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Zhang M, Yuan W, Li C, Chen C, Liu X, Ma Z, Xiang Y, Chen G, Wang C, Li L, Wang L, Xu Z, Xu C. Resveratrol and N-acetylcystein reduce hepatic steatosis but enhance initiation and progression of hepatocellular carcinoma by inhibiting GST-pi-MAPK axis in mice. Front Pharmacol 2025; 16:1574039. [PMID: 40356978 PMCID: PMC12066552 DOI: 10.3389/fphar.2025.1574039] [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: 02/10/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Accumulating evidence indicates that antioxidants promote tumor growth and metastasis after tumor onset in several cancer types. However, whether antioxidants prevent or accelerate hepatic tumorigenesis during steatosis remains unknown. Therefore, we investigated the effects of resveratrol (RES) and N-acetylcysteine (NAC) on hepatocellular carcinoma (HCC) development using two fatty liver mouse models. Methods High-fat diet (HFD) plus diethylnitrosamine (DEN)- and AKT/Ras-induced primary HCC mouse models were used. The weight, liver weight ratio and the number of HCC tumors were calculated and histological features of mouse HCC tissues were analyzed using immumohistochemical staining such as hematoxylin and eosin staining. Proteomic analysis was used to screen for differences in liver cancer progression between antioxidant-treated HCC and models. Protein inhibitor recovery experiments in mice and in vitro cells validate the targets screened by proteomic analysis. The expression of GST-pi, p-JNK and p-p38 signaling molecules in HCC were investigated using Western blotting. Results RES and NAC enhance HCC formation in both DEN/HFD and AKT/Ras mice. RES and NAC alleviate hepatosteatosis, and reduce ROS and DNA damage in mice. Proteomic analysis and protein inhibitor recovery assay demonstrated that GST-pi is a therapeutic target for antioxidant-induced hepatocellular carcinoma growth. Mechanistically, RES and NAC decreased p-JNK and p-p38, the two major mitogen-activated protein kinases, in HCC cells. Blockade of GST-pi abrogated the reduction in p-JNK and p-p38 levels and increased apoptosis of HCC cells. Conclusion Antioxidants may increase the incidence of HCC in a population with fatty liver, despite reduction in ROS production, by inhibiting GST-pi-MAPK axis.
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Affiliation(s)
- Mi Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Weigang Yuan
- Department of Clinical Laboratory, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, China
| | - Chun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chanyuan Chen
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhilu Ma
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifei Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guisha Chen
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Chunxu Wang
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingli Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhong Xu
- Department of Gastroenterology and Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Health Management Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Peng Z, Xu S, Wang H, Huang Y, Liu S, Jiao Z, Lin M, Zhu P, Chen Y, Shi Y, Wang Y, Li Y, Yuan W, Wu X, Jiang Z, Li F, Fan X. Identification of GDP as a small inhibitory molecule in HepG2 cells by non‑targeted metabolomics analysis. Oncol Lett 2025; 29:178. [PMID: 39990806 PMCID: PMC11843412 DOI: 10.3892/ol.2025.14924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/12/2024] [Indexed: 02/25/2025] Open
Abstract
Identifying the mechanism by which lipid metabolism regulates cancer may offer a novel approach for therapeutic intervention. It has previously been identified that a lipid metabolism-related factor, namely fatty acid hydroxylase domain containing 2 (FAXDC2), is downregulated in various types of cancer, and inhibits the proliferation and migration of liver cancer cells through a mechanism associated with ERK. The liver is important for lipid metabolism, and FAXDC2 is involved in the synthesis of cholesterol and sphingomyelin. However, the functional mechanism by which FAXDC2 influences liver cancer cells through metabolic processes and ERK signaling remains unclear. Therefore, the present study induced the overexpression of FAXDC2 in HepG2 liver cancer cells and performed a metabolomics analysis. This identified guanosine diphosphate (GDP) as a significantly altered metabolite. Using AlphaFold3, a robust interaction was predicted between FAXDC2 and GDP, which lead to the hypothesis that GDP may mediate the inhibitory effects of FAXDC2 on liver cancer cells by directly modulating the functional properties of the cells, thereby influencing their behavior and progression. Cell Counting Kit-8 assays were used to study the impact of elevated GDP concentrations on HepG2 cell growth. The results revealed a gradual reduction in the viability of HepG2 cells as the GDP concentration increased. In addition, western blotting showed that GDP treatment was accompanied by a significant downregulation of cyclin dependent kinase 4 and cyclin D1 expression levels, and Transwell experiments revealed that GDP treatment significantly decreased the invasion of HepG2 cells. Treatment with GDP also significantly inhibited the expression of ERK. In summary, the present study is the first to indicate that GDP is a metabolic small molecule with inhibitory activity in cancer cells, which has previously been overlooked in tumor metabolic reprogramming. The study findings offer new insights and strategies for the diagnosis and treatment of liver cancer, and potentially other types of cancer.
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Affiliation(s)
- Zhilin Peng
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Siting Xu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Haocheng Wang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Yanli Huang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Siyuan Liu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Zhongbei Jiao
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Mei Lin
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Ping Zhu
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yu Chen
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yan Shi
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yuequn Wang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Yongqing Li
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Wuzhou Yuan
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Xiushan Wu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Zhigang Jiang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Fang Li
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Xiongwei Fan
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
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Aoki T, Nishida N, Minami Y, Kudo M. The Impact of Normal Hepatobiliary Cell Zonation Programs on the Phenotypes and Functions of Primary Liver Tumors. Liver Cancer 2025; 14:92-103. [PMID: 40144466 PMCID: PMC11936443 DOI: 10.1159/000541077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/21/2024] [Indexed: 03/28/2025] Open
Abstract
Background Traditional tumor classifications have relied on cellular origin, pathological morphological features, gene expression profiles, and more recently, the tumor immune microenvironment. While these classifications provide valuable insights, incorporating physiological classifications focusing on liver metabolic functions may lead to new discoveries. Summary We proposed to reclassify benign and malignant hepatocellular neoplasms based on their physiological functions such as albumin production, bile acid production, glycolysis, glycogenesis, and adipogenesis. We further demonstrated the homology between signal pathways activated by the differentiation program of the normal hepatobiliary cells and those activated by genetic abnormalities in tumors. Specifically, Wnt/β-catenin, RAS, NOTCH, and TGF-β signaling not only contribute to cell differentiation via activation of liver-enriched transcription factors but also determine the tumor traits. Examining the distinctions between hepatocellular carcinomas (HCCs) that maintain or lose metabolic functions can yield valuable insights into the drivers of biological malignancy and tumor plasticity. Key Messages To confirm the homology between the differentiation programs of normal hepatobiliary cells, hepatocellular adenomas (HCA), and HCC we identify liver-specific functions such as catabolism and anabolism within tumors. HCCs and HCAs that have lost these metabolic functions exhibit characteristics such as dedifferentiation, resemblance to biliary cells, or increased glycolysis. Focusing on this underexplored area will likely stimulate active research into new tumor characteristics.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [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: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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Yu H, Wang C, Ke S, Xu Y, Lu S, Feng Z, Bai M, Qian B, Xu Y, Li Z, Yin B, Li X, Hua Y, Zhou M, Li Z, Fu Y, Ma Y. An integrative pan-cancer analysis of MASP1 and the potential clinical implications for the tumor immune microenvironment. Int J Biol Macromol 2024; 280:135834. [PMID: 39307490 DOI: 10.1016/j.ijbiomac.2024.135834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/07/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024]
Abstract
Mannose-binding lectin-associated serine protease 1 (MASP1) plays a crucial role in the complement lectin pathway and the mediation of immune responses. However, comprehensive research on MASP1 across various cancer types has not been performed to date. This study aimed to evaluate the significance of MASP1 in pan-cancer. The Cancer Genome Atlas (TCGA), UCSC Xena and Genotype Tissue Expression (GTEx) databases were used to evaluate the expression profiles, genomic features, prognostic relevance, and immune microenvironment associations of MASP1 across 33 cancer types. We observed significant dysregulation of MASP1 expression in multiple cancers, with strong associations between MASP1 expression levels and diagnostic value as well as patient prognosis. Mechanistic insights revealed significant correlations between MASP1 levels and various immunological and genomic factors, including tumor-infiltrating immune cells (TIICs), immune-related genes, mismatch repair (MMR), tumor mutation burden (TMB), and microsatellite instability (MSI), highlighting a critical regulatory function of MASP1 within the tumor immune microenvironment (TIME). In vitro and in vivo experiments demonstrated that MASP1 expression was markedly decreased in liver hepatocellular carcinoma (LIHC). Moreover, the overexpression of MASP1 in hepatocellular carcinoma (HCC) cell lines significantly inhibited their proliferation, invasion and migration. In conclusion, MASP1 exhibits differential expression in the pan-cancer analyses and might play an important role in TIME. MASP1 is a promising prognostic biomarker and a potential target for immunological research, particularly in LIHC.
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Affiliation(s)
- Hongjun Yu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoqun Wang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Shanjia Ke
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Xu
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Xihu University, Hangzhou, China
| | - Shounan Lu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhigang Feng
- The First Department of General Surgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China
| | - Miaoyu Bai
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baolin Qian
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Xu
- Department of Pediatrics, Hainan Hospital of PLA General Hospital, Hainan, China
| | - Zihao Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Yin
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongliang Hua
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Menghua Zhou
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongyu Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Fu
- Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Yong Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Valente LC, Bacil GP, Riechelmann-Casarin L, Barbosa GC, Barbisan LF, Romualdo GR. Exploring in vitro modeling in hepatocarcinogenesis research: morphological and molecular features and similarities to the corresponding human disease. Life Sci 2024; 351:122781. [PMID: 38848937 DOI: 10.1016/j.lfs.2024.122781] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 04/04/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
The hepatocellular carcinoma (HCC) features a remarkable epidemiological burden, ranking as the third most lethal cancer worldwide. As the HCC-related molecular and cellular complexity unfolds as the disease progresses, the use of a myriad of in vitro models available is mandatory in translational preclinical research setups. In this review paper, we will compile cutting-edge information on the in vitro bioassays for HCC research, (A) emphasizing their morphological and molecular parallels with human HCC; (B) delineating the advantages and limitations of their application; and (C) offering perspectives on their prospective applications. While bidimensional (2D) (co) culture setups provide a rapid low-cost strategy for metabolism and drug screening investigations, tridimensional (3D) (co) culture bioassays - including patient-derived protocols as organoids and precision cut slices - surpass some of the 2D strategies limitations, mimicking the complex microarchitecture and cellular and non-cellular microenvironment observed in human HCC. 3D models have become invaluable tools to unveil HCC pathophysiology and targeted therapy. In both setups, the recapitulation of HCC in different etiologies/backgrounds (i.e., viral, fibrosis, and fatty liver) may be considered as a fundamental guide for obtaining translational findings. Therefore, a "multimodel" approach - encompassing the advantages of different in vitro bioassays - is encouraged to circumvent "model-biased" outcomes in preclinical HCC research.
