|
1
|
Ahmed F, Abousaad S, Abouzeid A, Adhiambo C, Ongeri EM. Meprin β regulates osteopontin-signaling in ischemia/reperfusion-induced kidney injury. BMC Nephrol 2025; 26:90. [PMID: 39987047 PMCID: PMC11846229 DOI: 10.1186/s12882-025-03995-7] [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: 08/02/2024] [Accepted: 01/30/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Meprin metalloproteases have been implicated in the pathology of ischemia/reperfusion (IR) induced kidney injury. Meprin β proteolytically processes several mediators of cell signaling pathways involved in apoptosis and extracellular matrix metabolism. We previously showed that meprin β cleaves osteopontin (OPN) in vitro. The objective of the current study was to determine how meprin β expression affects OPN and downstream mediators of the OPN-signaling pathway in IR-induced kidney injury. METHODS Ischemia/Reperfusion injury was induced in wild-type (WT) and meprin β knockout (βKO) mice. Blood samples and kidney tissues were obtained at 24 h post-IR. The levels of OPN, Caspase-3, Bcl-2, and NFκB were evaluated using real-time PCR, western blot, and immunohistochemical approaches. Data analysis utilized a combination of 2-way ANOVA and unpaired t test. RESULTS OPN mRNA increased in both genotypes at 24 h post-IR. Immunohistochemical staining showed IR-associated increases in the levels of OPN in both genotypes. Additionally, we observed higher levels of OPN in the lumen of proximal tubules in WT only, suggesting that meprin β contributes to enhanced release of OPN into filtrate and ultimately into urine. Immunohistochemical staining showed significant increases in the levels of Caspase-3 and NFκB in select tubules of WT only, while Bcl-2 staining intensity increased significantly in both genotypes at 24 h post-IR. CONCLUSIONS These findings suggest that meprin β modulates OPN levels in IR-induced kidney injury and impacts apoptotic genes regulated by the OPN signaling pathway. CLINICAL TRIAL NUMBER Not applicable.
Collapse
Affiliation(s)
- Faihaa Ahmed
- Department of Kinesiology, North Carolina A&T State University, Greensboro, NC, 27411, USA
- Department of Biology, North Carolina A&T State University, Greensboro, NC, 27411, USA
| | - Shaymaa Abousaad
- Department of Kinesiology, North Carolina A&T State University, Greensboro, NC, 27411, USA
| | - Ayman Abouzeid
- Department of Agribusiness, Applied Economics and Agriscience Education, North Carolina A&T State University, Greensboro, NC, 27411, USA
| | - Christine Adhiambo
- Department of Kinesiology, North Carolina A&T State University, Greensboro, NC, 27411, USA
| | - Elimelda Moige Ongeri
- Department of Kinesiology, North Carolina A&T State University, Greensboro, NC, 27411, USA.
| |
Collapse
|
|
2
|
Boland PM, Ebos JML, Attwood K, Mastri M, Fountzilas C, Iyer RV, Banker C, Goey AKL, Bies R, Ma WW, Fakih M. A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer. JNCI Cancer Spectr 2024; 8:pkae017. [PMID: 38697618 PMCID: PMC11065487 DOI: 10.1093/jncics/pkae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/29/2023] [Accepted: 02/26/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER NCT02393755.
Collapse
Affiliation(s)
- Patrick M Boland
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - John M L Ebos
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michalis Mastri
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christos Fountzilas
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Renuka V Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christopher Banker
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Andrew K L Goey
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Robert Bies
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Marwan Fakih
- Department of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| |
Collapse
|
|
3
|
Liu Z, Yang G, Yi X, Zhang S, Feng Z, Cui X, Chen F, Yu L. Osteopontin regulates the growth and invasion of liver cancer cells via DTL. Oncol Lett 2023; 26:476. [PMID: 37809049 PMCID: PMC10551862 DOI: 10.3892/ol.2023.14064] [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: 02/07/2023] [Accepted: 07/19/2023] [Indexed: 10/10/2023] Open
Abstract
Osteopontin (OPN), a secreted phosphoglycoprotein, has important roles in tumor growth, invasion and metastasis in numerous types of cancers. Denticleless E3 ubiquitin protein ligase homolog (DTL), one of the CUL4-DDB1-associated factors (DCAFs), has also been associated with the invasion and metastasis of cancer cells. In the present study, OPN was found to induce DTL expression in liver cancer cells, and the results obtained using luciferase activity assays demonstrated that OPN could transcriptionally activate DTL expression in liver cancer cells. Furthermore, the results of the present study demonstrated that OPN could increase the expression of DTL via PI3K/AKT signaling. In conclusion, the present study demonstrated that OPN, as an extracellular matrix protein, is able to promote the growth and invasion of liver cancer cells through stimulation of the expression of DTL via the PI3K/AKT signaling pathway.
Collapse
Affiliation(s)
- Zhiyong Liu
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Guang Yang
- State Key Laboratory of Oncology in South China, Department of Imaging and Interventional Radiology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xiaoyu Yi
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Shijie Zhang
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhibo Feng
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xudong Cui
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Feilong Chen
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lei Yu
- Department of General Interventional Radiology, Guangxi Academy of Medical Sciences and The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| |
Collapse
|
|
4
|
Wang Y, Wang Z, Jia F, Xu Q, Shu Z, Deng J, Li A, Yu M, Yu Z. CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment. Bioact Mater 2022; 17:147-161. [PMID: 35386453 PMCID: PMC8965090 DOI: 10.1016/j.bioactmat.2022.01.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/31/2021] [Accepted: 01/02/2022] [Indexed: 02/06/2023] Open
Abstract
Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named PFH@LSLP) for sorafenib-resistant HCC treatment. The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O2-saturated PFH core could alleviate the tumor hypoxia by O2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8+ T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.
