|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
Collapse
Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| |
Collapse
|
|
3
|
Farinha D, Sarmento-Ribeiro AB, Faneca H. Combination of Gene Therapy and Chemotherapy in a New Targeted Hybrid Nanosystem to Hepatocellular Carcinoma. Int J Nanomedicine 2024; 19:12505-12527. [PMID: 39606562 PMCID: PMC11598603 DOI: 10.2147/ijn.s474665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
Purpose Hepatocellular carcinoma is the most frequent liver cancer and constitutes one of the main causes of cancer mortality. The combination of targeted therapy drugs, such as selumetinib and perifosine that inhibit cell signaling pathways involved in cell survival and proliferation, with the expression of tumor suppressor transgenes, such as PTEN, may result in an efficient therapeutic approach against HCC. Thus, the main objective of this work was to develop a new lipid-polymer hybrid nanosystem (HNP), composed of a PLGA core coated with a pH-sensitive lipid bilayer functionalized with the targeting ligand GalNAc, in order to specifically and efficiently deliver this novel combination of therapeutic agents in HCC cells. Methods Transmission electron microscopy, zeta potential, Fourier transform infrared spectroscopy, and dynamic light scattering were used to determine the physicochemical properties of hybrid nanosystems and their components. The biological activity and specificity of nanosystems were evaluated using luminescence and flow cytometry. A variety of techniques were used to assess the therapeutic activity of hybrid nanosystems, including the Alamar Blue assay for cell viability; flow cytometry for cell death mechanisms, mitochondrial membrane potential and cell cycle; luminescence for caspase activity; flow cytometry and fluorescence microscopy for cell proliferation; and Western blot for molecular targets levels. Results The obtained results showed that this new hybrid nanosystem not only has a high loading capacity of both drugs, but also allows for substantial expression of the PTEN transgene. In addition, the developed formulation has high stability, adequate physicochemical properties and high specificity to HCC cells. Moreover, the achieved data revealed that this innovative nanosystem presents a high antitumor effect, demonstrated not only by the enhancement on the programmed cell death, but also by the reduction in cell proliferation capacity. Conclusion The generated formulation shows a high anticancer effect, demonstrating a high translational potential for future clinical application in HCC treatment.
Collapse
Affiliation(s)
- Dina Farinha
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Ana Bela Sarmento-Ribeiro
- CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal
| | - Henrique Faneca
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| |
Collapse
|
|
4
|
Reid RM, Turkmen S, Cleveland BM, Biga PR. Direct actions of growth hormone in rainbow trout, Oncorhynchus mykiss, skeletal muscle cells in vitro. Comp Biochem Physiol A Mol Integr Physiol 2024; 297:111725. [PMID: 39122107 DOI: 10.1016/j.cbpa.2024.111725] [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: 06/08/2024] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) system regulates skeletal muscle growth and function. GH has a major function of targeting the liver to regulate IGF-1 production and release, and IGF-1 mediates the primary anabolic action of GH on growth. However, skeletal muscle is a target tissue of GH as evidenced by dynamic GH receptor expression, but it is unclear if GH elicits any direct actions on extrahepatic tissues as it is difficult to distinguish the effects of IGF-1 from GH. Fish growth regulation is complex compared to mammals, as genome duplication events have resulted in multiple isoforms of GHs, GHRs, IGFs, and IGFRs expressed in most fish tissues. This study investigated the potential for GH direct actions on fish skeletal muscle using an in vitro system, where rainbow trout myogenic precursor cells (MPCs) were cultured in normal and serum-deprived media, to mimic in vivo fasting conditions. Fasting reduces IGF-1 signaling in the muscle, which is critical for disentangling the roles of GH from IGF-1. The direct effects of GH were analyzed by measuring changes in myogenic proliferation and differentiation genes, as well as genes regulating muscle growth and proteolysis. This study provides the first in-depth analysis of the direct actions of GH on serum-deprived fish muscle cells in vitro. Data suggest that GH induces the expression of markers for proliferation and muscle growth in the presence of serum, but all observed GH action was blocked in serum-deprived conditions. Additionally, serum deprivation alone reduced the expression of several proliferation and differentiation markers, while increasing growth and proteolysis markers. Results also demonstrate dynamic gene expression response in the presence of GH and a JAK inhibitor in serum-provided but not serum-deprived conditions. These data provide a better understanding of GH signaling in relation to serum in trout muscle cells in vitro.
Collapse
Affiliation(s)
- Ross M Reid
- Department of Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Serhat Turkmen
- Department of Cell Development and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Beth M Cleveland
- National Center for Cool and Cold Water Aquaculture, Agricultural Research Service (ARS-USDA), Kearneysville, WV 25430, USA
| | - Peggy R Biga
- Department of Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| |
Collapse
|
|
5
|
Bjorklund GR, Rees KP, Balasubramanian K, Hewitt LT, Nishimura K, Newbern JM. Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning. Dis Model Mech 2024; 17:dmm050570. [PMID: 38826084 PMCID: PMC11247507 DOI: 10.1242/dmm.050570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 05/21/2024] [Indexed: 06/04/2024] Open
Abstract
Abnormal extracellular signal-regulated kinase 1/2 (ERK1/2, encoded by Mapk3 and Mapk1, respectively) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates forebrain development, we conditionally expressed a hyperactive MEK1 (MAP2K1) mutant, MEK1S217/221E, in cortical excitatory neurons of mice. MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in cortical axons, but not in soma/nuclei. We noted reduced axonal arborization in multiple target domains in mutant mice and reduced the levels of the activity-dependent protein ARC. These changes did not lead to deficits in voluntary locomotion or accelerating rotarod performance. However, skilled motor learning in a single-pellet retrieval task was significantly diminished in these MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits but did not affect motor learning. These results suggest that cortical excitatory neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, which coincide with reduced ARC expression, and deficits in skilled motor learning. Our data indicate that neuron-autonomous decreases in long-range axonal outgrowth may be a key aspect of neuropathogenesis in RASopathies.
Collapse
Affiliation(s)
- George R. Bjorklund
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA
| | - Katherina P. Rees
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | | | - Lauren T. Hewitt
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Kenji Nishimura
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Jason M. Newbern
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| |
Collapse
|
|
6
|
Negm WA, Elekhnawy E, Mahgoub S, Ibrahim HA, Ibrahim Elberri A, Abo Mansour HE, Mosalam EM, Moglad E, Alzahraa Mokhtar F. Dioon rzedowskii: An antioxidant, antibacterial and anticancer plant extract with multi-faceted effects on cell growth and molecular signaling. Int Immunopharmacol 2024; 132:111957. [PMID: 38554441 DOI: 10.1016/j.intimp.2024.111957] [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: 01/17/2024] [Revised: 03/18/2024] [Accepted: 03/26/2024] [Indexed: 04/01/2024]
Abstract
This study investigated the antioxidant, anticancer, antibacterial properties of Dioon rzedowskii extract, which had not been previously explored. We aimed to determine the extract's effect on liver and breast cancer cell lines and on solid Ehrlich carcinoma (SEC) mouse model to investigate the underlying molecular mechanisms. Three female albino mice groups were established: a tumor control group, a group treated with 100 mg/kg of the extract (D100), and a group treated with 200 mg/kg of the extract (D200) for 16 days after tumor development. Results showed that the D. rzedowskii extract inhibited cell growth in both MCF-7 and HepG2 cells in a concentration-dependent manner. This was achieved by suppressing the cell proliferation and inducing apoptosis. The extract also improved liver, heart, and kidney functions compared to the tumor control. Furthermore, oral administration of the extract reduced tumor volume and alleviated oxidative stress in tumor tissue. The anticancer effects were associated with overexpression of p53 and Bax and downregulation of cyclin D1 expression, which was attributed to decreased phosphorylated MAPK kinases. Additionally, D. rzedowskii exhibited antibacterial activity against K. pneumoniae isolated from cancer patients. The extract inhibited bacterial growth and reduced the membrane integrity. The study suggests that D. rzedowskii has promising potential as an adjunctive therapy for cancer treatment. Further investigations are needed to explore its combined anticancer efficacy. These results emphasize the value of natural products in developing compounds with potential anticancer activity and support a paradigm shift in cancer management to improve patients' quality of life.
Collapse
Affiliation(s)
- Walaa A Negm
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Engy Elekhnawy
- Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Sebaey Mahgoub
- Food Analysis Laboratory, Ministry of Health, Zagazig, Egypt
| | - Hanaa A Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Aya Ibrahim Elberri
- Genetic Engineering and Molecular Biology Division, Department of Zoology, Faculty of Science, Menoufia University, 32511 Shebin El-Kom, Menoufia, Egypt.
| | - Hend E Abo Mansour
- Biochemistry Department, Faculty of Pharmacy, Menoufia University, 32511 Shebin EL-Kom, Menoufia, Egypt.
| | - Esraa M Mosalam
- Biochemistry Department, Faculty of Pharmacy, Menoufia University, 32511 Shebin EL-Kom, Menoufia, Egypt; Department of Pharmacy, Faculty of Pharmacy, Jadara University, Irbid, Jordan.
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, P.O. Box 173, Alkharj 11942, Saudi Arabia.
| | - Fatma Alzahraa Mokhtar
- Department of Pharmacognosy, Faculty of Pharmacy, El Saleheya El Gadida University, El Saleheya El Gadida 44813, Sharkia, Egypt; Fujairah Research Centre, Sakamkam Road, Fujairah, United Arab Emirates
| |
Collapse
|
|
7
|
Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [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: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
Collapse
Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| |
Collapse
|
|
8
|
Peng Z, Xu S, Zhang Q, Yang X, Yuan W, Wang Y, Li Y, Zhu P, Wu X, Jiang Z, Li F, Fan X. FAXDC2 inhibits the proliferation and invasion of human liver cancer HepG2 cells. Exp Ther Med 2024; 27:27. [PMID: 38125362 PMCID: PMC10728893 DOI: 10.3892/etm.2023.12315] [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: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 12/23/2023] Open
Abstract
The reprogramming of lipid metabolism serves an important role in occurrence and development of liver cancer. Fatty acid hydroxylase domain containing 2 (FAXDC2) is a hydroxylase involved in the synthesis of cholesterol and sphingomyelin and downregulated in various types of cancer. There are no reports on the relationship between FAXDC2 and liver carcinogenesis. The present study used multiple portals and publicly available tools to explore its correlation with liver cancer. The results showed that the expression of FAXDC2 decreased in liver cancer and the methylation level near the promoter increased. Patients with liver cancer and with low expression of FAXDC2 had a poor prognosis. Gain of function and loss of function strategies were performed to evaluate its roles in liver cancer cells. CCK-8 assay showed that overexpression of FAXDC2 inhibited the viability of liver cancer cells (HepG2). Flow cytometry analysis indicated that HepG2 cells with overexpressing FAXDC2 showed an S phase arrest, associated with cyclin-dependent kinase 2 decreased. Transwell experiments showed that increasing FAXDC2 inhibited HepG2 cell invasion ability, accompanied by the upregulation of E-cadherin. Notably, knockdown of FAXDC2 had no significant effect on cell cycle and invasion functions. Based on the cBioPortal platform, FAXDC2 was predicted to closely correlate to the ERK signal in tumorigenesis. Western blotting results showed that overexpression of FAXDC2 decreased the phosphorylation level of ERK in liver cancer cells. The present study first identified FAXDC2 as a liver cancer suppressor, which might inhibit the proliferation and invasion of liver cancer cells through the mechanism associated with ERK signaling. The present study provided a possible new target for the diagnosis and treatment of liver cancer.