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Affiliation(s)
- Leticia Cardoso Valente
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | - Gabriel Prata Bacil
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Luana Riechelmann-Casarin
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | | | - Luís Fernando Barbisan
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Guilherme Ribeiro Romualdo
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil.
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Raghav A, Goo-Bo-Jeong. Two-Dimensional (2D) Based Hybrid Polymeric Nanoparticles as Novel Potential Therapeutics in the Treatment of Hepatocellular Carcinoma. ENGINEERING MATERIALS 2024:329-349. [DOI: 10.1007/978-981-99-8010-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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8
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Kim MS, Lee WS, Jin W. TrkB inhibition of DJ-1 degradation promotes the growth and maintenance of cancer stem cell characteristics in hepatocellular carcinoma. Cell Mol Life Sci 2023; 80:303. [PMID: 37749450 PMCID: PMC10520132 DOI: 10.1007/s00018-023-04960-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/06/2023] [Accepted: 09/10/2023] [Indexed: 09/27/2023]
Abstract
Although TrkB may be associated with the pathogenesis of various cancer by upregulation, how upregulation of TrkB led to tumor progression in hepatocellular carcinoma (HCC) and the signaling mechanisms by which TrkB induces motility, invasion, metastasis, drug resistance, and acquisition of self-renewal traits has remained unclear. Here, we demonstrated that TrkB was significantly upregulated in highly metastatic HCC cells and HCC patients. Also, the increased TrkB levels were significantly correlated with tumor stages and poor survival of HCC patients. Furthermore, the upregulated TrkB expression enhances the metastatic ability of HCC cells through reduced anoikis sensitivity, induced migration, and colony formation. Most strikingly, TrkB markedly enhances the activation of STAT3 by preventing DJ-1 degradation through the formation of the TrkB/DJ-1 complex. This signaling mechanism is responsible for triggering cellular traits of highly aggressive HCC. The activation of the EMT program of HCC via increasing DJ-1 stability by TrkB induces the gain of cancer stem cell states and chemoresistance via the upregulation of stem cells cell markers and ABC transporters. Also, TrkB-mediated inhibition of DJ-1 degradation promotes tumor formation and metastasizes to other organs in vivo. Our observations illustrate that TrkB is a prognostic and therapeutic targeting in promoting aggressiveness and metastasis of HCC.
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Affiliation(s)
- Min Soo Kim
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon, 21999, Republic of Korea
| | - Won Sung Lee
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon, 21999, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Korea
| | - Wook Jin
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon, 21999, Republic of Korea.
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Gorji L, Brown ZJ, Pawlik TM. Mutational Landscape and Precision Medicine in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4221. [PMID: 37686496 PMCID: PMC10487145 DOI: 10.3390/cancers15174221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC.
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Affiliation(s)
- Leva Gorji
- Department of Surgery, Kettering Health Dayton, Dayton, OH 45405, USA;
| | - Zachary J. Brown
- Department of Surgery, Division of Surgical Oncology, New York University—Long Island, Mineola, NY 11501, USA;
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus, OH 43210, USA
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Yagi K, Shimada S, Akiyama Y, Hatano M, Asano D, Ishikawa Y, Ueda H, Watanabe S, Akahoshi K, Ono H, Tanabe M, Tanaka S. Loss of SFXN1 mitigates lipotoxicity and predicts poor outcome in non-viral hepatocellular carcinoma. Sci Rep 2023; 13:9449. [PMID: 37296228 PMCID: PMC10256799 DOI: 10.1038/s41598-023-36660-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) imposes a huge global burden, arising from various etiological factors such as hepatitis virus infection and metabolic syndrome. While prophylactic vaccination and antiviral treatment have decreased the incidence of viral HCC, the growing prevalence of metabolic syndrome has led to an increase in non-viral HCC. To identify genes downregulated and specifically associated with unfavorable outcome in non-viral HCC cases, screening analysis was conducted using publically available transcriptome data. Among top 500 genes meeting the criteria, which were involved in lipid metabolism and mitochondrial function, a serine transporter located on inner mitochondrial membrane SFXN1 was highlighted. SFXN1 protein expression was significantly reduced in 33 of 105 HCC tissue samples, and correlated to recurrence-free and overall survival only in non-viral HCC. Human HCC cells with SFXN1 knockout (KO) displayed higher cell viability, lower fat intake and diminished reactive oxygen species (ROS) production in response to palmitate administration. In a subcutaneous transplantation mouse model, high-fat diet feeding attenuated tumorigenic potential in the control cells, but not in the SFXN1-KO cells. In summary, loss of SFXN1 expression suppresses lipid accumulation and ROS generation, preventing toxic effects from fat overload in non-viral HCC, and predicts clinical outcome of non-viral HCC patients.
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Affiliation(s)
- Kohei Yagi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Megumi Hatano
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Daisuke Asano
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshiya Ishikawa
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroki Ueda
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shuichi Watanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichi Akahoshi
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Ono
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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11
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Chen G, Zhang Z, Li J, Hu C, Gao D, Chen J, Zhang L, Xie X. Phosphatase regenerating liver 3 participates in Integrinβ1/FAK-Src/MAPK signaling pathway and contributes to the regulation of malignant behaviors in hepatocellular carcinoma cells. J Gastrointest Oncol 2023; 14:863-873. [PMID: 37201051 PMCID: PMC10186527 DOI: 10.21037/jgo-22-976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 02/10/2023] [Indexed: 12/09/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the leading cause of mortality worldwide. Phosphatase regenerating liver 3 (PRL-3) was associated with cancer metastasis. However, the significance of PRL-3 in the prognosis of HCC remains elusive. The aim of this study was to elucidate the role of PRL-3 in HCC metastasis and its prognosis. METHODS The expressions of PRL-3 in cancer tissues isolated from 114 HCC patients, who underwent curative hepatectomy from May to November in 2008, were analyzed by immunohistochemistry, and its prognostic significance was evaluated. Thereafter, the migration, invasion, and metastatic alterations in MHCC97H cells with PRL-3 overexpression or knockdown were explored and compared with the tumor size and lung metastasis in orthotopic HCC model of nude mice derived from MHCC97H cells with PRL-3 overexpression or knockdown. The underlying mechanism involving PRL-3-mediated effect on HCC migration, invasion, and metastasis was further examined. RESULTS Univariate and multivariate analysis demonstrated PRL-3 overexpression was an independent prognostic factor for poor overall survival (OS) and progression-free survival (PFS) of the HCC patients. Increased PRL-3 expression in MHCC97H cells was in accordance with the enhanced metastasis potential. PRL-3 knockdown inhibited the migration, invasiveness, and clone forming ability in MHCC97H cells, whereas PRL-3 overexpression reverted the above behavior. The growth of xenograft tumor in the liver was suppressed, and the lung metastasis in nude mice was inhibited by PRL-3 downregulation. The knockdown of PRL-3 could downregulate the expressions of Integrinβ1 and p-Src (Tyr416), p-Erk (Thr202/Tyr204) activation, and reduce MMP9 expression. Both MEK1/2 inhibitor (U0126) and Src inhibitor could repress PRL-3-induced invasiveness and migration in MHCC97H cells. CONCLUSIONS PRL-3 was significantly overexpressed and an independent prognostic factor to predict the death of HCC patients. Mechanically, PRL-3 plays a critical role in HCC invasive and metastasis via Integrinβ1/FAK-Src/RasMAPK signaling. Validation of PRL-3 as a clinical prediction marker in HCC warrants further research.
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Affiliation(s)
- Guobin Chen
- Department of Hepatic Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, China
| | - Zhenzhen Zhang
- Department of Hepatic Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, China
| | - Jinghuan Li
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chao Hu
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongmei Gao
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun Chen
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lan Zhang
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoying Xie
- Department of Hepatic Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, China
- Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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12
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Cunningham RP, Kang SWS, Porat-Shliom N. Location matters: cellular heterogeneity in the hepatic lobule and hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 2023; 324:G245-G249. [PMID: 36749570 PMCID: PMC10010932 DOI: 10.1152/ajpgi.00278.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tumor heterogeneity is a hallmark of cancer but a challenging problem to dissect mechanistically. Less recognized is that cells within normal tissues are also remarkably diverse. Hepatocytes are a great example because their spatial positioning and the local microenvironment govern their genetic heterogeneity. Recent studies show that primary liver tumors display heterogeneity similar to that observed in the normal tissue providing clues to the cellular precursor of the tumor and how variations in the lobule microenvironment support tumor formation and aggressiveness. Identifying the principles that control cellular diversity in a healthy liver may highlight potential mechanisms driving hepatic tumor heterogeneity.