PFH@LSLP was developed to overcome sorafenib resistance. LFC131 peptide blocked SDF-1α/CXCR4 to sensitize sorafenib. PLX3397 blocked CSF1/CSF1R to activate immune response.
Collapse
|
|
5
|
Zhang Y, Li Q, Jiang N, Su Z, Yuan Q, Lv L, Sang X, Chen R, Feng Y, Chen Q. Dihydroartemisinin beneficially regulates splenic immune cell heterogeneity through the SOD3-JNK-AP-1 axis. SCIENCE CHINA. LIFE SCIENCES 2022; 65:1636-1654. [PMID: 35226255 DOI: 10.1007/s11427-021-2061-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022]
Abstract
The immunomodulatory potential of dihydroartemisinin (DHA) has recently been highlighted; however, the potential mechanism remains to be clarified. Single-cell RNA sequencing was explored in combination with cellular and biochemical approaches to elucidate the immunomodulatory mechanisms of DHA. In this study, we found that DHA induced both spleen enlargement and rearrangement of splenic immune cell subsets in mice. It was revealed that DHA promoted the reversible expansion of effective regulatory T cells and interferon-γ+ cytotoxic CD8+ T cells in the spleen via induction of superoxide dismutase 3 (SOD3) expression and increased phosphorylation of c-Jun N-terminal kinases (JNK) and its downstream activator protein 1 (AP-1) transcription factors. Further, SOD3 knockout mice were resistant to the regulatory effect of DHA. Thus, DHA, through the activation of the SOD3-JNK-AP-1 axis, beneficially regulated immune cell heterogeneity and splenic immune cell homeostasis to treat autoimmune diseases.
Collapse
Affiliation(s)
- Yiwei Zhang
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Qilong Li
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Ning Jiang
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Ziwei Su
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Quan Yuan
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Lei Lv
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Xiaoyu Sang
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Ran Chen
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Ying Feng
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China
| | - Qijun Chen
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, China.
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, 110866, China.
| |
Collapse
|
|
6
|
Rogers MP, Mi Z, Li NY, Wai PY, Kuo PC. Tumor: Stroma Interaction and Cancer. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:59-87. [PMID: 35165860 DOI: 10.1007/978-3-030-91311-3_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.
Collapse
Affiliation(s)
- Michael P Rogers
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Zhiyong Mi
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Neill Y Li
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Philip Y Wai
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Paul C Kuo
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
| |
Collapse
|
|
7
|
Desert R, Ge X, Song Z, Han H, Lantvit D, Chen W, Das S, Athavale D, Abraham-Enachescu I, Blajszczak C, Chen Y, Musso O, Guzman G, Hoshida Y, Nieto N. Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis. Hepatol Commun 2021; 6:692-709. [PMID: 34730871 PMCID: PMC8948552 DOI: 10.1002/hep4.1845] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/13/2021] [Accepted: 10/02/2021] [Indexed: 12/24/2022] Open
Abstract
Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte‐derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome‐based OPN correlation network was associated with HCC incidence along 10 years of follow‐up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (OpnHep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep, which also showed more cancer stem/progenitor cells (CSCs, CD44+AFP+) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn−/− compared with wild‐type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44−/−OpnHep Tg mice. Conclusions: Hepatocyte‐derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro‐tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation.
Collapse
Affiliation(s)
- Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.,Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Ioana Abraham-Enachescu
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Chuck Blajszczak
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Yu Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Orlando Musso
- INSERM, University of Rennes, INRA, Institut NuMeCAN (Nutrition Metabolisms and Cancer), Rennes, France
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.,Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| |
Collapse
|
|
8
|
Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
Collapse
Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
| |
Collapse
|
|
9
|
Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma. Cell Commun Signal 2020; 18:97. [PMID: 32576292 PMCID: PMC7310503 DOI: 10.1186/s12964-020-00539-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 02/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. Methods Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. Results Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. Conclusions Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC.
|
|
10
|
Napoli S, Scuderi C, Gattuso G, Di Bella V, Candido S, Basile MS, Libra M, Falzone L. Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma. Cells 2020; 9:cells9051151. [PMID: 32392801 PMCID: PMC7291303 DOI: 10.3390/cells9051151] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.
Collapse
Affiliation(s)
- Salvatore Napoli
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Chiara Scuderi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Virginia Di Bella
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Maria Sofia Basile
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
| | - Luca Falzone
- Epidemiology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, 80131 Naples, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
| |
Collapse
|
|
11
|
Parikh ND, Mehta AS, Singal AG, Block T, Marrero JA, Lok AS. Biomarkers for the Early Detection of Hepatocellular Carcinoma. Cancer Epidemiol Biomarkers Prev 2020; 29:2495-2503. [PMID: 32238405 DOI: 10.1158/1055-9965.epi-20-0005] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/17/2020] [Accepted: 03/16/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the cancer with the fastest increase in mortality in the United States, with more than 39,000 cases and 29,000 deaths in 2018. As with many cancers, survival is significantly improved by early detection. The median survival of patients with early HCC is >60 months but <15 months when detected at an advanced stage. Surveillance of at-risk patients improves outcome, but fewer than 20% of those at risk for HCC receive surveillance, and current surveillance strategies have limited sensitivity and specificity. Ideally, blood-based biomarkers with adequate sensitivity or specificity would be available for early detection of HCC; however, the most commonly used biomarker for HCC, alpha-fetoprotein, has inadequate performance characteristics. There are several candidate serum proteomic, glycomic, and genetic markers that have gone through early stages of biomarker validation and have shown promise for the early detection of HCC, but these markers require validation in well-curated cohorts. Ongoing prospective cohort studies will permit retrospective longitudinal (phase III biomarker study) validation of biomarkers. In this review, we highlight promising candidate biomarkers and biomarker panels that have completed phase II evaluation but require further validation prior to clinical use.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
Collapse
Affiliation(s)
- Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
| | - Anand S Mehta
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina
| | - Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Timothy Block
- Baruch S. Blumberg Institute of The Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Jorge A Marrero
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
12
|
Jakobi K, Beyer S, Koch A, Thomas D, Schwalm S, Zeuzem S, Pfeilschifter J, Grammatikos G. Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro. Int J Mol Sci 2020; 21:ijms21072409. [PMID: 32244391 PMCID: PMC7177910 DOI: 10.3390/ijms21072409] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.