Collapse
Affiliation(s)
- Zhilin Peng
- The Center for Heart Development, College of Life Sciences, 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 Sciences, 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
| | - Qing Zhang
- The Center for Heart Development, College of Life Sciences, 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
| | - Xueting Yang
- The Center for Heart Development, College of Life Sciences, 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 Sciences, 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
| | - Yuequn Wang
- The Center for Heart Development, College of Life Sciences, 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 Sciences, 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, Guangzhou, Guangdong 510100, P.R. China
| | - Xiushan Wu
- The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou, Guangdong 510100, P.R. China
| | - Zhigang Jiang
- The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Fang Li
- The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Xiongwei Fan
- The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| |
Collapse
|
|
9
|
Bayat Z, Tarokhian A, Taherkhani A. Cinnamic acids as promising bioactive compounds for cancer therapy by targeting MAPK3: a computational simulation study. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2023; 20:621-630. [PMID: 37223879 DOI: 10.1515/jcim-2023-0046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023]
Abstract
OBJECTIVES Mitogen-activated protein kinase-3 (MAPK3) is the upstream regulator in the MAPK cascade and is involved in many critical signaling pathways and biological processes, such as cell proliferation, survival, and apoptosis. MAPK3 overexpression is linked to onset, development, metastasis, and drug resistance in several human cancers. Thus, identifying novel and effective MAPK3 inhibitors is highly demanded. Herein, we aimed to discover organic compounds from cinnamic acid derivatives as potential MAPK3 inhibitors. METHODS The binding affinity of 20 cinnamic acids to the MAPK3 active site was tested using the AutoDock 4.0 software. Top-ranked cinnamic acids were ranked based on the ΔG binding values between the ligands and the receptor's active site. Interaction modes between top-ranked cinnamic acids and MAPK3 catalytic site were indicated using the Discovery Studio Visualizer tool. Molecular dynamics (MD) simulation was carried out to study the stability of the docked pose for the most potent MAPK3 inhibitor in this study. RESULTS Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate exhibited a salient binding affinity to the MAPK3 active site with the criteria of ΔG binding <-10 k cal/mol. Further, the inhibition constant value for cynarin was calculated at the picomolar concentration. The docked pose of cynarin within the MAPK3 catalytic domain was stable in 100 ns simulation. CONCLUSIONS Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate might be helpful in cancer therapy by inhibiting MAPK3.
Collapse
Affiliation(s)
- Zeynab Bayat
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Aida Tarokhian
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Taherkhani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
10
|
Verma S, Sahu BD, Mugale MN. Role of lncRNAs in hepatocellular carcinoma. Life Sci 2023; 325:121751. [PMID: 37169145 DOI: 10.1016/j.lfs.2023.121751] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/21/2023] [Accepted: 04/29/2023] [Indexed: 05/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies.
Collapse
Affiliation(s)
- Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bidhya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101, Assam, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
11
|
He X, Chen F, Lu C, Wang S, Mao G, Jin W, Zhong W. Comparison of anti-tumor activities and underlying mechanisms of glucuronomannan oligosaccharides and its sulfated derivatives on the hepatocarcinoma Huh7.5 cells. Biochem Biophys Res Commun 2023; 652:103-111. [PMID: 36841097 DOI: 10.1016/j.bbrc.2023.02.049] [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: 02/09/2023] [Revised: 02/16/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor triggered by various factors such as virus infection and alcohol abuse. Glucuronomannan polysaccharide (Gx) is a subtype of fucoidans that possesses many bioactivities, but its anti-tumor activities in HCC have not been reported. In this paper, the anti-tumor effects of glucuronomannan oligosaccharides (Gx) and its sulfated derivatives (GxSy) on hepatocarcinoma Huh7.5 cells were investigated. The anti-proliferation, anti-metastasis activities, and underlying mechanism of Gx and GxSy on Huh7.5 cells were analyzed and compared by MTT, wound healing, transwell, and western blotting assays, respectively. Results showed that the best anti-proliferation effects were G4S1 and G4S2 among 13 drugs, which were 38.67% and 30.14%, respectively. The cell migration rates were significantly inhibited by G2S1, G4S2, G6S2, and unsulfated Gn. In addition, cell invasion effects treated with G4S1, G4S2, and G6S1 decreased to 48.62%, 36.26%, and 42.86%, respectively. Furthermore, sulfated G4 regulated the expression of (p-) FAK and MAPK pathway, and sulfated G6 down-regulated the MAPK signaling pathway while activating the PI3K/AKT pathway. On the contrary, sulfated G2 and unsulfated Gx had no inhibited effects on the FAK-mTOR pathway. These results indicated that sulfated Gx derivatives have better anti-tumor activities than unsulfated Gx in cell proliferation and metastasis process in vitro, and those properties depend on the sulfation group levels. Moreover, degrees of polymerization of Gx also played a vital role in mechanisms and bioactivities. This finding shows the structure-activity relationship for developing and applying the marine oligosaccharide candidates.
Collapse
Affiliation(s)
- Xinyue He
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Fen Chen
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Chenghui Lu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Sanying Wang
- Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310013, China
| | - Genxiang Mao
- Zhejiang Provincial Key Lab of Geriatrics, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310013, China.
| | - Weihua Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
| | - Weihong Zhong
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| |
Collapse
|
|
12
|
Hsu CH, Weng PW, Chen MY, Yeh CT, Setiawan SA, Yadav VK, Wu ATH, Tzeng DTW, Gong JX, Yang Z, Tzeng YM. Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways. Chem Biol Interact 2023; 370:110329. [PMID: 36565974 DOI: 10.1016/j.cbi.2022.110329] [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: 04/30/2022] [Revised: 12/01/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p < 0.001) and tumorsphere formation (p < 0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.
Collapse
Affiliation(s)
- Chia-Hung Hsu
- Department of Emergency Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei City, 11031, Taiwan; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Pei-Wei Weng
- Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chi-Tai Yeh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung, 95092, Taiwan
| | - Syahru Agung Setiawan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Vijesh Kumar Yadav
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Alexander T H Wu
- Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - David T W Tzeng
- School of Life Sciences, The Chinese University of Hong Kong, 999077, Hong Kong Special Administrative Region of China; Lifebit, London, EC2A 2AP, UK
| | - Jian-Xian Gong
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China
| | - Zhen Yang
- Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China.
| | - Yew-Min Tzeng
- Department of Applied Science, National Taitung University, Taitung, 95092, Taiwan; Department of Applied Chemistry, Chaoyang University of Technology, Taichung, 41349, Taiwan.
| |
Collapse
|
|
13
|
Song Y, Bi Z, Liu Y, Qin F, Wei Y, Wei X. Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: Current status in clinical trials. Genes Dis 2023; 10:76-88. [PMID: 37013062 PMCID: PMC10066287 DOI: 10.1016/j.gendis.2022.05.006] [Citation(s) in RCA: 98] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/23/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Molecular target inhibitors have been regularly approved by Food and Drug Administration (FDA) for tumor treatment, and most of them intervene in tumor cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation, survival, and differentiation. The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors. About 33% of tumors harbor RAS mutations, while 8% of tumors are driven by RAF mutations. Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades. In this review, we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment. Moreover, we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways. The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancer research and treatment.
Collapse
Affiliation(s)
| | | | - Yu Liu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Furong Qin
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
14
|
Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
Collapse
Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| |
Collapse
|
|
15
|
Chen PN, Lin CW, Yang SF, Chang YC. CLEFMA Induces the Apoptosis of Oral Squamous Carcinoma Cells through the Regulation of the P38/HO-1 Signalling Pathway. Cancers (Basel) 2022; 14:cancers14225519. [PMID: 36428612 PMCID: PMC9688613 DOI: 10.3390/cancers14225519] [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: 09/22/2022] [Revised: 10/28/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
The purpose of this research was to evaluate the impact and the underlying molecular mechanism of CLEFMA-induced cell death in human OSCC. The anti-tumour properties of CLEFMA in oral cancer were explored using colony formation, flow cytometry, human apoptosis array, Western blot, and immunohistochemistry assays. The in vivo anti-tumour effect of CLEFMA administered by oral gavage was evaluated using SCC-9-derived xenograft-bearing nude mouse models. CLEFMA significantly suppressed colony formation and elicited cellular apoptosis in oral cancer cells. CLEFMA treatment remarkably increased phosphorylated p38 and HO-1 along with cleavage of poly ADP-ribose polymerase and activation of caspase-8, -9, and -3 in HSC-3 and SCC-9 cells. Administration of HO-1 small interfering RNA significantly protected the cells from CLEFMA-induced caspase-3, -8, and -9 activation. Attenuation of p38 activity by the pharmacologic inhibitor SB203580 dramatically reduced CLEFMA-induced caspase-3, -8, and -9 activation and HO-1 expression in OSCC. The subcutaneous murine xenograft models showed that CLEFMA in vivo suppressed tumour growth in implanted SCC-9 cells. All of these findings indicated that CLEFMA induced apoptosis through the p38-dependent rise in HO-1 signal transduction cascades in OSCC.