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Affiliation(s)
- Rory P Cunningham
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Sun Woo Sophie Kang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Natalie Porat-Shliom
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
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13
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Pan Y, Zhang D, Chen Y, Li H, Wang J, Yuan Z, Sun L, Zhou Z, Chen M, Zhang Y, Hu D. Development and validation of robust metabolism-related gene signature in the prognostic prediction of hepatocellular carcinoma. J Cell Mol Med 2023; 27:1006-1020. [PMID: 36919714 PMCID: PMC10064027 DOI: 10.1111/jcmm.17718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/03/2023] [Accepted: 02/28/2023] [Indexed: 03/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Given metabolic reprogramming in tumours was a crucial hallmark, several studies have demonstrated its value in the diagnostics and surveillance of malignant tumours. The present study aimed to identify a cluster of metabolism-related genes to construct a prediction model for the prognosis of HCC. Multiple cohorts of HCC cases (466 cases) from public datasets were included in the present analysis. (GEO cohort) After identifying a list of metabolism-related genes associated with prognosis, a risk score based on metabolism-related genes was formulated via the LASSO-Cox and LASSO-pcvl algorithms. According to the risk score, patients were stratified into low- and high-risk groups, and further analysis and validation were accordingly conducted. The results revealed that high-risk patients had a significantly worse 5-year overall survival (OS) than low-risk patients in the GEO cohort. (30.0% vs. 57.8%; hazard ratio [HR], 0.411; 95% confidence interval [95% CI], 0.302-0.651; p < 0.001) This observation was confirmed in the external TCGA-LIHC cohort. (34.5% vs. 54.4%; HR 0.452; 95% CI, 0.299-0.681; p < 0.001) To promote the predictive ability of the model, risk score, age, gender and tumour stage were integrated into a nomogram. According to the results of receiver operating characteristic curves and decision curves analysis, the nomogram score possessed a superior predictive ability than conventional factors, which indicate that the risk score combined with clinicopathological features was able to achieve a robust prediction for OS and improve the individualized clinical decision making of HCC patients. In conclusion, the metabolic genes related to OS were identified and developed a metabolism-based predictive model for HCC. Through a series of bioinformatics and statistical analyses, the predictive ability of the model was approved.
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Affiliation(s)
- Yangxun Pan
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Deyao Zhang
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yuheng Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Huake Li
- Department of Oncology, Changning County People's Hospital, Baoshan, China
| | - Jiongliang Wang
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Ze Yuan
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Liyang Sun
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Zhongguo Zhou
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Minshan Chen
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yaojun Zhang
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Dandan Hu
- Department of Liver Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
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14
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Srivatsa S, Montazeri H, Bianco G, Coto-Llerena M, Marinucci M, Ng CKY, Piscuoglio S, Beerenwinkel N. Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens. Nat Commun 2022; 13:7748. [PMID: 36517508 PMCID: PMC9751287 DOI: 10.1038/s41467-022-35378-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 11/29/2022] [Indexed: 12/15/2022] Open
Abstract
The development of cancer therapies is limited by the availability of suitable drug targets. Potential candidate drug targets can be identified based on the concept of synthetic lethality (SL), which refers to pairs of genes for which an aberration in either gene alone is non-lethal, but co-occurrence of the aberrations is lethal to the cell. Here, we present SLIdR (Synthetic Lethal Identification in R), a statistical framework for identifying SL pairs from large-scale perturbation screens. SLIdR successfully predicts SL pairs even with small sample sizes while minimizing the number of false positive targets. We apply SLIdR to Project DRIVE data and find both established and potential pan-cancer and cancer type-specific SL pairs consistent with findings from literature and drug response screening data. We experimentally validate two predicted SL interactions (ARID1A-TEAD1 and AXIN1-URI1) in hepatocellular carcinoma, thus corroborating the ability of SLIdR to identify potential drug targets.
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Affiliation(s)
- Sumana Srivatsa
- Department of Biosystems Science and Engineering, ETH Zurich, 4058, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Hesam Montazeri
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Gaia Bianco
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland
| | - Mattia Marinucci
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Charlotte K Y Ng
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Department for BioMedical Research, University of Bern, 3008, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.
- Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
| | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zurich, 4058, Basel, Switzerland.
- SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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15
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Ke S, Lu S, Wang C, Xu Y, Bai M, Yu H, Feng Z, Yin B, Li Z, Huang J, Li X, Qian B, Hua Y, Pan S, Wu Y, Ma Y. Comprehensive analysis of the prognostic value and functions of prefoldins in hepatocellular carcinoma. Front Mol Biosci 2022; 9:957001. [PMID: 36438659 PMCID: PMC9691963 DOI: 10.3389/fmolb.2022.957001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 10/28/2022] [Indexed: 11/24/2024] Open
Abstract
Prefoldins (PFDNs), a group of proteins known to be associated with cytoskeletal rearrangement, are involved in tumor progression in various cancer types. However, little is known about the roles of PFDNs in hepatocellular carcinoma (HCC). Herein, we investigated the transcriptional and survival data of PFDNs from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the potential functions of PFDN1/2/3/4. We also detected the expression of PFDN1/2/3/4 via immunohistochemistry (IHC), Western blotting, and real-time PCR in our clinical samples. We found that the PFDN family showed elevated expression in HCC tissues, while only PFDN1/2/3/4 were found to be significantly correlated with poor prognosis of patients with HCC in the TCGA database. Further investigation was associated with PFDN1-4. We found that the expression of PFDN1/2/3/4 was significantly associated with advanced clinicopathologic features. Apart from the TCGA database, IHC, real-time PCR, and immunoblotting identified the overexpression of PFDN1/2/3/4 in HCC tissues and HCC cell lines. Taken together, these results indicated that PFDN1/2/3/4 might be novel prognostic biomarkers and treatment targets for patients with HCC.
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Affiliation(s)
- Shanjia Ke
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shounan Lu
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoqun Wang
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Xu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Miaoyu Bai
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongjun Yu
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhigang Feng
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- The First Department of General Surgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, China
| | - Bing Yin
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zihao Li
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingjing Huang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Li
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baolin Qian
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongliang Hua
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yaohua Wu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Thyroid Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yong Ma
- Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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16
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Charonpongsuntorn C, Tanasanvimon S, Korphaisarn K, Payapwattanawong S, Siripoon T, Pakvisal N, Juengsamarn J, Phaibulvatanapong E, Chindaprasirt J, Prasongsook N, Udomdamrongkul K, Ngamphaiboon N, Sirachainan E. Efficacy, Safety, and Patient-Reported Outcomes of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Thailand: A Multicenter Prospective Study. JCO Glob Oncol 2022; 8:e2200205. [PMID: 36455172 PMCID: PMC10166432 DOI: 10.1200/go.22.00205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
PURPOSE Atezolizumab plus bevacizumab treatment is a first-line therapy for unresectable hepatocellular carcinoma (HCC) worldwide. The efficacy, safety, and patient-reported outcomes (PROs) of HCC in Thailand have not yet been reported. This study aimed to evaluate the efficacy, safety, and PROs of atezolizumab plus bevacizumab. MATERIALS AND METHODS From September 2020 to August 2021, 30 patients with unresectable HCC who met the inclusion criteria of atezolizumab plus bevacizumab as first-line treatment were enrolled. Analysis was assessed for progression-free survival, overall survival, adverse events (AEs), and quality of life (QoL). RESULTS The median progression-free survival and overall survival periods were 6.7 and 10.2 months, respectively. The disease control rate was 63.3%. The frequent AEs were proteinuria, hypertension, and hepatitis. Serious AEs included gastrointestinal bleeding, but none of the patients died from serious AEs. The discontinuation rate was 23.3%, and the median number of treatment cycles was 10.5 cycles. In total, 23.3% of the patients continued treatment after 1 year of therapy. The global health status/QoL and physical function scores showed less deterioration at baseline than at 3 and 6 months (median scores = 76.7, 71.6, and 64.1 in QoL and 84.7, 79.6, and 79.0 in physical function, respectively). The HCC18 symptom score index data showed a slow progression of symptom scores from baseline to 3 and 6 months (12.7, 19.6, and 22.3, respectively). CONCLUSION This study demonstrates that atezolizumab plus bevacizumab is effective and has a safety profile comparable with that of previous studies as first-line therapy for unresectable HCC in a real-world setting and in Thai populations. Data on PROs also demonstrate benefits in terms of patients' QoL and symptoms.
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Affiliation(s)
- Chanchai Charonpongsuntorn
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand
| | - Suebpong Tanasanvimon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital Mahidol University, Bangkok, Thailand
| | - Songwit Payapwattanawong
- Oncology Unit, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Lak Hok, Thailand
| | - Teerada Siripoon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Nussara Pakvisal
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Jitlada Juengsamarn
- Oncology Unit, Department of Medicine, Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand
| | | | - Jarin Chindaprasirt
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Naiyarat Prasongsook
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Phramongkutklao University, Bangkok, Thailand
| | | | - Nuttapong Ngamphaiboon
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Ekaphop Sirachainan
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
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17
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Zi Q, Cui H, Liang W, Chi Q. Machine learning algorithm and deep neural networks identified a novel subtype in hepatocellular carcinoma. Cancer Biomark 2022; 35:305-320. [DOI: 10.3233/cbm-220147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Due to the lack of specific characteristics in the early stage of the disease, patients are usually diagnosed in the advanced stage of disease progression. OBJECTIVE: This study used machine learning algorithms to identify key genes in the progression of hepatocellular carcinoma and constructed a prediction model to predict the survival risk of HCC patients. METHODS: The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The differential expression analysis and COX proportional-hazards model participated in the identification of survival-related genes. K-Means, Random forests, and LASSO regression are involved in identifying novel subtypes of HCC and screening key genes. The prediction model was constructed by deep neural networks (DNN), and Gene Set Enrichment Analysis (GSEA) reveals the metabolic pathways where key genes are located. RESULTS: Two subtypes were identified with significantly different survival rates (p< 0.0001, AUC = 0.720) and 17 key genes associated with the subtypes. The accuracy rate of the deep neural network prediction model is greater than 93.3%. The GSEA analysis found that the survival-related genes were significantly enriched in hallmark gene sets in the MSigDB database. CONCLUSIONS: In this study, we used machine learning algorithms to screen out 17 genes related to the survival risk of HCC patients, and trained a DNN model based on them to predict the survival risk of HCC patients. The genes that make up the model are all key genes that affect the formation and development of cancer.