Collapse
Affiliation(s)
- Katja Jakobi
- Medizinische Klinik 1, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (K.J.); (S.Z.)
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
| | - Sandra Beyer
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
| | - Alexander Koch
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
| | - Dominique Thomas
- Institut für Klinische Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany;
| | - Stephanie Schwalm
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
| | - Stefan Zeuzem
- Medizinische Klinik 1, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (K.J.); (S.Z.)
| | - Josef Pfeilschifter
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
| | - Georgios Grammatikos
- Medizinische Klinik 1, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (K.J.); (S.Z.)
- Institut für Allgemeine Pharmakologie und Toxikologie, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt, Germany; (S.B.); (A.K.); (S.S.); (J.P.)
- St Luke’s Hospital, 55236 Thessaloniki, Greece
- Correspondence: ; Tel.: +30-2316-014-910
| |
Collapse
|
|
13
|
Zhang W, Cheng J, Diao P, Wang D, Zhang W, Jiang H, Wang Y. Therapeutically targeting head and neck squamous cell carcinoma through synergistic inhibition of LSD1 and JMJD3 by TCP and GSK-J1. Br J Cancer 2019; 122:528-538. [PMID: 31848446 PMCID: PMC7028736 DOI: 10.1038/s41416-019-0680-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 10/29/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The histone demethylase LSD1 is a key mediator driving tumorigenesis, which holds potential as a promising therapeutic target. However, treatment with LSD1 inhibitors alone failed to result in complete cancer regression. METHODS The synergistic effects of TCP (a LSD1 inhibitor) and GSK-J1 (a JMJD3 inhibitor) against HNSCC were determined in vitro and in preclinical animal models. Genes modulated by chemical agents or siRNAs in HNSCC cells were identified by RNA-seq and further functionally interrogated by bioinformatics approach. Integrative siRNA-mediated gene knockdown, rescue experiment and ChIP-qPCR assays were utilised to characterise the mediators underlying the therapeutic effects conferred by TCP and GSK-J1. RESULTS Treatment with TCP and GSK-J1 impaired cell proliferation, induced apoptosis and senescence in vitro, which were largely recapitulated by simultaneous LSD1 and JMJD3 knockdown. Combinational treatment inhibited tumour growth and progression in vivo. Differentially expressed genes modulated by TCP and GSK-J1 were significantly enriched in cell proliferation, apoptosis and cancer-related pathways. SPP1 was identified as the mediator of synergy underlying the pro-apoptosis effects conferred by TCP and GSK-J1. Co-upregulation of LSD1 and JMJD3 associated with worse prognosis in patients with HNSCC. CONCLUSIONS Our findings revealed a novel therapeutic strategy of simultaneous LSD1 and JMJD3 inhibition against HNSCC.
Collapse
Affiliation(s)
- Wei Zhang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Pengfei Diao
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Wei Zhang
- Department of Oral Pathology, Affiliated Stomatological Hospital, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, 210029, Nanjing, P. R. China
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 210029, Nanjing, P. R. China.
| |
Collapse
|
|
14
|
Long J, Chen P, Lin J, Bai Y, Yang X, Bian J, Lin Y, Wang D, Yang X, Zheng Y, Sang X, Zhao H. DNA methylation-driven genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma. Am J Cancer Res 2019; 9:7251-7267. [PMID: 31695766 PMCID: PMC6831284 DOI: 10.7150/thno.31155] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 08/05/2019] [Indexed: 12/21/2022] Open
Abstract
In this study, we performed a comprehensively analysis of gene expression and DNA methylation data to establish diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC). Methods: We collected gene expression and DNA methylation datasets for over 1,200 clinical samples. Integrated analyses of RNA-sequencing and DNA methylation data were performed to identify DNA methylation-driven genes. These genes were utilized in univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to build a prognostic model. Recurrence and diagnostic models for HCC were also constructed using the same genes. Results: A total of 123 DNA methylation-driven genes were identified. Two of these genes (SPP1 and LCAT) were chosen to construct the prognostic model. The high-risk group showed a markedly unfavorable prognosis compared to the low-risk group in both training (HR = 2.81; P < 0.001) and validation (HR = 3.06; P < 0.001) datasets. Multivariate Cox regression analysis indicated the prognostic model to be an independent predictor of prognosis (P < 0.05). Also, the recurrence model successfully distinguished the HCC recurrence rate between the high-risk and low-risk groups in both training (HR = 2.22; P < 0.001) and validation (HR = 2; P < 0.01) datasets. The two diagnostic models provided high accuracy for distinguishing HCC from normal samples and dysplastic nodules in the training and validation datasets, respectively. Conclusions: We identified and validated prognostic, recurrence, and diagnostic models that were constructed using two DNA methylation-driven genes in HCC. The results obtained by integrating multidimensional genomic data offer novel research directions for HCC biomarkers and new possibilities for individualized treatment of patients with HCC.