Collapse
Affiliation(s)
- Pei-Ni Chen
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Yu-Chao Chang
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Dentistry, Chung Shan Medical University, Taichung 402, Taiwan
- Correspondence:
| |
Collapse
|
|
16
|
Mohapatra P, Chandrasekaran N. Wnt/β-catenin targeting in liver carcinoma through nanotechnology-based drug repurposing: A review. Biomed Pharmacother 2022; 155:113713. [PMID: 36126453 DOI: 10.1016/j.biopha.2022.113713] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/08/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Liver cancer is the fifth most widespread in the world, with a high fatality rate and poor prognosis.However,surgicalresction,thermal/radiofrequencyablation,chemo/radioembolization and pathway targeting to the cancer cells are all possible options for treating Liver Carcinoma. Unfortunately, once the tumour has developed and spread, diagnosis often occurs too late. The targeted therapy has demonstrated notable, albeit modest, efficacy in some patients with advanced HCC. This demonstrates the necessity of creating additional focused treatments and, in pursuit of this end, the need to find ever-more pathways as prospective targets. Despite the critical need, there are currently no Wnt signalling directed therapy on the research field, only a few methods have progressed beyond the early stage of clinical studies. In the present study, we report that repurposing of drug previously licensed for other diseases is one possible strategy inhibit malignant cell proliferation and renewal by removing individuals protein expression in the Wnt/β-catenin pathway. Particularly β-catenin complex is present in Liver cancer, where tumour necrosis factor is indispensable for the complex formation and β-catenin interactions are disrupted upon drug in nano-carrier through nanotechnology. This study findings not only highlight that repurposing drug could improve liver cancer treatment outcomes but also focused to character traits and functions of the Wnt signalling cascade's molecular targets and how they could be used to get anti-tumour results method to targeting Wnt/β-catenin in liver carcinoma.
Collapse
|
|
17
|
Sun H, Qian X, Yang W, Zhou W, Zhou C, Liu S, Shi H, Tian W. Novel prognostic signature based on HRAS, MAPK3 and TFRC identified to be associated with ferroptosis and the immune microenvironment in hepatocellular carcinoma. Am J Transl Res 2022; 14:6924-6940. [PMID: 36398204 PMCID: PMC9641466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/18/2022] [Indexed: 06/16/2023]
Abstract
OBJECTIVES Ferroptosis, a programmed cell death, has been recognized recently. Several studies have shown the connection between ferroptosis and biological processes in cancer. However, the potential role and mechanism of ferroptosis-related genes in hepatocellular carcinoma (HCC) remain unclear, and understanding the crosstalk between the tumor immune microenvironment and ferroptosis is still a great challenge. METHOD We retrospectively analyzed the transcriptomic and clinical data of HCC from TCGA database. 74 ferroptosis-related genes (FRGs), including 14 immune-ferroptosis-related genes (IFRGs), were identified with differential expression in tumor and normal tissues. Then, we screened and constructed a prognostic signature using survival analysis and the least absolute shrinkage and selection operator. Furthermore, we validated the performance of the signature for assessing survival prognosis and clinicopathological staging. In addition, we investigated the link between the prognostic features and tumor-infiltrating immune cells using CIBERSORT. RESULT The results identified HRAS, MAPK3 and TFRC as prognostic IFRGs. The risk score was elevated when IFRGs were upregulated and patient outcomes worsened. In addition, the results show significant differences in tumor-infiltrating immune cells, especially immunosuppressive cells, including tumor-infiltrating macrophages cells and regulatory cells, implying that the expression of these three IFRGs may be an intrinsic barrier to strong ferritin-induced immune responses. Enrichment analysis revealed crosstalk between ferroptosis and tumor immunity. The effect of the risk score was validated in the ICGC cohort and the Human Protein Atlas database confirmed the high expression of IFRGs in tumor tissue. CONCLUSIONS In our study, these IFRGs may provide some new ideas for the study of ferroptosis and the tumor immunity. These findings may also provide new strategies for treatment of HCC.
Collapse
Affiliation(s)
- Hanyao Sun
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Xiyan Qian
- Department of Gerontology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Wei Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Weizhong Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Chungao Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Haibin Shi
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Wei Tian
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| |
Collapse
|
|
18
|
Rasl J, Grusanovic J, Klimova Z, Caslavsky J, Grousl T, Novotny J, Kolar M, Vomastek T. ERK2 signaling regulates cell-cell adhesion of epithelial cells and enhances growth factor-induced cell scattering. Cell Signal 2022; 99:110431. [PMID: 35933033 DOI: 10.1016/j.cellsig.2022.110431] [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: 03/29/2022] [Revised: 07/13/2022] [Accepted: 08/01/2022] [Indexed: 11/30/2022]
Abstract
The ERK signaling pathway, consisting of core protein kinases Raf, MEK and effector kinases ERK1/2, regulates various biological outcomes such as cell proliferation, differentiation, apoptosis, or cell migration. Signal transduction through the ERK signaling pathway is tightly controlled at all levels of the pathway. However, it is not well understood whether ERK pathway signaling can be modulated by the abundance of ERK pathway core kinases. In this study, we investigated the effects of low-level overexpression of the ERK2 isoform on the phenotype and scattering of cuboidal MDCK epithelial cells growing in discrete multicellular clusters. We show that ERK2 overexpression reduced the vertical size of lateral membranes that contain cell-cell adhesion complexes. Consequently, ERK2 overexpressing cells were unable to develop cuboidal shape, remained flat with increased spread area and intercellular adhesive contacts were present only on the basal side. Interestingly, ERK2 overexpression was not sufficient to increase phosphorylation of multiple downstream targets including transcription factors and induce global changes in gene expression, namely to increase the expression of pro-migratory transcription factor Fra1. However, ERK2 overexpression enhanced HGF/SF-induced cell scattering as these cells scattered more rapidly and to a greater extent than parental cells. Our results suggest that an increase in ERK2 expression primarily reduces cell-cell cohesion and that weakened intercellular adhesion synergizes with upstream signaling in the conversion of the multicellular epithelium into single migrating cells. This mechanism may be clinically relevant as the analysis of clinical data revealed that in one type of cancer, pancreatic adenocarcinoma, ERK2 overexpression correlates with a worse prognosis.
Collapse
Affiliation(s)
- Jan Rasl
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic; Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Josipa Grusanovic
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic
| | - Zuzana Klimova
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic
| | - Josef Caslavsky
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic
| | - Tomas Grousl
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic
| | - Jiri Novotny
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague, Czech Republic; Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, 160 00 Prague, Czech Republic
| | - Michal Kolar
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
| | - Tomas Vomastek
- Laboratory of Cell Signalling Institute of Microbiology of the Czech Academy of Sciences, 142 00 Prague, Czech Republic.
| |
Collapse
|
|
19
|
Núñez KG, Sandow T, Lakey MA, Fort D, Cohen AJ, Thevenot PT. Distinct Gene Expression Profiles in Viable Hepatocellular Carcinoma Treated With Liver-Directed Therapy. Front Oncol 2022; 12:809860. [PMID: 35785174 PMCID: PMC9248864 DOI: 10.3389/fonc.2022.809860] [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: 11/05/2021] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a heterogeneous tumor that accumulates a mutational burden and dysregulated signaling pathways that differ from early to advanced stages. Liver transplant candidates with early-stage hepatocellular carcinoma (HCC) undergo liver-directed therapy (LDT) to delay disease progression and serve as a bridge to liver transplantation (LT). Unfortunately, >80% of LDT-treated patients have viable HCC in the explant liver, dramatically increasing recurrence risk. Understanding the effect of LDT on early-stage HCC could help identify therapeutic targets to promote complete pathologic necrosis and improve recurrence-free survival. In this study, transcriptomic data from viable HCC in LDT-treated bridged to transplant patients were investigated to understand how treatment may affect tumor signaling pathways. METHODS Multiplex transcriptomic gene analysis was performed with mRNA extracted from viable tumors of HCC patients bridged to transplant using LDT. The NanoString nCounter® Tumor Signaling 360 panel was used that contained 780 genes from 48 pathways involved in tumor biology within the microenvironment as well as antitumoral immune responses. RESULTS Hierarchical clustering separated tumors into three subtypes (HCC-1, HCC-2, and HCC-3) each with distinct differences in anti-tumoral signaling and immune infiltration within the tumor microenvironment. Immune infiltration (neutrophils, T cells, and macrophages) were all lowest in subtype HCC-3. The tumor inflammatory signature consisting of 18 genes associated with PD-1/PD-L1 inhibition, antigen presentation, chemokine secretion, and adaptive immune responses was highest in subtype HCC-1 and lowest in HCC-3. History of decompensation and etiology were associated with HCC subtype favoring downregulations in inflammation and immune infiltration with upregulation of lipid metabolism. Gene expression among intrahepatic lesions was remarkably similar with >85% of genes expressed in both lesions. Genes differentially expressed (<8 genes per patient) in multifocal disease were all upregulated in LDT-treated tumors from pathways involving epithelial mesenchymal transition, extracellular matrix remodeling, and/or inflammation potentially implicating intrahepatic metastases. CONCLUSION Incomplete response to LDT may drive expression patterns that inhibit an effective anti-tumoral response through immune exclusion and induce intrahepatic spread.
Collapse
Affiliation(s)
- Kelley G. Núñez
- Institute of Translational Research, Ochsner Health System, New Orleans, LA, United States
| | - Tyler Sandow
- Interventional Radiology, Ochsner Health System, New Orleans, LA, United States
| | - Meredith A. Lakey
- Ochsner Biorepository, Ochsner Health System, New Orleans, LA, United States
| | - Daniel Fort
- Centers for Outcomes and Health Services Research, Ochsner Health System, New Orleans, LA, United States
| | - Ari J. Cohen
- Multi-Organ Transplant Institute, Ochsner Health System, New Orleans, LA, United States
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Paul T. Thevenot
- Institute of Translational Research, Ochsner Health System, New Orleans, LA, United States
| |
Collapse
|
|
20
|
Takao T, Masuda H, Kajitani T, Miki F, Miyazaki K, Yoshimasa Y, Katakura S, Tomisato S, Uchida S, Uchida H, Tanaka M, Maruyama T. Sorafenib targets and inhibits the oncogenic properties of endometrial cancer stem cells via the RAF/ERK pathway. Stem Cell Res Ther 2022; 13:225. [PMID: 35659728 PMCID: PMC9166406 DOI: 10.1186/s13287-022-02888-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 04/09/2022] [Indexed: 11/30/2022] Open
Abstract
Background Distinct subsets of cancer stem cells (CSCs) drive the initiation and progression of malignant tumors via enhanced self-renewal and development of treatment/apoptosis resistance. Endometrial CSC-selective drugs have not been successfully developed because most endometrial cell lines do not contain a sufficient proportion of stable CSCs. Here, we aimed to identify endometrial CSC-containing cell lines and to search for endometrial CSC-selective drugs.