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Affiliation(s)
- Quan Zi
- Department of Engineering Structure and Mechanics, Wuhan University of Technology, Wuhan, Hubei, China
| | - Hanwei Cui
- Department of Science and Education, Shenzhen Samii Medical Center, Shenzhen, Guangdong, China
| | - Wei Liang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qingjia Chi
- Department of Engineering Structure and Mechanics, Wuhan University of Technology, Wuhan, Hubei, China
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18
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TrkC-mediated inhibition of DJ-1 degradation is essential for direct regulation of pathogenesis of hepatocellular carcinoma. Cell Death Dis 2022; 13:850. [PMID: 36202793 PMCID: PMC9537181 DOI: 10.1038/s41419-022-05298-3] [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: 04/12/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/06/2022]
Abstract
None of the previous studies has systematically explored how upregulation of TrkC plays a central role in the pathogenesis of hepatocellular carcinoma (HCC) by regulating the underlying mechanisms that promote invasion and metastasis. In this report, we demonstrated the possible association between upregulation of TrkC and acquisition of cancer stem cells traits or chemoresistance in HCC. We show that upregulation of TrkC is closely associated with the survival and progression of HCC in vivo and in vitro. Most strikingly, activation of STAT3 by TrkC-mediated inhibition of DJ-1 degradation significantly enhances the efficacy of invasion and metastasis during the progression of HCC cells. Acquiring the traits of cancer stem cells (CSCs) by TrkC/DJ-1/STAT3 signaling pathway leads to the induction of chemoresistance via upregulation of ABC transporters and anti-apoptotic genes. Also, activating the epithelial-mesenchymal transition (EMT) program by inducing EMT-transcription factor (TF)s by TrkC/DJ-1/STAT3 signaling pathway is the direct cause of multiple tumor malignancies of HCC. Thus, understanding the mechanisms by which acquisition of anticancer drug resistance by TrkC-mediated inhibition of DJ-1 degradation can help enhance the efficacy of anticancer therapies.
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Luo W, Wu S, Zhang F, Chen X, Ma Y, Mo Y. Decreased expression of 3-hydroxybutyrate dehydrogenase 1 is a prognostic marker and promotes tumor progression in hepatocellular carcinoma. Pathol Res Pract 2022; 238:154111. [PMID: 36115334 DOI: 10.1016/j.prp.2022.154111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/22/2022] [Accepted: 08/31/2022] [Indexed: 11/22/2022]
Abstract
Growing evidence indicates that altered metabolism represents the hallmark of hepatocellular carcinoma (HCC). The mitochondrial 3-hydroxybutyrate dehydrogenase 1 (BDH1) is a key catalytic enzyme in ketogenesis with unknown roles in HCC. Hundred and four tissue sample pairs (HCC tissues, n = 104; matched normal tissues, n = 104) were obtained and analyzed with immunohistochemical (IHC) staining to investigate the clinical and functional role and the diagnostic and prognostic value of BDH1 in HCC. In addition, RNA-Seq datasets from the Tumor Immune Estimation Resource (TIMER) (HCC group, n = 371; normal group, n = 50) and microarray datasets from the Gene Expression Omnibus (GEO) database (HCC tissues, n = 1671; normal tissues, n = 1479) were used to assess BDH1 expression in HCC. Several bioinformatic methods were performed to identify pathways regulated by BDH1. The IHC staining showed that BDH1 expression decreased in HCC tissues (n = 69) compared with that in adjacent normal tissues (n = 35, P < 0.001). Low BDH1 expression was associated with advanced clinical stage (P = 0.033) and vascular invasion (P = 0.007). Moreover, ectopic expression of BDH1 reduced tumor proliferation and suppressed the migration and invasion of HCC cells in vitro. Therefore, our data suggest that BDH1 is a potentially valuable diagnostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Wenqi Luo
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shu Wu
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Fengyou Zhang
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaoyu Chen
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yun Ma
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yingxi Mo
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, China.
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20
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Zhang G, Lv X, Yang Q, Liu H. Identification of HM13 as a prognostic indicator and a predictive biomarker for immunotherapy in hepatocellular carcinoma. BMC Cancer 2022; 22:888. [PMID: 35964022 PMCID: PMC9375928 DOI: 10.1186/s12885-022-09987-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/02/2022] [Indexed: 12/12/2022] Open
Abstract
Background Histocompatibility minor 13 (HM13) is a signal sequence stubbed intramembrane cleavage catalytic protein that is essential for cell signaling, intracellular communication, and cancer. However, the expression of HM13 and its prognostic value, association with tumor-infiltrating immune cells (TIICs) in the microenvironment, and potential to predict immunotherapeutic response in HCC are unknown. Methods The HM13 expression, clinicopathology analysis, and its influence on survival were analyzed in multiple public databases and further verified in collected HCC and normal tissues by qRT-PCR and immunohistochemistry staining assay (IHC). Furthermore, the lentivirus vector encoding HM13-shRNA to manipulate HM13 expression was selected to investigate whether HM13 could influence the malignant growth and metastasis potential of HCC cells. Finally, significant impacts of HM13 on the HCC tumor microenvironment (TME) and reaction to immune checkpoint inhibitors were analyzed. Results Upregulated HM13 was substantially correlated with poor prognosis in patients with HCC, and could facilitate the proliferation and migratory potential of HCC cells. Additionally, patients with high HM13 expression might be more sensitive to immunotherapy. Conclusions HM13 might be a prognostic biomarker and potential molecular therapeutic target for HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09987-2.
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Affiliation(s)
- Genhao Zhang
- Department of Blood transfusion, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Xianping Lv
- Department of Blood transfusion, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Qiankun Yang
- Department of Blood transfusion, Zhengzhou University First Affiliated Hospital, Zhengzhou, China
| | - Hongchun Liu
- Department of Medical Laboratory, Zhengzhou University First Affiliated Hospital, Zhengzhou, China.
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21
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Üremiş N, Üremiş MM, Çiğremiş Y, Tosun E, Baysar A, Türköz Y. Cucurbitacin I exhibits anticancer efficacy through induction of apoptosis and modulation of JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways in HepG2 cell line. J Food Biochem 2022; 46:e14333. [PMID: 35866877 DOI: 10.1111/jfbc.14333] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/15/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma is a common cancer type, especially among men. Although cucurbitacin I (CuI), widely found in plants belonging to the Ecballium elaterium (E. L) plant family, has been shown to have antitumorigenic properties in many cancer types, its anticancer effect, molecular mechanism, and apoptotic effect mediated by signal pathways on hepatocellular carcinoma have not been fully clarified. In the present study, we investigated the anticancer effect of CuI treated at different doses on the HepG2 cell line and the underlying mechanism in vitro. High-purity CuI was obtained from the E. elaterium plant with the aid of HPLC. The effects of this substance on the viability of cells were studied by the MTT assay. The effects of CuI on cell cycle progression and apoptosis were studied with flow cytometry. DNA breaks were analyzed by the Comet assay method. The proteins and genes involved in the JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways were investigated using Western blot and qRT-PCR, respectively. The results of this study demonstrated that CuI significantly reduced HepG2 cell growth in vitro, induced antiproliferation, and G2/M phase of the cell cycle was interrupted. PRACTICAL APPLICATIONS: CuI administration was shown to downregulate the levels of proteins in the PI3K/AKT/mTOR, MAPK, and JAK2/STAT3 cascades in HepG2 cells. CuI also reduced the expression of MAPK, STAT3, mTOR, JAK2, and Akt genes in different concentrations. DNA breaks are formed as a result of this effect. CuI, by reducing cell proliferation and promoting apoptosis, was found to have potential as a chemotherapeutic agent of hepatocellular carcinoma.
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Affiliation(s)
- Nuray Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Muhammed Mehdi Üremiş
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Yılmaz Çiğremiş
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Emir Tosun
- Department of Chemical Engineering, Faculty of Engineering, Inonu University, Malatya, Turkey
| | - Ahmet Baysar
- Department of Chemical Engineering, Faculty of Engineering, Inonu University, Malatya, Turkey
| | - Yusuf Türköz
- Department of Medical Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
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22
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Eupalinolide B inhibits hepatic carcinoma by inducing ferroptosis and ROS-ER-JNK pathway. Acta Biochim Biophys Sin (Shanghai) 2022; 54:974-986. [PMID: 35866605 PMCID: PMC9827796 DOI: 10.3724/abbs.2022082] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Primary hepatic carcinoma is a common malignant tumor. The classic molecular targeted drug sorafenib is costly and is only effective for some patients. Therefore, it is of great clinical significance to search for new molecular targeted drugs. Eupalinolide B (EB) from Eupatorium lindleyanum DC. is used to treat chronic tracheitis in clinical practice. However, the role of EB in hepatic carcinoma is unknown. In this study, we first measure the effect of EB on tumor growth in a xenograft model and PDX model. The cell proliferation and migration are also detected in human hepatocarcinoma cell lines (SMMC-7721 and HCCLM3). Then, we investigate cell cycle, cell apoptosis, cell necrosis, cell autophagy, and ferroptosis by flow cytometry, western blot analysis and electron microscopy. The results demonstrate that EB exerts anti-proliferative activity in hepatic carcinoma by blocking cell cycle arrest at S phase and inducing ferroptosis mediated by endoplasmic reticulum (ER) stress, as well as HO-1 activation. When HO-1 is inhibited, EB-induced cell death and ER protein expression are rescued. The migration-related mechanism consists of activation of the ROS-ER-JNK signaling pathway and is not connected to ferroptosis. In summary, we first discover that EB inhibits cell proliferation and migration in hepatic carcinoma, and thus EB is a promising anti-tumor compound that can be used for hepatic carcinoma.