Collapse
|
|
15
|
Zhu Y, Yang J, Xu D, Gao XM, Zhang Z, Hsu JL, Li CW, Lim SO, Sheng YY, Zhang Y, Li JH, Luo Q, Zheng Y, Zhao Y, Lu L, Jia HL, Hung MC, Dong QZ, Qin LX. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut 2019; 68:1653-1666. [PMID: 30902885 DOI: 10.1136/gutjnl-2019-318419] [Citation(s) in RCA: 275] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.
Collapse
Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jing Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Da Xu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Xiao-Mei Gao
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Ze Zhang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jennifer L Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chia-Wei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Seung-Oe Lim
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuan-Yuan Sheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yu Zhang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jian-Hua Li
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qin Luo
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yue Zhao
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
16
|
Czauderna C, Castven D, Mahn FL, Marquardt JU. Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer-from Tumor Development to Therapeutic Implications. Cancers (Basel) 2019; 11:cancers11081053. [PMID: 31349670 PMCID: PMC6721782 DOI: 10.3390/cancers11081053] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/19/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions.
Collapse
Affiliation(s)
- Carolin Czauderna
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
| | - Darko Castven
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
| | - Friederike L Mahn
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
| | - Jens U Marquardt
- Department of Medicine I, Lichtenberg Research Group for Molecular Hepatocarcinogenesis, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
| |
Collapse
|
|
17
|
Potikha T, Pappo O, Mizrahi L, Olam D, Maller SM, Rabinovich GA, Galun E, Goldenberg DS. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J 2019; 33:7995-8007. [PMID: 30897344 PMCID: PMC9292271 DOI: 10.1096/fj.201900017r] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/18/2019] [Indexed: 04/16/2024]
Abstract
Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.-Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Maller, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model.
Collapse
Affiliation(s)
- Tamara Potikha
- The Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
| | - Orit Pappo
- Department of PathologyHadassah-Hebrew University Medical CenterJerusalemIsrael
| | - Lina Mizrahi
- The Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
| | - Devorah Olam
- The Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
| | - Sebastián M. Maller
- Laboratory of ImmunopathologyInstitute of Biology and Experimental Medicine (IBYME)Argentinean National Research Council (CONICET)Buenos AiresArgentina
| | - Gabriel A. Rabinovich
- Laboratory of ImmunopathologyInstitute of Biology and Experimental Medicine (IBYME)Argentinean National Research Council (CONICET)Buenos AiresArgentina
- Faculty of Exact and Natural SciencesUniversity of Buenos AiresBuenos AiresArgentina
| | - Eithan Galun
- The Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
| | - Daniel S. Goldenberg
- The Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
| |
Collapse
|
|
18
|
Li X, Zhang ZS, Zhang XH, Yang SN, Liu D, Diao CR, Wang H, Zheng FP. Cyanidin inhibits EMT induced by oxaliplatin via targeting the PDK1-PI3K/Akt signaling pathway. Food Funct 2019; 10:592-601. [PMID: 30672917 DOI: 10.1039/c8fo01611a] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Anthocyanins have been shown to exhibit antitumor activity in several cancers in vitro and in vivo. Oxaliplatin is widely used as an anti-cancer drug. However, a large proportion of patients receiving platinum-based anti-cancer drug treatments will relapse because of metastasis and drug resistance. The aim of this study is to discover an effective anthocyanin that possesses the combinational anti-metastatic effects of oxaliplatin. Our results showed that cyanidin, one of the main constituents of anthocyanins, widely found in black rice, black bean, Hawthorn and other foods, could reverse drug resistance and enhance the effects of oxaliplatin on hepatic cellular cancer (HCC). Cyanidin inhibited migration and reversed EMT biomarker changes induced by low dose OXA. Moreover, 3-phosphoinositide-dependent protein kinase 1 (PDK1) can be considered a potential target and cyanidin significantly increased OXA sensitivity and inhibited the EMT induced by OXA via PI3K/Akt signaling in HCC.
Collapse
Affiliation(s)
- Xiang Li
- School of Marine and Biological Engineering, Yancheng Teachers University, Yancheng 224051, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
The microRNA miR-181c enhances chemosensitivity and reduces chemoresistance in breast cancer cells via down-regulating osteopontin. Int J Biol Macromol 2019; 125:544-556. [DOI: 10.1016/j.ijbiomac.2018.12.075] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/03/2018] [Accepted: 12/07/2018] [Indexed: 01/10/2023]
|
|
20
|
Zhao W, Ajani JA, Sushovan G, Ochi N, Hwang R, Hafley M, Johnson RL, Bresalier RS, Logsdon CD, Zhang Z, Song S. Galectin-3 Mediates Tumor Cell-Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling. Gastroenterology 2018; 154:1524-1537.e6. [PMID: 29274868 DOI: 10.1053/j.gastro.2017.12.014] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 11/22/2017] [Accepted: 12/18/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is characterized by activated pancreatic stellate cells (PSCs), abundance of extracellular matrix (ECM), and production of cytokines and chemokines. Galectin 3 (GAL3), a β-galactoside-specific lectin, contributes to PDAC development but its effects on the stroma and cytokine production are unclear. METHODS The effect of recombinant human GAL3 (rGAL3) on activation of PSCs, production of cytokines, and ECM proteins was determined by proliferation, invasion, cytokine array, and quantitative polymerase chain reaction. We assessed co-cultures of PDAC cells with GAL3 genetic alterations with PSCs. Production of interleukin 8 (IL8) and activities of nuclear factor (NF)-κB were determined by enzyme-linked immunosorbent assay and luciferase reporter analyses. We studied the effects of inhibitors of NF-κB and integrin-linked kinase (ILK) on pathways activated by rGAL3. RESULTS In analyses of the Gene Expression Omnibus database and our dataset, we observed higher levels of GAL3, IL8, and other cytokines in PDAC than in nontumor tissues. Production of IL8, granulocyte-macrophage colony-stimulating factor, chemokine ligand 1, and C-C motif chemokine ligand 2 increased in PSCs exposed to rGAL3 compared with controls. Culture of PSCs with PDAC cells that express different levels of GAL3 resulted in proliferation and invasion of PSCs that increased with level of GAL3. GAL3 stimulated transcription of IL8 through integrin subunit beta 1 (ITGB1) on PSCs, which activates NF-κB through ILK. Inhibitors of ILK or NF-κB or a neutralizing antibody against ITGB1 blocked transcription and production of IL8 from PSCs induced by rGAL3. The GAL3 inhibitor significantly reduced growth and metastases of orthotopic tumors that formed from PDAC and PSC cells co-implanted in mice. CONCLUSION GAL3 activates PSC cells to produce inflammatory cytokines via ITGB1signaling to ILK and activation of NF-κB. Inhibition of this pathway reduced growth and metastases of pancreatic orthotopic tumors in mice.