Methods We first assessed the presence of CSCs by identifying side populations (SPs) in several endometrial cancer cell lines. We then characterized cell viability, colony-formation, transwell invasion and xenotransplantion capability using the isolated SP cells. We also conducted real-time RT-PCR, immunoblot and immunofluorescence analyses of the cells’ expression of CSC-associated markers. Focusing on 14 putative CSC-selective drugs, we characterized their effects on the proliferation and apoptosis of endometrial cancer cell lines, examining cell viability and annexin V staining. We further examined the inhibitory effects of the selected drugs, focusing on proliferation, invasion, expression of CSC-associated markers and tumor formation. Results We focused on HHUA cells, an endometrial cancer cell line derived from a well-differentiated endometrial adenocarcinoma. HHUA cells contained a sufficient proportion of stable CSCs with an SP phenotype (HHUA-SP). HHUA-SP showed greater proliferation, colony-formation, and invasive capabilities compared with the main population of HHUA cells (HHUA-MP). HHUA-SP generated larger tumors with higher expression of proliferation-related markers, Ki67, c-MYC and phosphorylated ERK compared with HHUA-MP when transplanted into immunodeficient mice. Among the 14 candidate drugs, sorafenib, an inhibitor of RAF pathways and multiple kinase receptors, inhibited cell proliferation and invasion in both HHUA-SP and -MP, but more profoundly in HHUA-SP. In vivo treatment with sorafenib for 4 weeks reduced the weights of HHUA-SP-derived tumors and decreased the expression of Ki67, ZEB1, and RAF1. Conclusions Our results suggest that HHUA is a useful cell line for discovery and identification of endometrial CSC-selective drugs, and that sorafenib may be an effective anti-endometrial cancer drug targeting endometrial CSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02888-y.
Collapse
Affiliation(s)
- Tomoka Takao
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.,Department of Regenerative Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikatacho, Kitaku, Okayama, 700-8558, Japan
| | - Hirotaka Masuda
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Takashi Kajitani
- Sakura No Seibo Junior College, 3-6, Hanazonocho, Fukushima, 960-8585, Japan
| | - Fumie Miki
- Sho Hospital, 1-41-14, Itabashi, Tokyo, 173-0004, Japan
| | - Kaoru Miyazaki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Yushi Yoshimasa
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Satomi Katakura
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Shoko Tomisato
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Sayaka Uchida
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Hiroshi Uchida
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Mamoru Tanaka
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan
| | - Tetsuo Maruyama
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
21
|
Al-Noshokaty TM, Mesbah NM, Abo-Elmatty DM, Abulsoud AI, Abdel-Hamed AR. Selenium nanoparticles overcomes sorafenib resistance in thioacetamide induced hepatocellular carcinoma in rats by modulation of mTOR, NF-κB pathways and LncRNA-AF085935/GPC3 axis. Life Sci 2022; 303:120675. [PMID: 35640776 DOI: 10.1016/j.lfs.2022.120675] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/19/2022] [Accepted: 05/26/2022] [Indexed: 12/16/2022]
Abstract
AIMS The first-line treatment for advanced hepatocellular carcinoma (HCC) is the multikinase inhibitor sorafenib (SOR). Sofafenib resistance is linked to protein kinase B/ mammalian target of rapamycin (AKT/mTOR) and nuclear factor kappa B (NF-κB) activation, apoptosis inhibition and oxidative stress. This study investigated selenium nanoparticles (SeNps) to overcome SOR resistance in thioacetamide (TAA) induced HCC in rats. MATERIALS AND METHODS TAA (200 mg/kg/twice weekly, i.p.) was administered for 16 weeks to induce HCC.s. Rats were treated with oral SOR (10 mg/Kg daily), selenium, and SeNps (5 mg/kg three times/week) alone or in combination, for two weeks. Apoptosis, proliferation, angiogenesis, metastasis and drug resistance were assessed. Cleaved caspase 3 (C. CASP3), mTOR, and NF-κB were determined by western blotting. Expression of p53 gene and long-noncoding RNA-AF085935 was determined by qRT-PCR. Expression of B- Cell Leukemia/Lymphoma 2 (Bcl2), Bcl associated X protein (Bax)and glypican 3 (GPC3) was determined by enzyme-linked immunosorbent assay. Liver functions, antioxidant capacity, histopathology and CD34 immunohistochemistry were performed. KEY FINDINGS SOR/SeNps reversed TAA-induced HCC in rats, through reduction of oxidative stress, activation of p53, Bax and CASP3, and inhibition of Bcl2. SOR/SeNps ameliorated the HCC-induced effect on cell proliferation and drug resistance by targeting mTOR and NF-κB pathways. SOR/SeNps decreased CD34 immunostaining indicating a decrease in angiogenesis and metastasis. SOR/SeNps regulated HCC epigenetically through the lncRNA-AF085935/GPC3 axis. SIGNIFICANCE SOR/SeNps are a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating apoptosis, AKT/mTOR and NF-κB pathways, as well as CD34 and lncRNA-AF085935/GPC3 axis.
Collapse
Affiliation(s)
- Tohada M Al-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Noha M Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Dina M Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Asmaa R Abdel-Hamed
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
| |
Collapse
|
|
22
|
Yang F, Deng K, Zheng H, Liu Z, Zheng Y. Progress of targeted and immunotherapy for hepatocellular carcinoma and the application of next-generation sequencing. Ann Hepatol 2022; 27:100677. [PMID: 35093601 DOI: 10.1016/j.aohep.2022.100677] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC), leading cancer worldwide, has a high degree of genetic heterogeneity; next-generation sequencing (NGS) technology has contributed significantly to the discovery of driving genes as well as high-frequency mutations in HCC. The detection of gene alterations may allow us to predict prognosis and adverse drug reactions for individuals, paving the way for personalized medicine in HCC patients. In this review, we summarized the common systemic therapy regimens for HCC and the predictive efficacy of genetic biomarkers on the prognosis of patients under these treatments. Finally, we put forward a future perspective on the potential of NGS technology for the guidance of targeted therapy and immunotherapy in HCC.
Collapse
Affiliation(s)
- Fan Yang
- Department of liver surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China
| | - Kaige Deng
- Department of liver surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China
| | - Haoran Zheng
- Department of liver surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China
| | - Zhenting Liu
- Department of liver surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China
| | - Yongchang Zheng
- Department of liver surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China.
| |
Collapse
|
|
23
|
Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Metabolic pathway-based target therapy to hepatocellular carcinoma: a computational approach. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA, VOLUME 2 2022:83-103. [DOI: 10.1016/b978-0-323-98807-0.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
|
|
24
|
Garcia PP, Albuquerque RM, Osório FMF, Couto CA, Lima AS, Vidigal PVT. B-RAF PROTEIN IMMUNOEXPRESSION IN HEPATOCELLULAR CARCINOMA DUE TO HEPATITIS C VIRUS RELATED CIRRHOSIS. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:419-423. [PMID: 34909843 DOI: 10.1590/s0004-2803.202100000-76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 06/15/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Hepatocarcinogenesis is a multistep process that lead to genetic changes in hepatocytes resulting in neoplasia. However, the mechanisms of malignant transformation seem to differ widely. To know carcinogenesis mechanisms is essential to develop new treatment and prevention methods. OBJECTIVE The aim of this study is to analyze B-Raf protein immunoexpression in explants with hepatocellular carcinoma (HCC) related to hepatitis C (HCV), in adjacent cirrhotic tissue and in normal livers. We also associated the immunoexpression with known HCC related histopathogical prognostic features. METHODS Livers from 35 patients with HCV related cirrhosis and HCC that underwent liver transplantation or hepatectomy at Clinical Hospital – UFMG and 25 normal livers from necropsy archives were studied. Tumors were classified according to: tumor size, vascular invasion and differentiation grade. B-Raf protein expression was determined by immunohistochemistry. RESULTS B-Raf was strongly expressed in the HCV cirrhotic parenchyma cytoplasm of 17.1% cases and in 62.9% of HCC samples. Strong B-Raf protein staining was associated with tumor tissue (P<0.0001; OR=8.18 (2.62–26.63)). All normal livers showed weak or negative expression for B-Raf. There was no significant association among B-Raf scores and tumor differentiation grade (P=0.9485), tumor size (P=0.4427) or with vascular invasion (P=0.2666). CONCLUSION We found B-Raf protein immunostaining difference in normal livers, in the areas of HCV cirrhosis and in the hepatocarcinoma. We did not find association between B-Raf expression and histopathological markers of tumor progression. Our data suggests that B-Raf may play an important role in initial HCC carcinogenesis. Larger studies are needed to validate these observations.
Collapse
Affiliation(s)
- Paula Piedade Garcia
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| | - Ronniel Morais Albuquerque
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| | - Fernanda Maria Farage Osório
- Universidade Federal de Minas Gerais, Hospital das Clínicas - EBSERH, Instituto Alfa de Gastroenterologia, Belo Horizonte, MG, Brasil
| | - Cláudia Alves Couto
- Universidade Federal de Minas Gerais, Hospital das Clínicas - EBSERH, Instituto Alfa de Gastroenterologia, Belo Horizonte, MG, Brasil
| | - Agnaldo Soares Lima
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Cirurgia, Belo Horizonte, MG, Brasil
| | - Paula Vieira Teixeira Vidigal
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| |
Collapse
|
|
25
|
El-Hanboshy SM, Helmy MW, Abd-Alhaseeb MM. Catalpol synergistically potentiates the anti-tumour effects of regorafenib against hepatocellular carcinoma via dual inhibition of PI3K/Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways. Mol Biol Rep 2021; 48:7233-7242. [PMID: 34596810 DOI: 10.1007/s11033-021-06715-0/figures/4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 09/23/2021] [Indexed: 05/26/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer characterized by dysregulation of several crucial cellular signaling pathways such as PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. Novel therapies targeting these pathways have been discovered such as regorafenib which is small molecular multi-kinase inhibitor mainly targets VEGF/VEGFR2. Catalpol is an iridoid glycoside richly found in rehmannia glutinosa which is a fundamental herb used extensively in traditional Chinese medicine. It is evidenced that catalpol has many pharmacological effects on nervous and cardiovascular systems, in addition to exhibiting hypoglycemic, anti-inflammatory, anti-proliferative and anti-tumour activities. However, its effect on HCC isn't clear enough. So, this study aimed to investigate the anti-tumour effects of catalpol either alone or in combination with regorafenib on HCC. METHODS AND RESULTS In vitro experiments were performed using HepG2 and HUH-7 hepatocellular carcinoma cell lines. MTT assays evaluated anti-proliferative effects of catalpol and/or regorafenib. Combination index was calculated via compusyn software to detect synergism. Tumour biomarkers were measured using ELISA technique. Results showed that catalpol has anti-tumour effects against HCC via targeting PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. In addition, results revealed that our novel combination of catalpol and regorafenib showed potent synergistic anti-tumour effect via suppressing both of PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and their downstreams. CONCLUSION Catalpol and/or regorafenib markedly suppressed PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and consequently showed potent anti-tumour effects against HCC. Results encourage further pre-clinical and clinical studies of this novel combination as a promising targeted therapy for HCC management.