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23
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Giardino Torchia ML, Letizia M, Gilbreth R, Merlino A, Sult E, Monks N, Chesebrough J, Tammali R, Chu N, Tong J, Meekin J, Schifferli K, Vashisht K, DaCosta K, Clarke L, Gesse C, Yao XT, Bridges C, Moody G. Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy. Cytotherapy 2022; 24:720-732. [DOI: 10.1016/j.jcyt.2022.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/28/2022] [Accepted: 03/18/2022] [Indexed: 12/11/2022]
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24
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Rimini M, Liscia N, Burgio V, Casadei-Gardini A. Why does survival of hepatocellular carcinoma patients remain so low? Key stumbling blocks and questions in preclinical and clinical development. Expert Opin Investig Drugs 2022; 31:483-494. [PMID: 35275784 DOI: 10.1080/13543784.2022.2053108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION : Hepatocellular carcinoma (HCC) is a complex disease which involves diverse molecular pathways and etiologies. In recent years, several new systemic treatments have improved survival in advanced stage disease, but numerous significant challenges remain. No significant improvements have been achieved in the intermediate stage disease; this may be attributed to the difficulties in stratification of patients and the broad spectrum of clinical situations in terms of tumor burden and liver function. AREAS COVERED : This article considers the recent progress in first- and second-line therapy for advanced HCC. Investigational strategies conducted in intermediate stage HCC, which involve mainly combination therapy with locoregional approaches and systemic drugs, antiangiogenics, immunotherapies (or both), are then examined. Later, the paper offers insights on the questions and challenges that lie ahead for treating HCC. EXPERT OPINION Clinical and biomolecular markers for the stratification of patients are needed for therapeutic progress. Further molecular profiling data could enhance our knowledge of the molecular pathways underlying this tumor and facilitate the identification of targetable aberrations. This could offer opportunities for precision medicine approaches and improved survival.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Nicole Liscia
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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25
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Liu C, Pan J, Liu H, Lin R, Chen Y, Zhang C. Daphnetin inhibits the survival of hepatocellular carcinoma cells through regulating Wnt/β-catenin signaling pathway. Drug Dev Res 2022; 83:952-960. [PMID: 35132666 DOI: 10.1002/ddr.21920] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 01/23/2023]
Abstract
Evidence has demonstrated that Daphnetin has antiangiogenesis activity, indicating it might be a new multi-targeted medication for cancer therapy. Here, we aimed to reveal Daphnetin role in hepatocellular carcinoma (HCC) progression and the underlying mechanism. Huh7 and SK-HEP-1, two human HCC cell lines were used in this study. MTT （3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide）, colony formation, flow cytometry, and tumor-bearing experiments were applied to evaluate the effects of different concentrations of Daphnetin on cell viability, apoptosis, cell cycle, and in vivo tumor formation, respectively. Real-time PCR （Polymerase Chain Reaction）and western blotting were applied to measure the mRNA and protein levels of β-catenin. We observed that Daphnetin inhibited cell viability and tumorigenesis, promoted cell apoptosis, and induced a G1 phase arrest in a dose-dependent manner in both Huh7 and SK-HEP-1 cells, which were rescued by SKL2001, an activator of the Wnt/β-catenin signaling. Taken together, this study reveals that Daphnetin exerts an antitumor role in HCC through the inactivation of Wnt/β-catenin signaling.
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Affiliation(s)
- Chaohui Liu
- Department of General Surgery, The 910th Hospital, Quanzhou, China
| | - Jiansheng Pan
- Department of General Surgery, The 910th Hospital, Quanzhou, China
| | - Hongyu Liu
- Department of General Surgery, The 910th Hospital, Quanzhou, China
| | - Rongkai Lin
- Department of General Surgery, The 910th Hospital, Quanzhou, China
| | - Yijie Chen
- Department of General Surgery, The 910th Hospital, Quanzhou, China
| | - Chenghua Zhang
- Department of General Surgery, The 910th Hospital, Quanzhou, China
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26
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Granzyme B PET Imaging Stratifies Immune Checkpoint Inhibitor Response in Hepatocellular Carcinoma. Mol Imaging 2021; 2021:9305277. [PMID: 35936114 PMCID: PMC9328186 DOI: 10.1155/2021/9305277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/06/2021] [Accepted: 11/14/2021] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [18F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [18F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [18F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [18F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment.
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27
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Pan C, Nie W, Wang J, Du J, Pan Z, Gao J, Lu Y, Che J, Zhu H, Dai H, Chen B, He Q, Dong X. Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors. Eur J Med Chem 2021; 225:113794. [PMID: 34488024 DOI: 10.1016/j.ejmech.2021.113794] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 11/27/2022]
Abstract
Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.
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Affiliation(s)
- Chenghao Pan
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Wenwen Nie
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jiao Wang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jiamin Du
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Zhichao Pan
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jian Gao
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Yang Lu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jinxin Che
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Haibin Dai
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Binhui Chen
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China.
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China; Cancer Center, Zhejiang University, Hangzhou, 310058, PR China.
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28
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Wu F, Xu L, Tu Y, Cheung OK, Szeto LL, Mok MT, Yang W, Kang W, Cao Q, Lai PB, Chan SL, Tan P, Sung JJ, Yip KY, Cheng AS, To KF. Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis. Cancer Lett 2021; 525:115-130. [PMID: 34736960 DOI: 10.1016/j.canlet.2021.10.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of ∼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.
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Affiliation(s)
- Feng Wu
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Liangliang Xu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yalin Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Otto Kw Cheung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lemuel Lm Szeto
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Myth Ts Mok
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Qin Cao
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Bs Lai
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Stephen L Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
| | - Joseph Jy Sung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kevin Y Yip
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Alfred Sl Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Ka F To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
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29
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You Z, Peng D, Cao Y, Zhu Y, Yin J, Zhang G, Peng X. P53 suppresses the progression of hepatocellular carcinoma via miR-15a by decreasing OGT expression and EZH2 stabilization. J Cell Mol Med 2021; 25:9168-9182. [PMID: 34510715 PMCID: PMC8500955 DOI: 10.1111/jcmm.16792] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/24/2021] [Accepted: 06/27/2021] [Indexed: 01/10/2023] Open
Abstract
Existing literature has highlighted the tumour suppressive capacity of microRNA-15a (miR-15a); however, its role in hepatocellular carcinoma (HCC) remains relatively unknown. This study aimed to investigate the role of miR-15a in HCC and the associated underlying mechanism. Initially, RT-qPCR was performed to detect the expression of miR-15a in HCC tissues and cells. Bioinformatics analysis, Pearson correlation coefficient, dual-luciferase reporter assay, and molecular approaches were all conducted to ascertain the interaction between miR-15a and O-linked N-acetylglucosamine (GlcNAc) transferase (OGT). PUGNAc treatment and cycloheximide (CHX) assay were performed to evaluate O-GlcNAc and the stabilization of the enhancer of zeste homolog 2 (EZH2). Finally, gain- and loss-of-function studies were employed to elucidate the role of P53 and the miR-15a/OGT/EZH2 axis in the progression of HCC, followed by in vivo experiments based on tumour-bearing nude mice. Our results demonstrated that the miR-15a expression was decreased in the HCC tissues and cells. P53 upregulated miR-15a expression, which inhibited the proliferation, migration and invasion of HCC cells, while inducing apoptosis and triggering a G0/G1 cell cycle phase arrest. OGT stabilized EZH2 via catalysing O-GlcNAc, which reversed the effect of P53 and miR-15a. The results of our in vivo study provided evidence demonstrating that P53 could suppress the development of HCC via the miR-15a/OGT/EZH2 axis. P53 was found to inhibit the OGT expression by promoting the expression of miR-15a, which destabilized EZH2 and suppressed the development of HCC. The key findings of our study highlight a promising novel therapeutic strategy for the treatment of HCC.
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Affiliation(s)
- Zhenyu You
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Dandan Peng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yixin Cao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanzhe Zhu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianjun Yin
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Guangxing Zhang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaodong Peng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Wu M, Miao H, Fu R, Zhang J, Zheng W. Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma. Curr Mol Pharmacol 2021; 13:261-272. [PMID: 32091349 DOI: 10.2174/1874467213666200224102820] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/24/2022]
Abstract
Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Huajie Miao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Rong Fu
- Department of Pathology, Affiliated Haian Hospital of Nantong University, 17 Zhongba Road, 226600, Haian, Jiangsu, China
| | - Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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Borhani AA, Catania R, Velichko YS, Hectors S, Taouli B, Lewis S. Radiomics of hepatocellular carcinoma: promising roles in patient selection, prediction, and assessment of treatment response. Abdom Radiol (NY) 2021; 46:3674-3685. [PMID: 33891149 DOI: 10.1007/s00261-021-03085-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/02/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022]
Abstract
Radiomics refers to the process of conversion of conventional medical images into quantifiable data ("features") which can be further mined to reveal complex patterns and relationships between the voxels in the image. These high throughput features can potentially reflect the histology of biologic tissues at macroscopic and microscopic levels. Several studies have investigated radiomics of hepatocellular carcinoma (HCC) before and after treatment. HCC is a heterogeneous disease with diverse phenotypical and genotypical landscape. Due to this inherent heterogeneity, HCC lesions can manifest variable aggressiveness with different response to treatment options, including the newer targeted therapies. Hence, radiomics can be used as a potential tool to enable patient selection for therapies and to predict response to treatments and outcome. Additionally, radiomics may serve as a tool for earlier and more efficient assessment of response to treatment. Radiomics, radiogenomics, and radio-immunoprofiling and their potential roles in management of patients with HCC will be discussed and critically reviewed in this article.