Collapse
Affiliation(s)
- Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) and Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China; Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
| | - Guha Sushovan
- Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Nobuo Ochi
- Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Rosa Hwang
- Department of Breast Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Margarete Hafley
- Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Randy L Johnson
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Robert S Bresalier
- Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Craig D Logsdon
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) and Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
| |
Collapse
|
|
21
|
Mirzaei A, Mohammadi S, Ghaffari SH, Yaghmaie M, Vaezi M, Alimoghaddam K, Ghavamzadeh A. Osteopontin b and c Splice isoforms in Leukemias and Solid
Tumors: Angiogenesis Alongside Chemoresistance. Asian Pac J Cancer Prev 2018; 19:615-623. [PMID: 29580029 PMCID: PMC5980831 DOI: 10.22034/apjcp.2018.19.3.615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Osteopontin (OPN) is a glycoprotein involved in regulation of various influences on tumor progression, such as cellular proliferation, apoptosis, angiogenesis, and metastasis. Vascular endothelial growth factor (VEGF) is a secreted molecule supporting angiogenesis in various cancers through activation of the PI3K/AKT/ERK1/2 pathway. OPN and VEGF have a number of isoforms with various activities. In spite of the well-defined association between OPN and VEGF isoform expression and cure rate for solid tumors, there is a scarcity of information as to any association in leukemia. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that OPN and VEGF isoform expression levels may impact on chemoresistance and relapse in leukemia the same as in solid tumors. Hence, the aim of our review was to explain relationships between OPN and VEGF isoforms and angiogenesis and related pathways in chemoresistance of leukemia and solid tumors. Our findings demonstrated that OPNb and OPNc alongside with VEGF isoforms and other gene pathways are involved in angiogenesis and also might promote chemoresistance and even recurrence in leukemia and solid tumors. To sum up, targeting OPN isoforms, particularly b and c, might be a novel therapeutic strategy for the treatment of leukemia as well as solid tumors.
Collapse
Affiliation(s)
- Akram Mirzaei
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Iran. ,
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Zhu Y, Gao X, Yang J, Xu D, Zhang Y, Lu M, Zhang Z, Sheng Y, Li J, Yu X, Zheng Y, Dong Q, Qin L. C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma. Cancer Sci 2018; 109:710-723. [PMID: 29285854 PMCID: PMC5834777 DOI: 10.1111/cas.13487] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/16/2017] [Accepted: 12/25/2017] [Indexed: 12/19/2022] Open
Abstract
In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.
Collapse
Affiliation(s)
- Ying Zhu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Xiao‐Mei Gao
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Jing Yang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Da Xu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yu Zhang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Ming Lu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Ze Zhang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yuan‐Yuan Sheng
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Jian‐Hua Li
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Xin‐Xin Yu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yan Zheng
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Qiong‐Zhu Dong
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Lun‐Xiu Qin
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| |
Collapse
|
|
23
|
Zhang C, Wu M, Zhang L, Shang LR, Fang JH, Zhuang SM. Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling. Oncotarget 2018; 7:45702-45714. [PMID: 27329720 PMCID: PMC5216754 DOI: 10.18632/oncotarget.10157] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 06/03/2016] [Indexed: 12/19/2022] Open
Abstract
The seeding of tumor cells is a critical step in the process of metastasis, but whether and how the microenvironment of target organs affects metastatic seeding remain largely unknown. Based on cell and mouse models, we found that the metastatic seeding and outgrowth of tumor cells were significantly enhanced in fibrotic lungs. The conditioned medium from both fibrotic lungs and the fibrotic lung-derived fibroblasts (CM-FLF) had a strong activity to chemoattract tumor cells and to inhibit the apoptosis of tumor cells. Subsequent investigations revealed that the levels of fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1) were significantly increased in fibrotic lungs. Silencing of FN1 in the fibrotic lung-derived fibroblasts dramatically decreased the chemoattracting activity of CM-FLF, while silencing of FN1 or SPP1 in fibroblasts attenuated the anti-apoptosis activity of CM-FLF. Moreover, the CM-FLF-induced apoptosis resistance or chemotaxis of tumor cells was attenuated when ITGAV, the common receptor of FN1 and SPP1, was silenced by RNA interference or blocked by GRGDS treatment in tumor cells. Consistently, ITGAV silencing or GRGDS treatment significantly inhibited the seeding and outgrowth of tumor cells in fibrotic lungs in vivo. Collectively, we suggest that fibrotic microenvironment may enhance the metastatic seeding of tumor cells in the lung by chemoattracting tumor cells and inhibiting their apoptosis via activating the FN1/SPP1-ITGAV signaling. These findings give a novel insight into the regulatory mechanisms of cancer metastasis and provide a potential target for anti-metastasis therapy.