Collapse
Affiliation(s)
- Sara Muhammad El-Hanboshy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.
| | - Maged Wasfy Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt
| | | |
Collapse
|
|
26
|
Dillon M, Lopez A, Lin E, Sales D, Perets R, Jain P. Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers. Cancers (Basel) 2021; 13:cancers13205059. [PMID: 34680208 PMCID: PMC8534156 DOI: 10.3390/cancers13205059] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/30/2021] [Accepted: 10/06/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation, and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid and blood cancers. Research often focuses on targeting the pathway to disrupt cancer initiation and progression. We aimed to provide an overview of the pathway’s physiologic role and regulation, interactions with other pathways involved in cancer development, and mutations that lead to malignancy. Several blood and solid cancers are analyzed to illustrate the impact of the pathway’s dysregulation, stemming from mutation or viral induction. Finally, we summarized different approaches to targeting the pathway and the associated novel treatments being researched or having recently achieved approval. Abstract The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
Collapse
|
|
27
|
El-Hanboshy SM, Helmy MW, Abd-Alhaseeb MM. Catalpol synergistically potentiates the anti-tumour effects of regorafenib against hepatocellular carcinoma via dual inhibition of PI3K/Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways. Mol Biol Rep 2021; 48:7233-7242. [PMID: 34596810 DOI: 10.1007/s11033-021-06715-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 09/23/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer characterized by dysregulation of several crucial cellular signaling pathways such as PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. Novel therapies targeting these pathways have been discovered such as regorafenib which is small molecular multi-kinase inhibitor mainly targets VEGF/VEGFR2. Catalpol is an iridoid glycoside richly found in rehmannia glutinosa which is a fundamental herb used extensively in traditional Chinese medicine. It is evidenced that catalpol has many pharmacological effects on nervous and cardiovascular systems, in addition to exhibiting hypoglycemic, anti-inflammatory, anti-proliferative and anti-tumour activities. However, its effect on HCC isn't clear enough. So, this study aimed to investigate the anti-tumour effects of catalpol either alone or in combination with regorafenib on HCC. METHODS AND RESULTS In vitro experiments were performed using HepG2 and HUH-7 hepatocellular carcinoma cell lines. MTT assays evaluated anti-proliferative effects of catalpol and/or regorafenib. Combination index was calculated via compusyn software to detect synergism. Tumour biomarkers were measured using ELISA technique. Results showed that catalpol has anti-tumour effects against HCC via targeting PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. In addition, results revealed that our novel combination of catalpol and regorafenib showed potent synergistic anti-tumour effect via suppressing both of PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and their downstreams. CONCLUSION Catalpol and/or regorafenib markedly suppressed PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and consequently showed potent anti-tumour effects against HCC. Results encourage further pre-clinical and clinical studies of this novel combination as a promising targeted therapy for HCC management.
Collapse
Affiliation(s)
- Sara Muhammad El-Hanboshy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.
| | - Maged Wasfy Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt
| | | |
Collapse
|
|
28
|
Lee HK, Lim HM, Park SH, Nam MJ. Knockout of Hepatocyte Growth Factor by CRISPR/Cas9 System Induces Apoptosis in Hepatocellular Carcinoma Cells. J Pers Med 2021; 11:jpm11100983. [PMID: 34683124 PMCID: PMC8540514 DOI: 10.3390/jpm11100983] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
Background: CRISPR/Cas9 system is a prokaryotic adaptive immune response system that uses noncoding RNAs to guide the Cas9 nuclease to induce site-specific DNA cleavage. Hepatocyte growth factor (HGF) is a well-known growth factor that plays a crucial role in cell growth and organ development. According to recent studies, it has been reported that HGF promoted growth of hepatocellular carcinoma (HCC) cells. Here, we investigated the apoptotic effects in HCC cells. Methods: Crispr-HGF plasmid was constructed using GeneArt CRISPR Nuclease Vector. pMex-HGF plasmid that targets HGF overexpressing gene were designed with pMex-neo plasmid. We performed real time-polymerase chain reaction to measure the expression of HGF mRNA. We performed cell counting assay and colony formation assay to evaluate cell proliferation. We also carried out migration assay and invasion assay to reveal the inhibitory effects of Crispr-HGF in HCC cells. Furthermore, we performed cell cycle analysis to detect transfection of Crispr-HGF induced cell cycle arrest. Collectively, we performed annexin V/PI staining assay and Western blot assay. Results: In Crispr-HGF-transfected group, the mRNA expression levels of HGF were markedly downregulated compared to pMex-HGF-transfected group. Moreover, Crispr-HGF inhibited cell viability in HCC cells. We detected that wound area and invaded cells were suppressed in Crispr-HGF-transfected cells. The results showed that transfection of Crispr-HGF induced cell cycle arrest and apoptosis in HCC cells. Expression of the phosphorylation of mitogen activated protein kinases and c-Met protein was regulated in Crispr-HGF-transfected group. Interestingly, we found that the expression of HGF protein in conditioned media significantly decreased in Crispr-HGF-transfected group. Conclusions: Taken together, we found that inhibition of HGF through transfection of Crispr-HGF suppressed cell proliferation and induced apoptotic effects in HCC Huh7 and Hep3B cells.
Collapse
Affiliation(s)
- Han Ki Lee
- Department of Biological Science, Gachon University, Seongnam 13120, Korea; (H.K.L.); (H.M.L.)
| | - Heui Min Lim
- Department of Biological Science, Gachon University, Seongnam 13120, Korea; (H.K.L.); (H.M.L.)
| | - See-Hyoung Park
- Department of Bio and Chemical Engineering, Hongik University, Sejong 30016, Korea
- Correspondence: (S.-H.P.); (M.J.N.); Tel.: +82-44-860-2126 (S.-H.P.); +82-31-750-4760 (M.J.N.)
| | - Myeong Jin Nam
- Department of Biological Science, Gachon University, Seongnam 13120, Korea; (H.K.L.); (H.M.L.)
- Correspondence: (S.-H.P.); (M.J.N.); Tel.: +82-44-860-2126 (S.-H.P.); +82-31-750-4760 (M.J.N.)
| |
Collapse
|
|
29
|
Qing X, Xu W, Zong J, Du X, Peng H, Zhang Y. Emerging treatment modalities for systemic therapy in hepatocellular carcinoma. Biomark Res 2021; 9:64. [PMID: 34419152 PMCID: PMC8380325 DOI: 10.1186/s40364-021-00319-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has long been a major global clinical problem as one of the most common malignant tumours with a high rate of recurrence and mortality. Although potentially curative therapies are available for the early and intermediate stages, the treatment of patients with advanced HCC remains to be resolved. Fortunately, the past few years have shown the emergence of successful systemic therapies to treat HCC. At the molecular level, HCC is a heterogeneous disease, and current research on the molecular characteristics of HCC has revealed numerous therapeutic targets. Targeted agents based on signalling molecules have been successfully supported in clinical trials, and molecular targeted therapy has already become a milestone for disease management in patients with HCC. Immunotherapy, a viable approach for the treatment of HCC, recognizes the antigens expressed by the tumour and treats the tumour using the immune system of the host, making it both selective and specific. In addition, the pipeline for HCC is evolving towards combination therapies with promising clinical outcomes. More drugs designed to focus on specific pathways and immune checkpoints are being developed in the clinic. It has been demonstrated that some drugs can improve the prognosis of patients with HCC in first- or second-line settings, and these drugs have been approved by the Food and Drug Administration or are nearing approval. This review describes targeting pathways and systemic treatment strategies in HCC and summarizes effective targeted and immune-based drugs for patients with HCC and the problems encountered.
Collapse
Affiliation(s)
- Xin Qing
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
| | - Wenjing Xu
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
| | - Jingjing Zong
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
| | - Xuanlong Du
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
| | - Hao Peng
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
| | - Yewei Zhang
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China.
| |
Collapse
|
|
30
|
Banerjee I, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC). Adv Cancer Res 2021; 152:329-381. [PMID: 34353442 DOI: 10.1016/bs.acr.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.
Collapse
Affiliation(s)
- Indranil Banerjee
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
| |
Collapse
|
|
31
|
Al Refaey HR, Newairy ASA, Wahby MM, Albanese C, Elkewedi M, Choudhry MU, Sultan AS. Manuka honey enhanced sensitivity of HepG2, hepatocellular carcinoma cells, for Doxorubicin and induced apoptosis through inhibition of Wnt/β-catenin and ERK1/2. Biol Res 2021; 54:16. [PMID: 34049576 PMCID: PMC8161992 DOI: 10.1186/s40659-021-00339-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 05/03/2021] [Indexed: 11/10/2022] Open
Abstract
Background Recently, there is increasing awareness focused on the identification of naturally occurring anticancer agents derived from natural products. Manuka honey (MH) has been recognized for its biological properties as antimicrobial, antioxidant, and anticancer properties. However, its antiproliferative mechanism in hepatocellular carcinoma is not investigated. The current study focused mainly on investigating the molecular mechanism and synergistic effect of anticancer properties of MH on Doxorubicin (DOX)-mediated apoptotic cell death, using two different p53 statuses (HepG2 and Hep3B) and one non-tumorigenic immortalized liver cell line. Results MH treatment showed a proliferative inhibitory effect on tested cells in a dose-dependent manner with IC50 concentration of (6.92 ± 0.005%) and (18.62 ± 0.07%) for HepG2 and Hep3B cells, respectively, and induced dramatic morphological changes of Hep-G2 cells, which considered as characteristics feature of apoptosis induction after 48 h of treatment. Our results showed that MH or combined treatments induced higher cytotoxicity in p53-wild type, HepG2, than in p53-null, Hep3B, cells. Cytotoxicity was not observed in normal liver cells. Furthermore, the synergistic effect of MH and Dox on apoptosis was evidenced by increased annexin-V-positive cells and Sub-G1 cells in both tested cell lines with a significant increase in the percentage of Hep-G2 cells at late apoptosis as confirmed by the flow cytometric analysis. Consistently, the proteolytic activities of caspase-3 and the degradation of poly (ADP-ribose) polymerase were also higher in the combined treatment which in turn accompanied by significant inhibitory effects of pERK1/2, mTOR, S6K, oncogenic β-catenin, and cyclin D1 after 48 h. In contrast, the MH or combined treatment-induced apoptosis was accompanied by significantly upregulated expression of proapoptotic Bax protein and downregulated expression of anti-apoptotic Bcl-2 protein after 48 h. Conclusions Our data showed a synergistic inhibitory effect of MH on DOX-mediated apoptotic cell death in HCC cells. To our knowledge, the present study provides the first report on the anticancer activity of MH and its combined treatment with DOX on HCC cell lines, introducing MH as a promising natural and nontoxic anticancer compound.
