zhenli Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Yanbing Huang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Fuli Xin
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Liman Qiu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Haipo Xu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Xiaoping Su
- Children's Heart Center, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
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12
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Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival. J Hepatol 2019; 70:1262-1277. [PMID: 30943423 DOI: 10.1016/j.jhep.2019.01.028] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/21/2018] [Accepted: 01/29/2019] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Around half of patients with HCC will receive systemic therapies during their life span. The pivotal positive sorafenib trial and regulatory approval in 2007 was followed by a decade of negative studies with drugs leading to marginal antitumoral efficacy, toxicity, or trials with a lack of enrichment strategies. This trend has changed over the last 2 years with several compounds, such as lenvatinib (in first-line) and regorafenib, cabozantinib, ramucirumab and nivolumab (in second-line), showing clinical benefit. These successes came at a cost of increasing the complexity of decision-making, and ultimately, impacting the design of future clinical trials. Nowadays, life expectancy with single active agents has surpassed the threshold of 1 year and sequential strategies have provided encouraging outcomes. Overall survival (OS) remains the main endpoint in phase III investigations, but as in other solid tumours, there is a clear need to define surrogate endpoints that both reliably recapitulate survival benefits and can be assessed before additional efficacious drugs are administered. A thorough analysis of 21 phase III trials published in advanced HCC demonstrated a moderate correlation between progression-free survival (PFS) or time to progression (TTP) and OS (R = 0.84 and R = 0.83, respectively). Nonetheless, the significant differences in PFS identified in 7 phase III studies only correlated with differences in OS in 3 cases. In these cases, the hazard ratio (HR) for PFS was ≤0.6. Thus, this threshold is herein proposed as a potential surrogate endpoint of OS in advanced HCC. Conversely, PFS with an HR between 0.6-0.7, despite significance, was not associated with better survival, and thus these magnitudes are considered uncertain surrogates. In the current review, we discuss the reasons for positive or negative phase III trials in advanced HCC, and the strengths and limitations of surrogate endpoints (PFS, TTP and objective response rate [ORR]) to predict survival.
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Affiliation(s)
- Josep M Llovet
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Catalonia, Spain; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
| | - Robert Montal
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Catalonia, Spain
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Voss MH, Chen D, Reising A, Marker M, Shi J, Xu J, Ostrovnaya I, Seshan VE, Redzematovic A, Chen YB, Patel P, Han X, Hsieh JJ, Hakimi AA, Motzer RJ. PTEN Expression, Not Mutation Status in TSC1, TSC2, or mTOR, Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma Treated on the Randomized RECORD-3 Trial. Clin Cancer Res 2018; 25:506-514. [PMID: 30327302 DOI: 10.1158/1078-0432.ccr-18-1833] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 09/06/2018] [Accepted: 10/11/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Genomic alterations in key components of PI3K/mTOR pathway have been proposed as candidate predictive markers for rapalog therapy in renal cell carcinoma (RCC). We tested this hypothesis in patients from a randomized phase II trial of everolimus versus sunitinib. PATIENTS AND METHODS Archival specimens collected at baseline were analyzed with targeted next-generation sequencing (NGS). Focus of interest were alterations in key PI3K pathway components. PTEN expression was assessed by IHC. Association between molecular findings and treatment outcomes was investigated; same associations were tested for 2 everolimus-treated trial cohorts in gastric and hepatocellular carcinoma (HCC). RESULTS Among 184 everolimus-treated patients with RCC with NGS data, mutation rates in genes of interest were 6% (TSC1), 4.4% (TSC2), and 8.2% (mTOR); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence versus absence of mutations in TSC1, TSC2, or mTOR progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; P = 0.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; P = 0.806). Everolimus-treated patients with retained (n = 50) versus lost (n = 50) PTEN IHC expression had median PFS of 5.3 months versus 10.5 months (HR, 2.5; P < 0.001). Such differences were not seen with sunitinib (10.9 months vs. 10.3 months; HR, 0.8; P = 0.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts. CONCLUSIONS Association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome on everolimus was not confirmed. Clinically meaningful differences in PFS were seen based on PTEN expression by IHC, lost in >50% of patients.