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Affiliation(s)
- Amir A Borhani
- Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 800, Chicago, IL, 60611, USA.
| | - Roberta Catania
- Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 800, Chicago, IL, 60611, USA
| | - Yuri S Velichko
- Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 800, Chicago, IL, 60611, USA
| | - Stefanie Hectors
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine At Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine At Mount Sinai, 1Gustave L. Levy Place, New York, NY, 1470, USA
| | - Bachir Taouli
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine At Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine At Mount Sinai, 1Gustave L. Levy Place, New York, NY, 1470, USA
| | - Sara Lewis
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine At Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine At Mount Sinai, 1Gustave L. Levy Place, New York, NY, 1470, USA
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Chu Q, Mu W, Lan C, Liu Y, Gao T, Guan L, Fang Y, Zhang Z, Liu Y, Liu Y, Zhang N. High-Specific Isolation and Instant Observation of Circulating Tumour Cell from HCC Patients via Glypican-3 Immunomagnetic Fluorescent Nanodevice. Int J Nanomedicine 2021; 16:4161-4173. [PMID: 34168446 PMCID: PMC8219227 DOI: 10.2147/ijn.s307691] [Citation(s) in RCA: 5] [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: 02/24/2021] [Accepted: 05/17/2021] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Specific targeting receptors for efficiently capturing and applicable nanodevice for separating and instant observing of circulating tumour cells (CTC) are critical for early diagnosis of cancer. However, the existing CTC detection system based on epithelial cell adhesion molecule (EpCAM) was seriously limited by low expression and poor specificity of targeting receptors, and not instant observation in clinical application. METHODS Herein, an alternative glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of CTC from hepatocellular carcinoma (HCC) patients' peripheral blood was developed. The high-specific HCC targeting receptor, GPC3, was employed for improving the sensitivity and accuracy in CTC detection. GPC3 monoclonal antibody (mAb) was linked to immunomagnetic mesoporous silica for specific targeting capture and separate CTC, and fluorescent molecule coumarin-6 (C6) was loaded for instant detection of CTC. RESULTS The cell recovery (%) of C6/MMSN-GPC3 increased in 106 HL-60 cells (from 49.7% to 83.0%) and in whole blood (from 42% to 80.3%) compared with MACS® Beads. In clinical samples, the C6/MMSN-GPC3 could capture more CTC in the 13 cases of HCC patients and the capture efficiency was improved by 83.3%-350%. Meanwhile, the capture process of C6/MMSN-GPC3 was harmless, facilitating for the subsequent culture. Significantly, the C6/MMSN-GPC3 achieved the high-specific isolation and instant observation of CTC from HCC patients' blood samples, and successfully separated CTC from one patient with early stage of HCC (Stage I) and one post-surgery patient, further indicating the potential ability of C6/MMSN-GPC3 for HCC early diagnosis and prognosis evaluation. CONCLUSION Our study provides a feasible glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of HCC CTC.
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Affiliation(s)
- Qihui Chu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Weiwei Mu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Chuanjin Lan
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, 250021, People’s Republic of China
| | - Yang Liu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Tong Gao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Li Guan
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Yuxiao Fang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Zipeng Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Yingchao Liu
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, 250021, People’s Republic of China
| | - Yongjun Liu
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
| | - Na Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China
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Cadoux M, Caruso S, Pham S, Gougelet A, Pophillat C, Riou R, Loesch R, Colnot S, Nguyen CT, Calderaro J, Celton-Morizur S, Guerra N, Zucman-Rossi J, Desdouets C, Couty JP. Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. J Hepatol 2021; 74:1386-1397. [PMID: 33484773 DOI: 10.1016/j.jhep.2021.01.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 12/30/2020] [Accepted: 01/07/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account. METHODS The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. RESULTS We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in patients with HCC, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. CONCLUSIONS We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. LAY SUMMARY The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
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Affiliation(s)
- Mathilde Cadoux
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional genomics of solid tumors Team, Labex Immuno-Oncology, Paris, France
| | - Sandrine Pham
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France
| | - Angélique Gougelet
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Oncogenic functions of β-catenin signalling in the liver team F-75006 Paris, France
| | - Céline Pophillat
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France
| | - Rozenn Riou
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Oncogenic functions of β-catenin signalling in the liver team F-75006 Paris, France
| | - Robin Loesch
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Oncogenic functions of β-catenin signalling in the liver team F-75006 Paris, France
| | - Sabine Colnot
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Oncogenic functions of β-catenin signalling in the liver team F-75006 Paris, France
| | - Công Trung Nguyen
- Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Julien Calderaro
- Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Séverine Celton-Morizur
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France
| | - Nadia Guerra
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional genomics of solid tumors Team, Labex Immuno-Oncology, Paris, France
| | - Chantal Desdouets
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France
| | - Jean-Pierre Couty
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Team Proliferation Stress and Liver Physiopathology, F-75006 Paris, France.
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Wang H, Yang J, Zhang K, Liu J, Li Y, Su W, Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets. Front Pharmacol 2021; 12:650388. [PMID: 33935756 PMCID: PMC8082422 DOI: 10.3389/fphar.2021.650388] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of primary liver cancer with poor prognosis, and its incidence and mortality rate are increasing worldwide. It is refractory to conventional chemotherapy and radiotherapy owing to its high tumor heterogeneity. Accumulated genetic alterations and aberrant cell signaling pathway have been characterized in HCC. The fibroblast growth factor (FGF) family and their receptors (FGFRs) are involved in diverse biological activities, including embryonic development, proliferation, differentiation, survival, angiogenesis, and migration, etc. Data mining results of The Cancer Genome Atlas demonstrate high levels of FGF and/or FGFR expression in HCC tumors compared with normal tissues. Moreover, substantial evidence indicates that the FGF/FGFR signaling axis plays an important role in various mechanisms that contribute to HCC development. At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.
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Affiliation(s)
- Haijun Wang
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jie Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Ke Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jia Liu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yushan Li
- School of Public Health, Xinxiang Medical University, Xinxiang, China
| | - Wei Su
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Na Song
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
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Bao X, Shen N, Lou Y, Yu H, Wang Y, Liu L, Tang Z, Chen X. Enhanced anti-PD-1 therapy in hepatocellular carcinoma by tumor vascular disruption and normalization dependent on combretastatin A4 nanoparticles and DC101. Theranostics 2021; 11:5955-5969. [PMID: 33897892 PMCID: PMC8058708 DOI: 10.7150/thno.58164] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/23/2021] [Indexed: 12/23/2022] Open
Abstract
Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for this is the imbalance between CD8+ T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (L-glutamic acid)-graft-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8+ T cells, successfully regulating the abovementioned imbalance in an H22 tumor model. Methods: Blood vessel density, tumor cell proliferation, and necrosis were evaluated to reveal the effects on reducing tumor burden by CA4-NP treatment. Pericyte coverage of blood vessels, tumor blood vessel perfusion, tumor hypoxia, and intratumoral immune cells were examined to verify their role in vascular normalization and immune cell homing of DC101. Furthermore, the effects of CA4-NPs + DC101 on reducing tumor burden and increasing the number of immune cells were studied. Finally, tumor suppression, intratumoral CD8+ T cell activation, and the synergistic effects of anti-PD-1 combined with CA4-NPs + DC101 were verified. Results: The tumor inhibition rate of anti-PD-1 antibody combined with CA4-NPs + DC101 reached 86.4%, which was significantly higher than that of anti-PD-1 (16.8%) alone. Importantly, the Q value reflecting the synergy between CA4-NPs + DC101 and anti-PD-1 was 1.24, demonstrating a strong synergistic effect. Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8+ T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%). Conclusion: These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.
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Affiliation(s)
- Xin Bao
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun 130041, P. R. China
- Department of Thyroid, The Second Hospital of Jilin University, Changchun, 130041, P. R. China
| | - Na Shen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Yan Lou
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, 130041, P. R. China
| | - Haiyang Yu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Yue Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Linlin Liu
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun 130041, P. R. China
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 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
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Su SG, Li QL, Zhang MF, Zhang PW, Shen H, Zhang CZ. An E2F1/DDX11/EZH2 Positive Feedback Loop Promotes Cell Proliferation in Hepatocellular Carcinoma. Front Oncol 2021; 10:593293. [PMID: 33614480 PMCID: PMC7892623 DOI: 10.3389/fonc.2020.593293] [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: 08/10/2020] [Accepted: 12/15/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for one of the leading causes of cancer-related death, and is attributed to the dysregulation of genes involved in genome stability. DDX11, a DNA helicase, has been implicated in rare genetic disease and human cancers. Yet, its clinical value, biological function, and the underlying mechanism in HCC progression are not fully understood. Here, we show that DDX11 is upregulated in HCC and exhibits oncogenic activity via EZH2/p21 signaling. High expression of DDX11 is significantly correlated with poor outcomes of HCC patients in two independent cohorts. DDX11 overexpression increases HCC cell viabilities and colony formation, whereas DDX11 knockdown arrests cells at G1 phase without alteration of p53 expression. Ectopic expression of DDX11 reduces, while depletion of DDX11 induces the expression of p21. Treatment of p21 siRNA markedly attenuates the cell growth suppression caused by DDX11 silence. Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination-mediated protein degradation, consequently resulting in the downregulation of p21. In addition, E2F1 is identified as one of the upstream regulators of DDX11, and forms a positive feedback loop with EZH2 to upregulate DDX11 and facilitate cell proliferation. Collectively, our data suggest DDX11 as a promising prognostic factor and an oncogene in HCC via a E2F1/DDX11/EZH2 positive feedback loop.
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Affiliation(s)
- Shu-Guang Su
- Department of Pathology, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, China
| | - Qiu-Li Li
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mei-Fang Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peng-Wei Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Huimin Shen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chris Zhiyi Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
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Lim H, Ramjeesingh R, Liu D, Tam VC, Knox JJ, Card PB, Meyers BM. Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review. J Natl Cancer Inst 2021; 113:123-136. [PMID: 32898239 PMCID: PMC7850551 DOI: 10.1093/jnci/djaa119] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/16/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. METHODS Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA). RESULTS Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. CONCLUSIONS Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.
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Affiliation(s)
- Howard Lim
- Department of Medicine, Division of Medical Oncology, BC Cancer - Vancouver Site, University of British Columbia, Vancouver, BC, Canada
| | - Ravi Ramjeesingh
- Department of Medicine, Division of Medical Oncology, Dalhousie University, Halifax, NS, Canada
| | - Dave Liu
- Department of Radiology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Vincent C Tam
- Tom Baker Cancer Centre, Department of Oncology, University of Calgary, Calgary, AB, Canada
| | - Jennifer J Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Paul B Card
- Kaleidoscope Strategic, Inc, Toronto, ON, Canada
| | - Brandon M Meyers
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
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Hu W, Zheng S, Guo H, Dai B, Ni J, Shi Y, Bian H, Li L, Shen Y, Wu M, Tian Z, Liu G, Hossain MA, Yang H, Wang D, Zhang Q, Yu J, Birnbaumer L, Feng J, Yu D, Yang Y. PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity. Hepatology 2021; 73:674-691. [PMID: 32335942 DOI: 10.1002/hep.31293] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/02/2020] [Accepted: 04/07/2020] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. APPROACH AND RESULTS In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. CONCLUSIONS This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.