Collapse
Affiliation(s)
- Chong Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Mengzhi Wu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Lizhen Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Li-Ru Shang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jian-Hong Fang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Shi-Mei Zhuang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| |
Collapse
|
|
24
|
Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Int J Mol Sci 2017; 19:ijms19010007. [PMID: 29267211 PMCID: PMC5795959 DOI: 10.3390/ijms19010007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.
Collapse
|
|
25
|
Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:656-671. [PMID: 29248454 DOI: 10.1016/j.ajpath.2017.11.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/01/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
Abstract
Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.
Collapse
|
|
26
|
Dong Q, Zhu X, Dai C, Zhang X, Gao X, Wei J, Sheng Y, Zheng Y, Yu J, Xie L, Qin Y, Qiao P, Zhou C, Yu X, Jia H, Ren N, Zhou H, Ye Q, Qin L. Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin. Oncotarget 2017; 7:12997-3012. [PMID: 26824421 PMCID: PMC4914337 DOI: 10.18632/oncotarget.7016] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 01/05/2016] [Indexed: 01/11/2023] Open
Abstract
Our previous studies have found that osteopontin (OPN) is a promoter for hepatocellular carcinoma (HCC) progression. However, the molecular mechanism by which OPN enhances HCC metastasis remains elusive. Epithelial-mesenchymal transition (EMT) of cancer cells plays a pivotal role in promoting metastatic process. In this study, we demonstrated that OPN promotes HCC metastasis by inducing an EMT-like, more aggressive cellular phenotype in vitro and in vivo. Furthermore, OPN was identified to interact with vimentin by reciprocal OPN and vimentin immunoprecipitation as well as co-immunofluorescence examination. By using deletion mutants, we found that the residues between 246 and 406 in vimentin are required for binding to OPN. Importantly, OPN significantly increased vimentin stability through inhibition of its protein degradation. Knockdown of vimentin neutralized the EMT induced by OPN both in vitro and in vivo. Moreover, a significant correlation between OPN and vimentin levels was found in clinical HCC specimens and their combination had a worse prognosis with shorter overall survival (OS) and time to recurrence (TTR). In multivariate analysis, OPN and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Collectively, this study indicates that OPN can induce EMT of HCC cells through increasing vimentin stability, which provides more in-depth understanding about the molecular mechanisms of OPN in promoting HCC metastasis and opens tantalizing therapeutic possibilities in HCC.
Collapse
Affiliation(s)
- Qiongzhu Dong
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xuchao Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chun Dai
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaofei Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China
| | - Xiaomei Gao
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jinwang Wei
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yuanyuan Sheng
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yan Zheng
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jian Yu
- Shanghai Center for Bioinformation Technology, Shanghai, China
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai, China
| | - Yi Qin
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Peng Qiao
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chuang Zhou
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Xinxin Yu
- Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Huliang Jia
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China
| | - Ning Ren
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Haijun Zhou
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Qinghai Ye
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
|
27
|
Sengupta S, Parikh ND. Biomarker development for hepatocellular carcinoma early detection: current and future perspectives. Hepat Oncol 2017; 4:111-122. [PMID: 30191058 DOI: 10.2217/hep-2017-0019] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/16/2017] [Indexed: 02/07/2023] Open
Abstract
Early detection of hepatocellular carcinoma (HCC) leads to improved survival; however, current early detection strategies for HCC surveillance are ineffective. Thus, there has been interest in developing biomarkers to aid in the early detection HCC. In this review, we discuss the five phases of biomarker discovery that are necessary for clinical implementation. We also describe the most promising investigational biomarkers and their phase of discovery. We review several promising technologies for the early detection of HCC, including miRNA, metabolomics and proteomics. Promisingly, there are samples from multiple longitudinal cohorts of patients with cirrhosis in the USA that are being collected in order to validate candidate biomarkers for HCC. A biomarker-based strategy has the potential to become the primary surveillance method for HCC detection.
Collapse
Affiliation(s)
- Shreya Sengupta
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Neehar D Parikh
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
28
|
Labrousse-Arias D, Martínez-Ruiz A, Calzada MJ. Hypoxia and Redox Signaling on Extracellular Matrix Remodeling: From Mechanisms to Pathological Implications. Antioxid Redox Signal 2017; 27:802-822. [PMID: 28715969 DOI: 10.1089/ars.2017.7275] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE The extracellular matrix (ECM) is an essential modulator of cell behavior that influences tissue organization. It has a strong relevance in homeostasis and translational implications for human disease. In addition to ECM structural proteins, matricellular proteins are important regulators of the ECM that are involved in a myriad of different pathologies. Recent Advances: Biochemical studies, animal models, and study of human diseases have contributed to the knowledge of molecular mechanisms involved in remodeling of the ECM, both in homeostasis and disease. Some of them might help in the development of new therapeutic strategies. This review aims to review what is known about some of the most studied matricellular proteins and their regulation by hypoxia and redox signaling, as well as the pathological implications of such regulation. CRITICAL ISSUES Matricellular proteins have complex regulatory functions and are modulated by hypoxia and redox signaling through diverse mechanisms, in some cases with controversial effects that can be cell or tissue specific and context dependent. Therefore, a better understanding of these regulatory processes would be of great benefit and will open new avenues of considerable therapeutic potential. FUTURE DIRECTIONS Characterizing the specific molecular mechanisms that modulate matricellular proteins in pathological processes that involve hypoxia and redox signaling warrants additional consideration to harness the potential therapeutic value of these regulatory proteins. Antioxid. Redox Signal. 27, 802-822.