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Affiliation(s)
- Martin H Voss
- Memorial Sloan Kettering Cancer Center, New York City, New York.
| | - David Chen
- Novartis Oncology, East Hanover, New Jersey
| | | | | | - Jiayuan Shi
- Bristol-Myers Squibb Company, Hopewell township, New Jersey
| | - Jianning Xu
- Memorial Sloan Kettering Cancer Center, New York City, New York
| | | | | | | | - Ying-Bei Chen
- Memorial Sloan Kettering Cancer Center, New York City, New York
| | | | - Xia Han
- Novartis Oncology, East Hanover, New Jersey
| | | | - A Ari Hakimi
- Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Robert J Motzer
- Memorial Sloan Kettering Cancer Center, New York City, New York
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14
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Zhu X, Wang Z, Qiu X, Wang W, Bei C, Tan C, Qin L, Ren Y, Tan S. Rs2303428 of MSH2 Is Associated with Hepatocellular Carcinoma Prognosis in a Chinese Population. DNA Cell Biol 2018; 37:634-641. [PMID: 29874113 DOI: 10.1089/dna.2018.4224] [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] [Indexed: 12/13/2022] Open
Abstract
The defects of DNA repair genes may lead to genomic instability and cancer. As an important DNA mismatch repair gene that maintains genomic stability from DNA replication errors, genetic variants of mutS homolog 2 (MSH2) are associated with some cancers. In this study, 1021 hepatocellular carcinoma (HCC) cases and 1021 non-HCC controls from Guangxi were included to explore the association between MSH2 single-nucleotide polymorphisms (SNPs) and HCC. Among the eight MSH2 SNPs, only genotype distribution of rs2303428 was significantly different from HCC and non-HCC patients (p < 0.05). Moreover, CT, TT, and CT/TT genotype of rs2303428 could increase HCC risk [OR (95% CI) = 1.758 (1.195-2.657), 1.846 (1.213-2.896), and 1.823 (1.219-2.763), respectively] and decrease the survival time of HCC patients [codominant, HR (95% CI) = 1.267 (1.046-1.535); dominant, HR (95% CI) = 1.675 (1.162-2.414)]. In addition, rs2303428 was found to interact with HBV infection and family history to increase HCC risk by gene-environment analysis (p < 0.05). Finally, multivariate COX regression analysis showed that rs2303428, tumor number, tumor staging, and metastasis had a significant influence on HCC prognosis. Our results provide MSH2 SNP, rs2303428, as a new prognostic biomarker for HCC patients.
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Affiliation(s)
- Xiaonian Zhu
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Zhigang Wang
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Xiaoqiang Qiu
- 2 Department of Epidemiology and Statistics, School of Public Health, Guangxi Medical University , Nanning, China
| | - Weiwei Wang
- 3 Department of Liver Transplantation, People's Hospital of Zhengzhou University , Zhengzhou, China
| | - Chunhua Bei
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Chao Tan
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Linyuan Qin
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Yuan Ren
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
| | - Shengkui Tan
- 1 Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University , Guilin, China
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15
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Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib. Oncotarget 2018; 7:72622-72633. [PMID: 27579536 PMCID: PMC5341932 DOI: 10.18632/oncotarget.11621] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/20/2016] [Indexed: 02/06/2023] Open
Abstract
ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. CONCLUSIONS Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.
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16
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Bouattour M, Raymond E, Qin S, Cheng A, Stammberger U, Locatelli G, Faivre S. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology 2018; 67:1132-1149. [PMID: 28862760 PMCID: PMC5873445 DOI: 10.1002/hep.29496] [Citation(s) in RCA: 200] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 07/25/2017] [Accepted: 08/18/2017] [Indexed: 12/16/2022]
Abstract
Aberrant c-Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may indicate that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. (Hepatology 2018;67:1132-1149).