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Affiliation(s)
- Weiwei Hu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Shufang Zheng
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Haixin Guo
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Beiying Dai
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Jiaping Ni
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Yaohong Shi
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Hanrui Bian
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Lanxin Li
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Yumeng Shen
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Mo Wu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Zhoutong Tian
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Guilai Liu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Md Amir Hossain
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Hongbao Yang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Duowei Wang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Qin Zhang
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Jun Yu
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Lutz Birnbaumer
- Institute of Biomedical ResearchCatholic University of ArgentinaBuenos AiresArgentina
| | - Jifeng Feng
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Decai Yu
- Department of general SurgeryAffiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Yong Yang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
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Bhat M, Pasini E, Pastrello C, Rahmati S, Angeli M, Kotlyar M, Ghanekar A, Jurisica I. Integrative analysis of layers of data in hepatocellular carcinoma reveals pathway dependencies. World J Hepatol 2021; 13:94-108. [PMID: 33584989 PMCID: PMC7856865 DOI: 10.4254/wjh.v13.i1.94] [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] [Received: 08/06/2020] [Revised: 11/19/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma (HCC).
AIM To comprehensively analyze and characterize all publicly available genomic, gene expression, methylation, miRNA and proteomic data in HCC, covering 85 studies and 3355 patient sample profiles, to identify the key dysregulated genes and pathways they affect.
METHODS We collected and curated all well-annotated and publicly available high-throughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue. Comprehensive pathway enrichment analysis was performed using pathDIP for each data type (genomic, gene expression, methylation, miRNA and proteomic), and the overlap of pathways was assessed to elucidate pathway dependencies in HCC.
RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples, published until December 2016. The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor (EGFR) and β1-integrin pathways. Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival. Using CTD database, estradiol would best modulate and revert these genes appropriately.
CONCLUSION By analyzing and integrating all available high-throughput genomic, transcriptomic, miRNA, methylation and proteomic data from human HCC tissue, we identified EGFR, β1-integrin and axon guidance as pathway dependencies in HCC. These are master regulators of key pathways in HCC, such as the mTOR, Ras/Raf/MAPK and p53 pathways. The genes implicated in these pathways had prognostic value in HCC, with Netrin and Slit3 being novel proteins of prognostic importance to HCC. Based on this integrative analysis, EGFR, and β1-integrin are master regulators that could serve as potential therapeutic targets in HCC.
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Affiliation(s)
- Mamatha Bhat
- Multi Organ transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Elisa Pasini
- Multi Organ transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health NetworkandKrembil Research Institute, University Health Network, Toronto M5T 0S8, Canada
| | - Sara Rahmati
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health NetworkandKrembil Research Institute, University Health Network, Toronto M5T 0S8, Canada
| | - Marc Angeli
- Multi Organ transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Max Kotlyar
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health NetworkandKrembil Research Institute, University Health Network, Toronto M5T 0S8, Canada
| | - Anand Ghanekar
- Surgery, University Health Network, Toronto M5G 2C4, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health NetworkandKrembil Research Institute, University Health Network, Toronto M5T 0S8, Canada
- Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto M5T 0S8, Canada
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Zhao E, Chen S, Dang Y. Development and External Validation of a Novel Immune Checkpoint-Related Gene Signature for Prediction of Overall Survival in Hepatocellular Carcinoma. Front Mol Biosci 2021; 7:620765. [PMID: 33553243 PMCID: PMC7859359 DOI: 10.3389/fmolb.2020.620765] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/15/2020] [Indexed: 12/24/2022] Open
Abstract
Objective: The purpose of this study was to develop and validate a novel immune checkpoint-related gene signature for prediction of overall survival (OS) in hepatocellular carcinoma (HCC). Methods: mRNA expression profiles and clinical follow-up information were obtained in the International Cancer Genome Consortium database. An external dataset from The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma database was used to validate the results. The univariate and multivariate Cox regression analyses were performed based on the differentially expressed genes. We generated a four-mRNA signature to predict patient survival. Furthermore, the reliability and validity were validated in TCGA cohort. An integrated bioinformatics approach was performed to evaluate its diagnostic and prognostic value. Results: A four-gene (epidermal growth factor, mutated in colorectal cancer, mitogen-activated protein kinase kinase 2, and NRAS proto-oncogene, GTPase) signature was built to classify patients into two risk groups using a risk score with different OS in two cohorts (all P < 0.0001). Multivariate regression analysis demonstrated the signature was an independent predictor of HCC. Furthermore, the signature presented an excellent diagnostic power in differentiating HCC and adjacent tissues. Immune cell infiltration analysis revealed that the signature was associated with a number of immune cell subtypes. Conclusion: We identified a four-immune checkpoint-related gene signature as a robust biomarker with great potential for clinical application in risk stratification and OS prediction in HCC patients and could be a potential indicator of immunotherapy in HCC. The diagnostic signature had been validated to accurately distinguish HCC from adjacent tissues.
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Affiliation(s)
- Enfa Zhao
- Department of Structural Heart Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shimin Chen
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Taihe Country, Taihe, China
| | - Ying Dang
- Department of Ultrasound Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Abstract
The diagnosis of hepatocellular carcinoma relies largely on non-invasive imaging, and is well suited for radiomics analysis. Radiomics is an emerging method for quantification of tumor heterogeneity by mathematically analyzing the spatial distribution and relationships of gray levels in medical images. The published studies on radiomics analysis of HCC provide encouraging data demonstrating potential utility for prediction of tumor biology, molecular profiles, post-therapy response, and outcome. The combination of radiomics data and clinical/laboratory information provides added value in many studies. Radiomics is a multi-step process that requires optimization and standardization, the development of semi-automated or automated segmentation methods, robust data quality control, and refinement of algorithms and modeling approaches for high-throughput data analysis. While radiomics remains largely in the research setting, the strong associations of predictive models and nomograms with certain pathologic, molecular, and immune markers with tumor aggressiveness and patient outcomes, provide great potential for clinical applications to inform optimized treatment strategies and patient prognosis.
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Kabashima A, Shimada S, Shimokawa M, Akiyama Y, Tanabe M, Tanaka S. Molecular and immunological paradigms of hepatocellular carcinoma: Special reference to therapeutic approaches. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:62-75. [PMID: 33259135 DOI: 10.1002/jhbp.874] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/09/2020] [Accepted: 10/11/2020] [Indexed: 12/14/2022]
Abstract
The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular-targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune-checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune-associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune-combination approaches from a molecular pathological point.
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Affiliation(s)
- Ayano Kabashima
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masahiro Shimokawa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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López-Cánovas JL, Del Rio-Moreno M, García-Fernandez H, Jiménez-Vacas JM, Moreno-Montilla MT, Sánchez-Frias ME, Amado V, L-López F, Fondevila MF, Ciria R, Gómez-Luque I, Briceño J, Nogueiras R, de la Mata M, Castaño JP, Rodriguez-Perálvarez M, Luque RM, Gahete MD. Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma. Cancer Lett 2021; 496:72-83. [PMID: 33038489 DOI: 10.1016/j.canlet.2020.10.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022]
Abstract
Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.
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Affiliation(s)
- Juan L López-Cánovas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Mercedes Del Rio-Moreno
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Helena García-Fernandez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Juan M Jiménez-Vacas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - M Trinidad Moreno-Montilla
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marina E Sánchez-Frias
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Víctor Amado
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Fernando L-López
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marcos F Fondevila
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Irene Gómez-Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Javier Briceño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Rubén Nogueiras
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Manuel de la Mata
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Justo P Castaño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel Rodriguez-Perálvarez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
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Wang D, Lu S, Zhang X, Huang L, Zhao H. Co-expression of KIAA1199 and hypoxia-inducible factor 1α is a biomarker for an unfavorable prognosis in hepatocellular carcinoma. Medicine (Baltimore) 2020; 99:e23369. [PMID: 33327261 PMCID: PMC7738140 DOI: 10.1097/md.0000000000023369] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Advanced studies demonstrated that hypoxic stress induced KIAA1199 expression leading to enhanced cell migration. KIAA1199 is a protein related with cancer metastasis. Hypoxia inducible factor 1α (HIF-1α) is a transcriptional factor that maintains oxygen homeostasis. Both KIAA1199 and HIF-1α were upregulated in many human cancers. In the present study, co-expression of KIAA1199 and HIF-1α was evaluated for the clinicopathological characteristics and survival in hepatocellular carcinoma (HCC). Clinical-pathological information and follow-up data were collected from 152 HCC patients. KIAA1199 and HIF-1α expression were scored based on the percentage and intensity of immunohistochemical staining in pathological slide. Correlations between clinical features and the expression of KIAA1199 and HIF-1α were evaluated by Chi-square test, Kaplan-Meier curves and multivariate Cox regression analysis. The frequency of KIAA1199 high expression was higher in HCC than adjacent tissue. KIAA1199(H)/HIF-1α(H) tumors were more frequently of TNM (P = .011), tumor size (P = .021), vascular invasion (P = .002) and HBV (P = .001). In survival analysis, KIAA1199(H)/HIF-1α(H) patients had the worst prognosis. Using the combination of the two parameters increased the prognostic value (P < .01 vs P = .03). KIAA1199 in combination with HIF-1α expression tends to indicate a more accurate prognosis.