Collapse
Affiliation(s)
- David Labrousse-Arias
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain
| | - Antonio Martínez-Ruiz
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .,2 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) , Madrid, Spain
| | - María J Calzada
- 1 Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .,3 Departmento de Medicina, Universidad Autónoma de Madrid , Madrid, Spain
| |
Collapse
|
|
29
|
Grbčić P, Tomljanović I, Klobučar M, Kraljević Pavelić S, Lučin K, Sedić M. Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling. Biochem Biophys Res Commun 2017; 487:782-788. [DOI: 10.1016/j.bbrc.2017.04.100] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 04/18/2017] [Indexed: 12/23/2022]
|
|
30
|
De Filippis A, Buommino E, Domenico MD, Feola A, Brunetti-Pierri R, Rizzo A. Chlamydia trachomatis induces an upregulation of molecular biomarkers podoplanin, Wilms' tumour gene 1, osteopontin and inflammatory cytokines in human mesothelial cells. MICROBIOLOGY-SGM 2017; 163:654-663. [PMID: 28535856 DOI: 10.1099/mic.0.000465] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Chlamydia trachomatis is the most prevalent infection of the genital tract in women worldwide. C. trachomatis has a tendency to cause persistent infection and induce a state of chronic inflammation, which has been reported to play a role in carcinogenesis. We report that persistent C. trachomatis infection increases the expression of inflammatory tumour cytokines and upregulates molecular biomarkers such as podoplanin, Wilms' tumour gene 1 and osteopontin in primary cultures of mesothelial cells (Mes1) and human mesothelioma cells (NCI). Infection experiments showed that Mes1 and NCI supported the growth of C. trachomatisin vitro, and at an m.o.i. of 4, the inclusion-forming units/cell showed many intracellular inclusion bodies after 3 days of infection. However, after 7 days of incubation, increased proliferative and invasive activity was also observed in Mes1 cells, which was more evident after 14 days of incubation. ELISA analysis revealed an increase in vascular endothelial growth factor, IL-6, IL-8, and TNF-α release in Mes1 cells infected for a longer period (14 days). Finally, real-time PCR analysis revealed a strong induction of podoplanin, Wilms' tumour gene 1 and osteopontin gene expression in infected Mes1 cells. The aim of the present study was to investigate the inflammatory response elicited by C. trachomatis persistent infection and the role played by inflammation in cell proliferation, secretion of proinflammatory cytokines and molecular biomarkers of cancer. The results of this study suggest that increased molecular biomarkers of cancer by persistent inflammation from C. trachomatis infection might support cellular transformation, thus increasing the risk of cancer.
Collapse
Affiliation(s)
- Anna De Filippis
- Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Faculty of Medicine and Surgery - Second University of Naples, Via Santa Maria di Costantinopoli, 16 - 80138 Naples, Italy
| | - Elisabetta Buommino
- Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Faculty of Medicine and Surgery - Second University of Naples, Via Santa Maria di Costantinopoli, 16 - 80138 Naples, Italy
| | - Marina Di Domenico
- Department of Biochemistry, Biophysics and General Pathology - Second University of Naples, Via Santa Maria di Costantinopoli, 16 - 80138 Naples, Italy
| | - Antonia Feola
- Department of Biochemistry, Biophysics and General Pathology - Second University of Naples, Via Santa Maria di Costantinopoli, 16 - 80138 Naples, Italy
| | - Raffaella Brunetti-Pierri
- Multidisciplinary Department of Medical-Surgical and Dental Specialties - Second University of Naples, Via Pansini, 5 - 80131 Naples, Italy
| | - Antonietta Rizzo
- Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Faculty of Medicine and Surgery - Second University of Naples, Via Santa Maria di Costantinopoli, 16 - 80138 Naples, Italy
| |
Collapse
|
|
31
|
Karpinsky G, Fatyga A, Krawczyk MA, Chamera M, Sande N, Szmyd D, Izycka-Swieszewska E, Bien E. Osteopontin: its potential role in cancer of children and young adults. Biomark Med 2017; 11:389-402. [DOI: 10.2217/bmm-2016-0308] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Objective: Osteopontin (OPN) is aglyco-phosphoprotein, involved in tissue remodeling, inflammation and boneresorption. In various adult neoplasms OPN was shown to correlate with cancer progression, invasiveness and metastasis. Aim: to define the role of OPN in malignancies of children and young adults. Material and methods: a structured PubMed and Google Scholar literature analysis based on reports published in English between I'1995 and XII'2015. Results: 14 studies (four on hematological malignancies, four on bone tumors, three on CNS tumors, two on dendritic proliferative diseases and one on renal tumors) were identified. Higher levels of serum and cerebro-spinal fluid OPN protein, and high expressions of OPN mRNA and SPP1 gene were present in more aggressive and advanced childhood malignancies. In children with acute lymphoblastic leukemia with CNS involvement and with atypical teratoid/rhabdoid tumor (AT/RT) and medulloblastoma, the serum and CSF OPN levels reflected tumor bulk and response to therapy, while in children with AT/RT and multisystem Langerhans cell histiocytosis with high-risk organs involvement, high OPN serum levels correlated with poorer survival. To the contrary, in osteosarcoma, high OPN mRNA and SPP1 gene expressions correlated with better survival and good response to chemotherapy. Conclusions: The literature review suggests that OPN may play important roles in the development and progression of selected cancers of children and young adults, including acute lymphoblastic leukemia, malignant gliomas, AT/RT and Langerhans cell histiocytosis. However, limited number of published studies prevents from definite concluding on the clinical utility of OPN as a marker of diagnosis, prognosis and treatment monitoring in these pediatric cancers. Further studies performed in more numerous groups of patients with particular types of cancers of children and young adults are warranted.