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Affiliation(s)
- Mohamed Bouattour
- Digestive Oncology DepartmentBeaujon University HospitalClichyFrance
| | - Eric Raymond
- Oncology UnitGroupe Hospitalier Paris Saint JosephParisFrance
| | - Shukui Qin
- Medical Oncology DepartmentNanjing Bayi HospitalNanjingChina
| | | | | | | | - Sandrine Faivre
- Medical Oncology DepartmentBeaujon University HospitalClichyFrance
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17
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Cai X, Chen Z, Chen J, Ma X, Bai M, Wang T, Chen X, Wu D, Wei L, Li X, Lin Q, Wen J, Ruan D, Lin Z, Dong M, Wu X. Albumin-to-Alkaline Phosphatase Ratio as an Independent Prognostic Factor for Overall Survival of Advanced Hepatocellular Carcinoma Patients without Receiving Standard Anti-Cancer Therapies. J Cancer 2018; 9:189-197. [PMID: 29290785 PMCID: PMC5743727 DOI: 10.7150/jca.21799] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Albumin-to-Alkaline Phosphatase Ratio (ALB/ALP ratio, AAPR), a newly developed index of liver function, has been rarely discussed about its prognostic value in malignancies. The current study attempted to evaluate the prognostic prediction of AAPR in advanced HCC. Methods 237 advanced HCC patients who refused any standard anti-cancer therapies were retrospectively analyzed. The threshold value of AAPR was determined by receiver operating characteristic (ROC) curve. Univariate analyses using Kaplan-Meier method and log-rank test, and multivariate analysis using Cox proportional hazards regression model were conducted. Comparisons of ROC curves and likelihood ratio test (LRT) were utilized to compare the value of different factors in predicting survival. Results ROC curve analysis confirmed 0.38 as the optimal cutoff value of AAPR in evaluating overall survival (OS). Patients with an AAPR > 0.38 exhibited significantly lower frequencies of ascites, portal vein tumor thrombus, Child-Pugh grade B & C, and KPS < 70 (all P < 0.05). These patients also displayed a longer median survival time than those with an AAPR ≤ 0.38 (5.8 m vs 2.4 m, P < 0.01). Univariate and multivariate analyses identified AAPR as an independent prognostic indicator (HR = 0.592, P = 0.007). Furthermore, we integrated AAPR with TNM system and found that area under curve of AAPR-TNM system was significantly larger than that of TNM system when predicting 3-month survival (0.670 vs 0.611, P < 0.01). Moreover, LRT indicated that AAPR-TNM system had a significantly larger χ2 (26.4 vs 16.4, P < 0.01) and a significantly smaller Akaike information criterion value (1936 vs 1948, P < 0.01) comparing with TNM system. Conclusions Our study implied that AAPR was a potentially valuable prognostic index for advanced HCC patients without receiving any standard anti-cancer therapies. AAPR-TNM system preceded TNM system in predicting overall survival in this study.
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Affiliation(s)
- Xiurong Cai
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Zhanhong Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
- Department of Medical Oncology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, Guangzhou, 510060, People's Republic of China
| | - Jie Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiaokun Ma
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Mingjun Bai
- Department of Intervention and Radiology, Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Tiantian Wang
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiangwei Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Donghao Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Li Wei
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xing Li
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Qu Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Jingyun Wen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Danyun Ruan
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Zexiao Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Min Dong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
| | - Xiangyuan Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People's Republic of China
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Bei C, Zhang Y, Wei R, Zhu X, Wang Z, Zeng W, Chen Q, Tan S. Clinical significance of CMTM4 expression in hepatocellular carcinoma. Onco Targets Ther 2017; 10:5439-5443. [PMID: 29180877 PMCID: PMC5694205 DOI: 10.2147/ott.s149786] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
CMTM4 is the most conserved member of chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family on chromosome 16q22.1, a locus that harbors a number of tumor-suppressor genes. In previous studies, CMTM4 was reported to be downregulated and exhibited tumor-suppressor activities by regulating cell growth and cell cycle in clear cell renal cell carcinoma. However, its roles in tumorigenesis of hepatocellular carcinoma (HCC) remain poorly studied. This study first investigated the expression of CMTM4 in HCC, and then examined the association between the expression of CMTM4 with the clinicopathological features and prognosis of HCC patients. It was found that CMTM4 was downregulated in HCC tissues, compared with matched adjacent nontumor tissues, as detected by immunohistochemistry. In addition, Kaplan-Meier survival analysis showed that the negative expression of CMTM4 was associated with decreased overall survival rates in patients with HCC. The results of this study suggest CMTM4 plays a role as a tumor suppressor in HCC and CMTM4 negative expression is a risk factor for poor prognosis of HCC.