Collapse
Affiliation(s)
- Heba R Al Refaey
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Al-Sayeda A Newairy
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mayssaa M Wahby
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Chris Albanese
- Oncology and Radiology Departments, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Mohamed Elkewedi
- Department of Medical Laboratory Technology, Faculty of Applied Health Sciences Technology, Pharos University, Alexandria, Egypt
| | - Muhammad Umer Choudhry
- Oncology Department, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Ahmed S Sultan
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt. .,Oncology Department, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
| |
Collapse
|
|
32
|
LINC00978 promotes hepatocellular carcinoma carcinogenesis partly via activating the MAPK/ERK pathway. Biosci Rep 2021; 40:222177. [PMID: 32077915 PMCID: PMC7064789 DOI: 10.1042/bsr20192790] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/20/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Objective: To study the role of long non-coding RNA (lncRNA) LINC00978 in hepatocellular carcinoma (HCC) carcinogenesis. Materials and methods: LINC00978 expression level was measured by reverse transcription quantitative real-time PCR (RT-qPCR) in HCC tissues and adjacent healthy liver tissues from 49 HCC patients. MTT assay, colony forming assay, and flow cytometry were performed to evaluate the effects of shRNA-mediated LINC00978 knockdown on HCC cell proliferation, cell cycle progression, and apoptosis in vitro. Xenograft tumor model was performed to determine the effects of LINC00978 knockdown on HCC tumor growth in vivo. Western blot was used to assess the activation of signaling molecules in the apoptosis and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Results: LINC00978 expression was significantly up-regulated in human HCC tissue relative to adjacent normal tissue, and LINC00978 high expression was correlated with poor HCC overall survival. LINC00978 was up-regulated in HCC cell lines. ShRNA-mediated LINC00978 knockdown significantly decreased HCC cell proliferation, and induced HCC cell cycle arrest and apoptosis in vitro. LINC00978 knockdown led to significant decrease in tumor xenograft size in vivo. Western blots revealed LINC00978 inhibition decreased ERK, p38, and c-Jun N-terminal kinase (JNK) phosphorylation in HCC cells. Conclusions: LINC00978 is highly expressed in human HCC tissue and correlates with poor HCC prognosis. LINC00978 promotes HCC cell proliferation, cell cycle progression, and survival, partially by activating the MAPK/ERK pathway. Our findings partially elucidated the roles of LINC00978 in HCC carcinogenesis, and identified a therapeutic target for HCC.
Collapse
|
|
33
|
Jiang N, Li H, Sun Y, Zeng J, Yang F, Kantawong F, Wu J. Network Pharmacology and Pharmacological Evaluation Reveals the Mechanism of the Sanguisorba Officinalis in Suppressing Hepatocellular Carcinoma. Front Pharmacol 2021; 12:618522. [PMID: 33746755 PMCID: PMC7969657 DOI: 10.3389/fphar.2021.618522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 01/20/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Sanguisorba Officinalis L. (SO) is a well-known traditional Chinese medicine (TCM), commonly applied to treat complex diseases, such as anticancer, antibacterial, antiviral, anti-inflammatory, anti-oxidant and hemostatic effects. Especially, it has been reported to exert anti-tumor effect in various human cancers. However, its effect and pharmacological mechanism on hepatocellular carcinoma (HCC) remains unclear. Methods: In this study, network pharmacology approach was applied to characterize the underlying mechanism of SO on HCC. Active compounds and potential targets of SO, as well as related genes of HCC were obtained from the public databases, the potential targets and signaling pathways were determined by protein-protein interaction (PPI), gene ontology (GO) and pathway enrichment analyses. And the compound-target and target-pathway networks were constructed. Subsequently, in vitro experiments were also performed to further verify the anticancer effects of SO on HCC. Results: By using the comprehensive network pharmacology analysis, 41 ingredients in SO were collected from the corresponding databases, 12 active ingredients screened according to their oral bioavailability and drug-likeness index, and 258 potential targets related to HCC were predicted. Through enrichment analysis, SO was found to show its excellent therapeutic effects on HCC through several pathways, mainly related to proliferation and survival via the EGFR, PI3K/AKT, NFκB and MAPK signaling pathways. Additionally, in vitro, SO was found to inhibit cell proliferation, induce apoptosis and down-regulate cell migration and invasion in various HCC cells. Moreover, western blot analysis showed that SO treatment down-regulated the expression of p-EGFR, p-PI3K, p-AKT, p-NFκB and p-MAPK proteins in HepG2 cells. These results validated that SO exerted its therapeutic effects on HCC mainly by the regulation of cell proliferation and survival via the EGFR/MAPK and EGFR/PI3K/AKT/NFκB signaling pathways. Conclusion: Taken together, this study, revealed the anti-HCC effects of SO and its potential underlying therapeutic mechanisms in a multi-target and multi-pathway manner.
Collapse
Affiliation(s)
- Nan Jiang
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- School of Pharmacy, Southwest Medical University, Luzhou, China
- International Education School, Southwest Medical University, Luzhou, China
| | - Hong Li
- School of Pharmacy, Southwest Medical University, Luzhou, China
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China
| | - Yueshan Sun
- School of Pharmacy, Southwest Medical University, Luzhou, China
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China
| | - Jing Zeng
- School of Pharmacy, Southwest Medical University, Luzhou, China
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China
| | - Fei Yang
- School of Pharmacy, Southwest Medical University, Luzhou, China
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China
| | - Fahsai Kantawong
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Jianming Wu
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- School of Pharmacy, Southwest Medical University, Luzhou, China
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Drugability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China
| |
Collapse
|
|
34
|
Wang N, Tan HY, Lu Y, Chan YT, Wang D, Guo W, Xu Y, Zhang C, Chen F, Tang G, Feng Y. PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma. Signal Transduct Target Ther 2021; 6:86. [PMID: 33633112 PMCID: PMC7907082 DOI: 10.1038/s41392-021-00485-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/24/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023] Open
Abstract
Altered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.
Collapse
Affiliation(s)
- Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Yuanjun Lu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Yau-Tuen Chan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun City, Jilin Province, People's Republic of China
| | - Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Yu Xu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Feiyu Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Guoyi Tang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
| |
Collapse
|
|
35
|
A model of seven immune checkpoint-related genes predicting overall survival for head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2021; 278:3467-3477. [PMID: 33449165 DOI: 10.1007/s00405-020-06540-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/30/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by different molecular subtypes with different prognosis and response to treatment. Therefore, the aim of this study was to construct reliable gene signatures based on immune checkpoint-related genes to distinguish between subgroups of patients with different risks. METHODS We obtained the HNSCC data from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) as a training set and the external validation set, respectively. First, differentially expressed immune checkpoint-related genes in tumor tissues and normal tissues were determined, and the potential functions of differential genes were explored through GO function annotation and KEGG pathway enrichment analysis. Using univariate Cox regression analysis, 20 immune checkpoint-related genes in HNSCC patients were significantly associated with overall survival (OS). Subsequently, seven genes were selected by multivariate Cox regression analysis to create a gene signature. Next, the stability of gene signatures was assessed using Kaplan-Meier curve, Time-dependent receiver operating characteristic (ROC) curve. Finally, we constructed a nomogram visualization modelled to facilitate subsequent clinical applications. RESULTS A total of 80 differentially expressed genes (DEGs) were obtained, the GO analysis of these DEGs indicated that they were significantly enriched in positive regulation of cell activation, T cell activation; the KEGG analysis results performed and showed that the DEGs were enriched in the MAPK signaling pathway, PI3K - Akt signaling pathway. 7 genes (PPP2R1B, MYD88, CD86, CD80, MAP2K1, TRIB3 and ICOS) were screened by univariate and multivariate Cox regression, and they were used to construct a prognostic model. In the TCGA and GEO datasets, Kaplan-Meier analysis indicated that patients in the high-risk group have a poor prognosis. The sensitivity and specificity evaluation of prognostic model for 1-, 3-, 5-year OS in TCGA were 0.644, 0.661 and 0.625, respectively; and in GSE41613 were 0.748, 0.719, and 0.727, respectively. The calibration chart curve showed that the nomogram has strong clinical performance in the prognosis prediction of HNSCC patients. CONCLUSIONS A novel immune checkpoint-related gene signature can effectively predict and stratify OS in HNSCC patients.
Collapse
|
|
36
|
Darwish NM, Elnahas YM, AlQahtany FS. Diabetes induced renal complications by leukocyte activation of nuclear factor κ-B and its regulated genes expression. Saudi J Biol Sci 2021; 28:541-549. [PMID: 33424337 PMCID: PMC7783672 DOI: 10.1016/j.sjbs.2020.10.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 01/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by inappropriate insulin function. Despite wide progress in genome studies, defects in gene expression for diabetes prognosis still incompletely identified. Prolonged hyperglycemia activates NF-κB, which is a main player in vascular dysfunctions of diabetes. Activated NF-κB, triggers expression of various genes that promote inflammation and cell adhesion process. Alteration of pro-inflammatory and profibrotic gene expression contribute to the irreversible functional and structural changes in the kidney resulting in diabetic nephropathy (DN). To identify the effect of some important NF-κB related genes on mediation of DN progression, we divided our candidate genes on the basis of their function exerted in bloodstream into three categories (Proinflammatory; NF-κB, IL-1B, IL-6, TNF-α and VEGF); (Profibrotic; FN, ICAM-1, VCAM-1) and (Proliferative; MAPK-1 and EGF). We analyzed their expression profile in leukocytes of patients and explored their correlation to diabetic kidney injury features. Our data revealed the overexpression of both proinflammatory and profibrotic genes in DN group when compared to T2D group and were associated positively with each other in DN group indicating their possible role in DN progression. In DN patients, increased expression of proinflammatory genes correlated positively with glycemic control and inflammatory markers indicating their role in DN progression. Our data revealed that the persistent activation NF-κB and its related genes observed in hyperglycemia might contribute to DN progression and might be a good diagnostic and therapeutic target for DN progression. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.
Collapse
Key Words
- 2hPPBG, 2 h post prandial blood glucose.
- ACR, albumin creatinine ratio
- BMI, body mass index.
- DBP, Diastolic blood pressure.
- DN, diabetic nephropathy.
- FBS, fasting blood glucose.
- FN
- HDL, High density lipoprotein-cholesterol.
- HbA1c, Glycosylated hemoglobin.
- ICAM-1
- IL-1β
- IL-6
- LDL, Low density lipoprotein-cholesterol.
- M, male, F, female.
- NF-κB
- S.Cr, serum creatinine.
- SBP, Systolic blood pressure.