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Affiliation(s)
- Dan Wang
- Institute of Special Environmental Medicine, Nantong University
- Department of Clinical Biobank
| | - Shu Lu
- Department of Intensive Care Unit
| | | | - Linlin Huang
- Institute of Special Environmental Medicine, Nantong University
| | - Hui Zhao
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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Wang P, Xun W, Han T, Cheng Z. FAIM-S functions as a negative regulator of NF-κB pathway and blocks cell cycle progression in NSCLC cells. Cell Cycle 2020; 19:3458-3467. [PMID: 33249986 DOI: 10.1080/15384101.2020.1843811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Tumorigenesis is closely related to the disorder of the cell cycle. The cell cycle progression includes the interphase (G0/G1, S, and G2 phase) and mitosis (M phase). CCND1 is a key protein that regulates the entry of the G0/G1 phase into the S phase. In our study, we found that the short form of Fas Apoptosis Inhibitory Molecule 1 (FAIM-S) could regulate the expression of CCND1 and had a tumor-suppressing role in non-small cell lung cancer (NSCLC). Overexpressing FAIM-S significantly inhibited the proliferation and cell cycle progression in NSCLC cells. Further studies demonstrated that FAIM-S could interact with IKK-α, reducing its protein stability. This effect led to the suppression of the NF-κB pathway, resulting in the decreased expression of CCND1. Thus, our study demonstrated that FAIM-S functioned as a negative regulator of the NF-κB pathway and played a tumor-suppressing role through blocking cell cycle progression in NSCLC cells.
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Affiliation(s)
- Pengcheng Wang
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China.,Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Wenze Xun
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Tianyu Han
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
| | - Zhujun Cheng
- Department of Burn, The First Affiliated Hospital of Nanchang University , Nanchang, P.R.China
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Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8897918. [PMID: 33163086 PMCID: PMC7607277 DOI: 10.1155/2020/8897918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 10/04/2020] [Accepted: 10/17/2020] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. Scutellariae Radix (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine systems pharmacology database and the traditional Chinese medicine integrated database. HCC-related targets were acquired from the liver cancer databases OncoDB.HCC and Liverome. The gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. Component-component target and protein-protein interaction networks were set up. A total of 143 components of SR were identified, and 37 of them were considered as candidate active components. Fifty targets corresponding to 29 components of SR were mapped with targets of HCC. Functional enrichment analysis indicated that SR exerted an antihepatocarcinoma effect by regulating pathways in cancer, hepatitis B, viral carcinogenesis, and PI3K-Akt signaling. The holistic approach of network pharmacology can provide novel insights into the mechanistic study and therapeutic drug development of SR for HCC treatment.
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Zhou J, Zhou Q, Shu G, Wang X, Lu Y, Chen H, Hu T, Cai J, Du Y, Yu R. Dual-Effect of Magnetic Resonance Imaging Reporter Gene in Diagnosis and Treatment of Hepatocellular Carcinoma. Int J Nanomedicine 2020; 15:7235-7249. [PMID: 33061378 PMCID: PMC7533905 DOI: 10.2147/ijn.s257628] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 08/10/2020] [Indexed: 12/22/2022] Open
Abstract
Propose The early diagnosis of hepatocellular carcinoma (HCC) with ferritin heavy chain (Fth) modified by alpha-fetoprotein (AFP) promoter has been studied. However, no study has focused on the considerable upregulation and specific targeting effects of transferrin receptors (TfR) caused by the transfection of plasmids encoded with the AFP promoter. Thus, the objective of our study was to investigate whether the transfection of Fth gene modified with AFP promoter (AFP@Fth) could be used for early diagnosis and enhanced treatment of HCC. Methods The AFP@Fth plasmid was transfected into AFP positive cells. The expression of intracellular Ferritin was verified by Western blot, and the upregulation of TfR was confirmed by immunofluorescence and flow cytometry analysis. Cellular iron accumulation resulting in decreased imaging signals was examined by magnetic resonance imagining. Doxorubicin liposome modified with transferrin (Tf-LPD) was prepared to investigate the efficiency of the subsequent treatment after transfection. The enhanced drug distribution and effects were investigated both in vitro and in vivo. Results Both Ferritin and TfR were overexpressed after transfection. The transfected cells showed higher intracellular iron accumulation and resulted in a lower MR T2-weighted imaging (T2WI) intensity, suggesting that the transfection of AFP@Fth could be a potential strategy for early diagnosis of liver cancer. The following treatment efficacy was revealed by Tf-LPD. As compared with un-transfected cells, transfected cells exhibited higher uptake of transferrin-modified liposomes (Tf-LP), which was due to the specific interaction between Tf and TfR overexpressed on the transfected cells. This is also the reason why Tf-LPD showed better in vitro and in vivo anticancer ability than doxorubicin loaded liposome (LPD). These results suggested that transfection of AFP@Fth could result in enhanced therapy of liver cancer. Conclusion Transfection of AFP@Fth could be used for early diagnosis and for enhanced treatment of live cancers.
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Affiliation(s)
- Jiaping Zhou
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Qiaomei Zhou
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Gaofeng Shu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Xiaojie Wang
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Yuanfei Lu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Haiyan Chen
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Tingting Hu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Jinsong Cai
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
| | - Yongzhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, People's Republic of China
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48
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Dong H, Wang M, Chang C, Sun M, Yang F, Li L, Feng M, Zhang L, Li Q, Zhu Y, Qiao Y, Xie T, Chen J. Erianin inhibits the oncogenic properties of hepatocellular carcinoma via inducing DNA damage and aberrant mitosis. Biochem Pharmacol 2020; 182:114266. [PMID: 33035506 DOI: 10.1016/j.bcp.2020.114266] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/30/2020] [Accepted: 10/01/2020] [Indexed: 01/14/2023]
Abstract
Natural compounds have been confirmed as one of the most feasible solutions for hard-to-treat cancers such as hepatocellular carcinoma (HCC). Erianin, a natural bibenzyl compound from Dendrobium chrysotoxum, has been recently discovered with anticancer property in cancer cells. However, the roles and the molecular mechanisms of erianin in HCC remain unknown. The present study evaluates the effect of erianin on human HCC cells by inhibiting cell proliferation, inducing apoptotic-related cell death and hampering tumorigenicity. Furthermore, it was found that erianin could cause irreparable DNA damage, induce G2/M arrest and deregulate mitotic regulators. It was also observed that many cells with damaged DNA induced by erianin could overcome G2/M arrest and enter mitosis, leading to abnormal mitosis, and subsequently mitotic catastrophe and apoptotic-related cell death. The present study confirmed that erianin could be a potential antitumor agent for HCC clinical treatment.
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Affiliation(s)
- Heng Dong
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Menglan Wang
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Cunjie Chang
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Mengqing Sun
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Fan Yang
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Lina Li
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Mengqing Feng
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Lele Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou 310003, China
| | - Qian Li
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Yannan Zhu
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Yiting Qiao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou 310003, China.
| | - Tian Xie
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| | - Jianxiang Chen
- College of Pharmacy, School of Medicine, Department of Hepatology, Institute of Hepatology and Metabolic Diseases, Institute of Integrated Chinese and Western Medicine for Oncology, the Affiliated Hospital of Hangzhou Normal University, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
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49
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Qin SK, Li Q, Ming Xu J, Liang J, Cheng Y, Fan Y, Jiang J, Ye H, Tao H, Li L, Zheng L, Wei Z, Li S, Meng K, Ye B, Sun Y. Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival. Cancer Sci 2020; 111:4218-4231. [PMID: 32889778 PMCID: PMC7648021 DOI: 10.1111/cas.14641] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/27/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Advanced hepatitis B virus (HBV)-related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin-6 (IL-6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid-derived suppressor cells (MDSCs) is involved in HBV-related immunosuppression and CD8+ T-cell activation through ERK/IL-6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL-6/JAK/STAT3 pathways in tumor cells and immune cells including CD8+ T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV-related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV-related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child-Pugh B classification, and metastasis. Clinical end-points included safety, tumor response, and overall survival (OS). Icaritin treatment-induced dynamics of serum cytokines IL-6, IL-8, IL-10, and tumor necrosis factor-α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA-4 were assessed. No grade III/IV treatment-related adverse events were observed. Time-to-progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329-565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high-level α-fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune-modulatory regimen to treat advanced HCC patients with poor prognosis.
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Affiliation(s)
- Shu-Kui Qin
- Clinical Oncology Department, Nanjing Jinling Hospital, Nanjing, China
| | - Qing Li
- National Cancer Center/National Clinical Research Center, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jian Ming Xu
- The 5th Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Jun Liang
- Clinical Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ying Cheng
- Clinical Oncology Department, Jilin Cancer Hospital, Changchun, China
| | - Ying Fan
- National Cancer Center/National Clinical Research Center, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jun Jiang
- National Cancer Center/National Clinical Research Center, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hao Ye
- Research & Development Department, SinoTech Genomics, Shanghai, China
| | - Huimin Tao
- School of Life Science, Sun Yat-Sen University, Guangzhou, China
| | - Lian Li
- School of Life Science, Sun Yat-Sen University, Guangzhou, China
| | - Limin Zheng
- School of Life Science, Sun Yat-Sen University, Guangzhou, China
| | - Zhaohui Wei
- Biostatistical Department, Tigermed Consulting Co., Ltd., Shanghai, China
| | - Shu Li
- Research & Clinical Development, Shenogen Pharma Group, Beijing, China
| | - Kun Meng
- Research & Clinical Development, Shenogen Pharma Group, Beijing, China
| | - Bin Ye
- Research & Clinical Development, Shenogen Pharma Group, Beijing, China
| | - Yan Sun
- National Cancer Center/National Clinical Research Center, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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50
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Wan Z, Liu T, Wang L, Wang R, Zhang H. MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression. Aging (Albany NY) 2020; 12:18192-18208. [PMID: 33021963 PMCID: PMC7585128 DOI: 10.18632/aging.103670] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 06/01/2020] [Indexed: 01/27/2023]
Abstract
We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3'UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.
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Affiliation(s)
- Zhong Wan
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China,Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Tingyu Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Liang Wang
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China
| | - Rong Wang
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China
| | - Hai Zhang
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China
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