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Affiliation(s)
- Chunhua Bei
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
| | - Ying Zhang
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
| | - Riming Wei
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
| | - Xiaonian Zhu
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
| | - Zhigang Wang
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
| | - Wen Zeng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University
| | - Qiuyue Chen
- Department of Pathology, 181st Hospital of Chinese People's Liberation Army, Guilin, People's Republic of China
| | - Shengkui Tan
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University
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19
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Soluble intercellular adhesion molecule-1 is associated with hepatocellular carcinoma risk: multiplex analysis of serum markers. Sci Rep 2017; 7:11169. [PMID: 28894136 PMCID: PMC5593940 DOI: 10.1038/s41598-017-10498-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Individualized assessment of hepatocellular carcinoma (HCC) risk in chronic liver disease remains challenging. Serum biomarkers including cytokines may offer helpful adjuncts to standard parameters for risk prediction. Our aim was to identify markers associated with increased HCC incidence. This was a prospective cohort study of 282 patients with both viral or non-viral chronic liver disease. Baseline serum cytokines and other markers were measured in multiplex with a commercially-available Luminex-based system. Patients were followed until death or HCC diagnosis. We performed Lasso-based survival analysis to determine parameters associated with HCC development. Cytokine mean florescence intensity (MFI) was the primary predictor and HCC development the primary outcome. 25 patients developed HCC with total follow-up of 1,363 person-years. Parameters associated with increased HCC incidence were cirrhosis, hepatic decompensation, and soluble serum intercellular adhesion molecule 1 (sICAM-1) MFI. No other molecules increased predictive power for HCC incidence. On univariate analysis, the parameters associated with HCC incidence in patients with cirrhosis were age, antiviral treatment, and high sICAM-1 MFI; on multivariate analysis, sICAM-1 remained associated with HCC development (adjusted HR = 2.75). On unbiased screening of serum cytokines and other markers in a diverse cohort, baseline sICAM-1 MFI is associated with HCC incidence.
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20
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Rimassa L, Pressiani T, Personeni N, Santoro A. Regorafenib for the treatment of unresectable hepatocellular carcinoma. Expert Rev Anticancer Ther 2017; 17:567-576. [PMID: 28580808 DOI: 10.1080/14737140.2017.1338955] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions.
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Affiliation(s)
- Lorenza Rimassa
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy
| | - Tiziana Pressiani
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy
| | - Nicola Personeni
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy.,b Department of Medical Biotechnology and Translational Medicine , University of Milan , Milan , Italy
| | - Armando Santoro
- a Medical Oncology and Hematology Unit, Humanitas Cancer Center , Humanitas Clinical and Research Center , Rozzano ( Milan ), Italy.,c Humanitas University , Rozzano ( Milan ), Italy
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21
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Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. Oncotarget 2017; 8:55715-55730. [PMID: 28903454 PMCID: PMC5589693 DOI: 10.18632/oncotarget.18382] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients.
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22
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Zhu X, Liu W, Qiu X, Wang Z, Tan C, Bei C, Qin L, Ren Y, Tan S. Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population. Oncotarget 2017; 8:80039-80049. [PMID: 29108386 PMCID: PMC5668119 DOI: 10.18632/oncotarget.16899] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 03/27/2017] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 (MLH1) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.
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Affiliation(s)
- Xiaonian Zhu
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Wei Liu
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Xiaoqiang Qiu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China
| | - Zhigang Wang
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Chao Tan
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Chunhua Bei
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Linyuan Qin
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Yuan Ren
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
| | - Shengkui Tan
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical University, Guilin 541004, Guangxi, People's Republic of China
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Sia D, Villanueva A, Friedman SL, Llovet JM. Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis. Gastroenterology 2017; 152:745-761. [PMID: 28043904 DOI: 10.1053/j.gastro.2016.11.048] [Citation(s) in RCA: 816] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/09/2016] [Accepted: 11/26/2016] [Indexed: 12/11/2022]
Abstract
Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor β, and Wnt-catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making.
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Affiliation(s)
- Daniela Sia
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott L Friedman
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, BCLC, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
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24
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Zeng W, Zhu XN, Luo W, Chen QY, Zhang Y, Tan SK. Clinical significance of expression of CMTM7 in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2016; 24:4568-4575. [DOI: 10.11569/wcjd.v24.i34.4568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of CMTM7 in hepatocellular carcinoma (HCC) and to analyze its clinical significance.
METHODS Tissue microarray and immunohistochemistry method were used to detect 75 pairs of HCC tissues and tumor-adjacent normal tissues. The relationship of CMTM7 expression with clinical pathological features and overall survival of postoperative patients was analyzed statistically.
RESULTS The expression rate of CMTM7 in HCC tissues (20.00%, 15/75) was significantly lower than that in paired para-carcinoma normal tissues (81.33%, 61/75; P < 0.05). The expression of CMTM7 in HCC had no obvious correlation with gender, age, smoking history, drinking history, family history of hepatitis B virus infection or tumor, tumor number, pathological classification, or clinical stage. However, CMTM7 expression had a significant correlation with liver cirrhosis, distant metastasis, tumor size, TNM stage, and α-fetoprotein levels (P < 0.05). The survival time of postoperative HCC patients in the CMTM7 negative group was obviously lower than that of patients in the CMTM7 positive group, suggesting that CMTM7 expression may be related to the prognosis of HCC patients.
CONCLUSION The down-regulated expression of CMTM7 may be closely related with the occurrence and development of HCC.
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25
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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