- T2D, type 2 diabetes mellitus without nephropathy.
- TC, total cholesterol.
- TGs, Triglyceride.
- TNF-α
- VCAM-1
- VEGF
- VLDL, Very low-density lipoprotein.
- e-GFR, estimated glomerular filtration rate.
Collapse
Affiliation(s)
- Noura M. Darwish
- Department of Biochemistry, Faculty of Science, Ain Shams University, 11566, Egypt
- Ministry of Health Laboratories, Tanta, Egypt
| | - Yousif M. Elnahas
- Department of Surgery, College of Medicine, King Saud University, Medical City, Riyadh 24251, Saudi Arabia
| | - Fatmah S. AlQahtany
- Department of Pathology, Hematopathology Unit, College of Medicine, King Saud University, Medical City, King Saud University, Riyadh 24251, Saudi Arabia
| |
Collapse
|
|
37
|
Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21249405. [PMID: 33321903 PMCID: PMC7764786 DOI: 10.3390/ijms21249405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/30/2022] Open
Abstract
The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.
Collapse
|
|
38
|
Luo D, Li H, Hu J, Zhang M, Zhang S, Wu L, Han B. Development and Validation of Nomograms Based on Gamma-Glutamyl Transpeptidase to Platelet Ratio for Hepatocellular Carcinoma Patients Reveal Novel Prognostic Value and the Ratio Is Negatively Correlated With P38MAPK Expression. Front Oncol 2020; 10:548744. [PMID: 33344225 PMCID: PMC7744698 DOI: 10.3389/fonc.2020.548744] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 10/30/2020] [Indexed: 12/15/2022] Open
Abstract
Background Early prediction of recurrence and death risks is significant to the treatment of hepatocellular carcinoma (HCC) patients. We aimed to develop and validate prognosis nomogram models based on the gamma-glutamyl transpeptidase (GGT)-to-platelet (PLT) ratio (GPR) for HCC and to explore the relationship between the GPR and inflammation-related signaling pathways. Methods All data were obtained from 2000 to 2012 in the Affiliated Hospital of Qingdao University. In the training cohort, factors included in the nomograms were determined by univariate and multivariate analyses. In the training and validation cohorts, the concordance index (C-index) and calibration curves were used to assess predictive accuracy, and receiver operating characteristic curves were used to assess discriminative ability. Clinical utility was evaluated using decision curve analysis. Moreover, improvement of the predictive accuracy of the nomograms was evaluated by calculating the decision curve analysis, the integrated discrimination improvement, and the net reclassification improvement. Finally, the relationship between the GPR and inflammation-related signaling pathways was evaluated using the independent-samples t-test. Results A larger tumor size and higher GPR were common independent risk factors for both disease-free survival (DFS) and overall survival (OS) in HCC (P < 0.05). Good agreement between our nomogram models' predictions and actual observations was detected by the C-index and calibration curves. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models (P < 0.05). Online webserver and scoring system tables were built based on the proposed nomogram for convenient clinical use. Notably, including the GPR greatly improved the predictive ability of our nomogram models (P < 0.05). In the validation cohort, p38 mitogen-activated protein kinase (P38MAPK) expression was significantly negatively correlated with the GPR (P < 0.01) and GGT (P = 0.039), but was not correlated with PLT levels (P = 0.063). And we found that P38MAPK can regulate the expression of GGT by quantitative real-time PCR and Western blotting experiments. Conclusions The dynamic nomogram based on the GPR provides accurate and effective prognostic predictions for HCC, and P38MAPK-GGT may be a suitable therapeutic target to improve the prognosis of HCC patients.
Collapse
Affiliation(s)
- Dingan Luo
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haoran Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jie Hu
- Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
39
|
Yao X, Zhao CR, Yin H, Wang K, Gao JJ. Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells. Acta Pharmacol Sin 2020; 41:1609-1620. [PMID: 32300243 PMCID: PMC7921114 DOI: 10.1038/s41401-020-0395-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
Sorafenib is currently the standard chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC). But its efficacy requires improvement, it is imperative to seek therapeutic strategies that combine sorafenib with other anticancer agents. In this study we investigated the synergistic anticancer effect of combining sorafenib and artesunate, an anti-malaria drug derivative, against HCC in vitro and in vivo. We first showed that artesunate (1-100 μM) alone dose-dependently inhibited the proliferation of five HCC cell lines tested with IC50 values of around 100 μM. Artesunate treatment dose-dependently increased the ROS level in both HuH7 and Hep3B cells; addition of NAC significantly ameliorated the antiproliferation effect of artesunate against HuH7 and Hep3B cells. Then we demonstrated that combination of sorafenib and artesunate exerted synergistic antiproliferation effect and induced synergistic apoptosis in HCC cell lines. In nude mice bearing Hep3B xenografts, combined administration of sorafenib and artesunate significantly enhanced the suppression on tumor growth. We further revealed that sorafenib dose-dependently decreased the levels of p-ERK and p-STAT3, whereas artesunate markedly increased the levels of p-ERK and p-STAT3 in HuH7 and Hep3B cells. When used in combination, sorafenib abolished artesunate-elevated levels of p-STAT3 and p-ERK. Moreover, pharmacological inhibition of ERK by inhibitor PD0325901 or STAT3 by inhibitor Stattic markedly enhanced the anticancer activity of artesunate, suggesting that suppression of ERK and STAT3 signaling by sorafenib contributes to the synergistic anticancer activity against HCC caused by combination of sorafenib and artesunate. Taken together, our results provide an evidence for possible use of sorafenib plus artesunate or artemisinin analogs for treatment of HCC in the future.
Collapse
Affiliation(s)
- Xu Yao
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China
| | - Chen-Ru Zhao
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China
| | - Hao Yin
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China
| | - KeWei Wang
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China
| | - Jian-Jun Gao
- Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China.
| |
Collapse
|
|
40
|
Garcia-Lezana T, Lopez-Canovas JL, Villanueva A. Signaling pathways in hepatocellular carcinoma. Adv Cancer Res 2020; 149:63-101. [PMID: 33579428 DOI: 10.1016/bs.acr.2020.10.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite the recent introduction of new effective systemic agents, the survival of patients with hepatocellular carcinoma (HCC) at advanced stages remains dismal. This underscores the need for new therapies, which has spurred extensive research on the identification of the main drivers of pathway de-regulation as a source of novel therapeutic targets. Frequently altered pathways in HCC involve growth factor receptors (e.g., VEGFR, FGFR, TGFA, EGFR, IGFR) and/or its cytoplasmic intermediates (e.g., PI3K-AKT-mTOR, RAF/ERK/MAPK) as well as key pathways in cell differentiation (e.g., Wnt/β-catenin, JAK/STAT, Hippo, Hedgehog, Notch). Somatic mutations, chromosomal aberrations and epigenetic changes are common mechanisms for pathway deregulation in HCC. Aberrant pathway activation has also been explored as a biomarker to predict response to specific therapies, but currently, these strategies are not implemented when deciding systemic therapies in HCC patients. Beyond the well-established molecular cascades, there are numerous emerging signaling pathways also deregulated in HCC (e.g., tumor microenvironment, non-coding RNA, intestinal microbiota), which have opened new avenues for therapeutic exploration.
Collapse
Affiliation(s)
- Teresa Garcia-Lezana
- Division of Liver Diseases, Liver Cancer Program, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Juan Luis Lopez-Canovas
- Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| |
Collapse
|
|
41
|
Kase AM, Copland III JA, Tan W. Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer. Onco Targets Ther 2020; 13:10499-10513. [PMID: 33116629 PMCID: PMC7576355 DOI: 10.2147/ott.s266085] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.
Collapse
Affiliation(s)
- Adam M Kase
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
| | - John A Copland III
- Mayo Clinic Florida Department of Cancer Biology, Jacksonville, FL32224, USA
| | - Winston Tan
- Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL32224, USA
| |
Collapse
|
|
42
|
El Dika I, Capanu M, Chou JF, Harding JJ, Ly M, Hrabovsky AD, Do RK, Shia J, Millang B, Ma J, O’Reilly EM, Abou‐Alfa GK. Phase II trial of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma after disease progression on sorafenib. Cancer Med 2020; 9:7453-7459. [PMID: 32841541 PMCID: PMC7571806 DOI: 10.1002/cam4.3389] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/15/2020] [Accepted: 07/25/2020] [Indexed: 12/24/2022] Open
Abstract
Background Patients with advanced hepatocellular carcinoma (HCC) who received second line sorafenib plus doxorubicin following disease progression on sorafenib were shown retrospectively to have improved progression free survival (PFS) and overall survival (OS). Sorafenib plus doxorubicin combination may synergistically promote ASK‐1 mediated apoptosis in cancer cells through RAF‐1 inhibition. Thus, we conducted this phase II study of sorafenib and doxorubicin combination following progression on sorafenib. Methods Patients with histologically confirmed advanced HCC, confirmed radiologic progression on sorafenib, Karnofsky performance status (KPS) ≥70%, and Child‐Pugh A liver cirrhosis were eligible. Patients received sorafenib 400 mg twice daily and doxorubicin 60 mg/m2 once every 3‐weeks. The primary endpoint was OS at 6 months (OS6). Secondary endpoints included safety, PFS, OS, response rate (RR) by RECIST 1.1. Additional endpoints included baseline and on‐treatment tumor ASK‐1 and pERK expression levels by immunohistochemistry (IHC) and the correlation with PFS, RR, and OS. Results Thirty patients were enrolled in the study, 86% were male, median age was 64 years. OS6 was 76.6% (95%CI: 57.2%‐88.1%). Median OS was 8.6 (95%CI: 7.3‐12) months, and median PFS reached 3.9 (95%CI: 2.4‐4.6) months. Three (11%) partial responses were observed and 17 patients (61%) had stable disease. Pertinent grade 3‐4 adverse events that occurred in more than 10% of patients included neutropenia (16%), febrile neutropenia (10%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). No association with the difference in baseline and post‐treatment ASK‐1 and pERK level of expression by IHC and survival outcomes was detected. Conclusion Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome. We do not recommend further development or use of this combination in HCC.
Collapse
Affiliation(s)
- Imane El Dika
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| | | | | | - James J. Harding
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| | - Michele Ly
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Sidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPAUSA
| | | | - Richard K.G. Do
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| | - Jinru Shia
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| | | | - Jennifer Ma
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Albert Einstein College of MedicineNew YorkNYUSA
| | - Eileen M. O’Reilly
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| | - Ghassan K. Abou‐Alfa
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA
- Weill Cornell College of MedicineNew YorkNYUSA
| |
Collapse
|
|
43
|
Pei XD, He SQ, Shen LQ, Wei JC, Li XS, Wei YY, Zhang YM, Wang XY, Lin F, He ZL, Jiang LH. 14,15β-dihydroxyklaineanone inhibits HepG2 cell proliferation and migration through p38MAPK pathway. J Pharm Pharmacol 2020; 72:1165-1175. [PMID: 32419149 DOI: 10.1111/jphp.13289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 04/21/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Eurycoma longifolia Jack (Simaroubaceae) is commonly distributed in the Southeast Asia and Indo China, which has been shown to possess antianxiety, antibacterial, anticancer, antifungal, anti-inflammatory, antimalarial and antioxidant biological activities. 14,15β-dihydroxyklaineanone is a diterpene isolated from E. longifolia Jack, which is cytotoxic against human lung cancer and human breast cancer cell lines. However, the effects and underlying mechanisms of 14,15β-dihydroxyklaineanone on hepatocellular carcinoma remain unknown. METHODS Cell viability assay and colony formation assay were used to measure HepG2 cell proliferation. Flow cytometry was used to analyse cell cycle and apoptosis. Wound-healing assay and transwell assay were used to observe cells migration. RNA sequencing and the enrichment of differentially expressed genes (DEGs) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to find and determine underlying pathways. KEY FINDINGS We found that 14,15β-dihydroxyklaineanone inhibited the growth and migration of HepG2 cells but did not induce cell apoptosis. 14,15β-dihydroxyklaineanone induced S cell cycle arrest by downregulating the expression levels of cyclin A, p-CDK2, cyclin B1, p21, E2F-1 and PCNA. In addition, RNA sequencing showed that 14,15β-dihydroxyklaineanone regulated MAPK pathway by increasing the expression levels of phosphor-p38. Downregulating of p38 via both p38 inhibitor (SB203580) and p38-siRNA could antagonize the inhibition of cell proliferation and migration and reverse the changes in p-p38, E-cadherin, N-cadherin and PCNA expression induced by 14,15β-dihydroxyklaineanone treatment. CONCLUSIONS 14,15β-dihydroxyklaineanone inhibited cell proliferation and migration through regulating p38 MAPK pathway in HCC cells.
Collapse
Affiliation(s)
- Xiao-Dong Pei
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, China
| | - Song-Qing He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li-Qun Shen
- Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi University for Nationalities, Nanning, China
| | - Jing-Chen Wei
- Department of Pharmacology, Guilin Medical University, Guilin, China
| | - Xue-Sheng Li
- Institute of Pesticide and Environmental Toxicology, College of Agriculture, Guangxi University, Nanning, China
| | - Yan-Yan Wei
- Cultivation Base of Guangxi Key Laboratory for Agro-Environment and Agro-Products Safety, National Demonstration Center for Experimental Plant Science Education, College of Agriculture, Guangxi University, Nanning, China
| | - Yu-Meng Zhang
- Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
| | - Xin-Yu Wang
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Feng Lin
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Zhi-Long He
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China
| | - Li-He Jiang
- College of Light Industry and Food Engineering, Guangxi University, Nanning, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, China
| |
Collapse
|
|
44
|
Dimri M, Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020491. [PMID: 32093152 PMCID: PMC7072513 DOI: 10.3390/cancers12020491] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
Collapse
|
|
45
|
Li X, Qiu M, Wang S, Zhu H, Feng B, Zheng L. A Phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours. Cancer Chemother Pharmacol 2020; 85:593-604. [DOI: 10.1007/s00280-020-04031-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 01/07/2020] [Indexed: 01/01/2023]
|
|
46
|
Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma. Sci Rep 2019; 9:19095. [PMID: 31836811 PMCID: PMC6911098 DOI: 10.1038/s41598-019-55666-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022] Open
Abstract
Sorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-β1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.
Collapse
|
|
47
|
Yiu SPT, Hui KF, Münz C, Lo KW, Tsao SW, Kao RYT, Yang D, Chiang AKS. Autophagy-Dependent Reactivation of Epstein-Barr Virus Lytic Cycle and Combinatorial Effects of Autophagy-Dependent and Independent Lytic Inducers in Nasopharyngeal Carcinoma. Cancers (Basel) 2019; 11:cancers11121871. [PMID: 31769432 PMCID: PMC6966612 DOI: 10.3390/cancers11121871] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/09/2019] [Accepted: 11/22/2019] [Indexed: 12/14/2022] Open
Abstract
Autophagy, a conserved cellular mechanism, is manipulated by a number of viruses for different purposes. We previously demonstrated that an iron-chelator-like small compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle by activating the ERK1/2-autophagy axis in epithelial cancers. Here, we aim to identify the specific stage of autophagy required for EBV lytic reactivation, determine the autophagy dependency of EBV lytic inducers including histone deacetylase inhibitor (HDACi) and C7/iron chelators, for EBV lytic reactivation and measure the combinatorial effects of these types of lytic inducers in nasopharyngeal carcinoma (NPC). Inhibition of autophagy initiation by 3-MA and autolysosome formation by chloroquine demonstrated that only autophagy initiation is required for EBV lytic reactivation. Gene knockdown of various autophagic proteins such as beclin-1, ATG5, ATG12, ATG7, LC3B, ATG10, ATG3 and Rab9, revealed the importance of ATG5 in EBV lytic reactivation. 3-MA could only abrogate lytic cycle induction by C7/iron chelators but not by HDACi, providing evidence for autophagy-dependent and independent mechanisms in EBV lytic reactivation. Finally, the combination of C7 and SAHA at their corresponding reactivation kinetics enhanced EBV lytic reactivation. These findings render new insights in the mechanisms of EBV lytic cycle reactivation and stimulate a rational design of combination drug therapy against EBV-associated cancers.
Collapse
Affiliation(s)
- Stephanie Pei Tung Yiu
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China; (S.P.T.Y.); (K.F.H.)
| | - Kwai Fung Hui
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China; (S.P.T.Y.); (K.F.H.)
| | - Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zurich, CH-8006 Zurich, Switzerland;
| | - Kwok-Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Sai Wah Tsao
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China;
- Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, China
| | - Richard Yi Tsun Kao
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
| | - Dan Yang
- Department of Chemistry, The University of Hong Kong, Hong Kong, China;
| | - Alan Kwok Shing Chiang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China; (S.P.T.Y.); (K.F.H.)
- Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, China
- Correspondence:
| |
Collapse
|
|
48
|
Refai NS, Louka ML, Halim HY, Montasser I. Long non-coding RNAs (CASC2 and TUG1) in hepatocellular carcinoma: Clinical significance. J Gene Med 2019; 21:e3112. [PMID: 31301261 DOI: 10.1002/jgm.3112] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/18/2019] [Accepted: 07/07/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND The biology of hepatocellular carcinoma remains poorly understood. Long non-coding RNAs (lncRNAs) have been confirmed to be key regulators of most cell processes and cancer. The lncRNA cancer susceptibility candidate 2 (CASC2) was originally identified as a downregulated gene in endometrial cancer and acted as a tumor suppressor. The lncRNA taurine up-regulated gene 1 (TUG1) has been shown to play an oncogenic role in various cancers. However, the relative expression of CASC2 and TUG1 in hepatocellular carcinoma (HCC) on top of hepatitis C virus (HCV) and the relationship between both remains unclear. The present study aimed to evaluate both lncRNA CASC2 and TUG1 relative gene expression in whole blood of HCC/HCV patients in relation to HCV and healthy subjects and to relate them to each other and to different clinicopathological factors. METHODS The relative expression of CASC2 and TUG1 was estimated by a quantitative reverse transcriptase-polymerase chain reaction in 30 HCC/HCV patients and compared with 20 cases of HCV patients and 20 controls. RESULTS CASC2 was downregulated in HCC/HCV patients, whereas TUG1 was overexpressed in relation to HCV and the control group, indicating their antagonistic effect. This suggests their role in the pathogenesis of HCC on top of HCV. Their expression was correlated to Barcelona Clinic Liver Cancer stage and serum alpha-fetoprotein level. CONCLUSIONS CASC2 and TUG1 could be new potential biomarkers with a valid non-invasive technique.
Collapse
Affiliation(s)
- Noha S Refai
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manal L Louka
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hany Y Halim
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Iman Montasser
- Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
49
|
Chuang CY, Tang CM, Ho HY, Hsin CH, Weng CJ, Yang SF, Chen PN, Lin CW. Licochalcone A induces apoptotic cell death via JNK/p38 activation in human nasopharyngeal carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2019; 34:853-860. [PMID: 30983163 DOI: 10.1002/tox.22753] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/20/2019] [Accepted: 03/22/2019] [Indexed: 06/09/2023]
Abstract
Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti-inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen-activated protein kinase-related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase-8 and caspase-9, caspase-3 activation, and cleaved-poly ADP-ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co-administration of a JNK inhibitor (JNK-IN-8) or p38 inhibitor (SB203580) abolishes the activation of caspase-9, caspase-8, and caspase-3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells.
Collapse
Affiliation(s)
- Chun-Yi Chuang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Cheng-Ming Tang
- Graduate Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hsin-Yu Ho
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chung-Han Hsin
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chia-Jui Weng
- Department of Living Services Industry, Tainan University of Technology, Tainan City, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Pei-Ni Chen
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Chiao-Wen Lin
- Graduate Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
50
|
Jin Z, Jia B, Tan L, Liu Y. miR-330-3p suppresses liver cancer cell migration by targeting MAP2K1. Oncol Lett 2019; 18:314-320. [PMID: 31289502 PMCID: PMC6540343 DOI: 10.3892/ol.2019.10280] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 02/08/2018] [Indexed: 01/11/2023] Open
Abstract
MicroRNAs, considered as a promising focus for the treatment of tumors, are key regulators of a large number of genes. The aim of the present study was to investigate the biological functions of microRNA (miR)-330-3p in liver cancer as it had been identified previously that miR-330-3p was deregulated in liver cancer. In order to identify the function of miR-330-3p in liver cancer, the expression of miR-330-3p was determined in liver cancer tissues and adjacent non-tumor tissues using reverse transcription-quantitative polymerase chain reaction analysis. To elucidate the function of miR-330-3p in liver cancer, miR-330-3p was overexpressed using mimic transfection. Cell migration was inhibited by miR-330-3p in liver cancer cells. The miRNA target prediction databases were used to identify potential target genes of miR-330-3p in liver cancer. The RNA level of mitogen-activated protein kinase kinase 1 (MAP2K1) was downregulated by miR-330-3p in liver cancer cells. In conclusion, miR-330-3p suppresses cell migration by targeting MAP2K1 in liver cancer cells.
Collapse
Affiliation(s)
- Zhe Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Baoxing Jia
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ludong Tan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| |
Collapse
|