Collapse
Affiliation(s)
- Gabrielle Karpinsky
- Children's Hospital of Michigan, Detroit Medical Center, 3901 Beaubien Street, Detroit, MI 48201, USA
| | - Aleksandra Fatyga
- Department of Pediatrics, Hematology & Oncology, University Clinic Center, 7 Debinki Street, 80–952 Gdansk, Poland
| | - Malgorzata Anna Krawczyk
- Department of Pediatrics, Hematology & Oncology, Medical University of Gdansk, 7 Debinki Street, 80–211 Gdansk, Poland
| | - Madeleine Chamera
- The English Division Pediatric Oncology Scientific Circle, Medical University of Gdansk, 7 Debinki Street, 80–211 Gdansk, Poland
| | - Natalia Sande
- The English Division Pediatric Oncology Scientific Circle, Medical University of Gdansk, 7 Debinki Street, 80–211 Gdansk, Poland
| | - Dagmara Szmyd
- Coronary Care Unit, Cardiology Department, West Cumberland Hospital, Whitehaven, United Kingdom
| | - Ewa Izycka-Swieszewska
- Department of Pathology & Neuropathology, Medical University of Gdansk, 1 Debinki Street, 80–211 Gdansk, Poland
| | - Ewa Bien
- Department of Pediatrics, Hematology & Oncology, Medical University of Gdansk, 7 Debinki Street, 80–211 Gdansk, Poland
| |
Collapse
|
|
32
|
Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity. Cell Death Dis 2016; 7:e2564. [PMID: 28032860 PMCID: PMC5261026 DOI: 10.1038/cddis.2016.422] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/03/2016] [Accepted: 11/10/2016] [Indexed: 02/04/2023]
Abstract
Tumor metastasis leads to high mortality; therefore, understanding the mechanisms that underlie tumor metastasis is crucial. Generally seen as a secretory protein, osteopontin (OPN) is involved in multifarious pathophysiological events. Here, we present a novel pro-metastatic role of OPN during metastatic colonization. Unlike secretory OPN (sOPN), which triggers the epithelial–mesenchymal transition (EMT) to initiate cancer metastasis, intracellular/nuclear OPN (iOPN) induces the mesenchymal–epithelial transition (MET) to facilitate the formation of metastases. Nuclear OPN is found to interact with HIF2α and impact the subsequent AKT1/miR-429/ZEB cascade. In vivo assays confirm that the progression of metastatic colonization is accompanied by the nuclear accumulation of OPN and the MET process. Furthermore, evidence of nuclear OPN in the lung metastases is exhibited in clinical specimens. Finally, VEGF in the microenvironment was shown to induce the translocation of OPN into the nucleus through a KDR/PLCγ/PKC-dependent pathway. Taken together, our results describe the pleiotropic roles of OPN in the tumor metastasis cascade, which indicate its potential as an effective target for both early and advanced tumors.
Collapse
|
|
33
|
Lee SH, Park JW, Woo SH, Go DM, Kwon HJ, Jang JJ, Kim DY. Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice. Oncotarget 2016; 7:87219-87231. [PMID: 27888617 PMCID: PMC5349983 DOI: 10.18632/oncotarget.13529] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 11/01/2016] [Indexed: 12/16/2022] Open
Abstract
Previous clinical reports have found elevated osteopontin (OPN) levels in tumor tissues to be indicative of greater malignancy in human hepatocellular carcinoma (HCC). However, the role of OPN on carcinogenesis and its underlying mechanism remain unclear. In the present study, we investigated the oncogenic role of OPN in diethylnitrosamine (DEN)-induced hepatic carcinogenesis in mice. The overall incidence of hepatic tumors at 36 weeks was significantly lower in OPN knockout (KO) mice than in wild-type (WT) mice. Apoptosis was significantly enhanced in OPN KO mice, and was accompanied by the downregulation of epidermal growth factor receptor (EGFR). In the in vitro study, OPN suppression also led to lower mRNA and protein levels of EGFR associated with the downregulation of c-Jun in Hep3B and Huh7 human HCC cells lines, which resulted in increased apoptotic cell death in both cell lines. Moreover, a positive correlation was clearly identified between the expression of OPN and EGFR in human HCC tissues. These data demonstrate that the OPN deficiency reduced the incidence of chemically induced HCC by suppressing EGFR-mediated anti-apoptotic signaling. An important implication of our findings is that OPN positively contributes to hepatic carcinogenesis.
Collapse
Affiliation(s)
- Su-Hyung Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
| | - Jun-Won Park
- Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea
| | - Sang-Ho Woo
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
| | - Du-Min Go
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
| | - Hyo-Jung Kwon
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 305-764, South Korea
| | - Ja-June Jang
- Department of Pathology, College of Medicine, Seoul National University, Seoul 110-799, Korea
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
| |
Collapse
|
|
34
|
Grün NG, Zeyda K, Moreno-Viedma V, Strohmeier K, Staffler G, Zeyda M, Stulnig TM. A humanized osteopontin mouse model and its application in immunometabolic obesity studies. Transl Res 2016; 178:63-73.e2. [PMID: 27490454 DOI: 10.1016/j.trsl.2016.07.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 07/04/2016] [Accepted: 07/11/2016] [Indexed: 10/21/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein involved in several inflammatory processes and pathogeneses including obesity-related disorders and cancer. OPN binds to a variety of integrin receptors and CD44 resulting in a proinflammatory stimulus. Therefore, OPN constitutes a novel interesting target to develop new therapeutic strategies, which counteract OPN's proinflammatory properties. We established a humanized SPP1 (hSPP1) mouse model and evaluated its suitability as a model for obesity and insulin resistance. Unchallenged hSPP1 animals did not significantly differ in body weight and gross behavioral properties compared to wild-type (WT) animals. High-fat diet-challenged hSPP1 similarly developed obesity and inflammation, whereas insulin resistance was markedly changed. However, OPN expression profile in tissues was significantly altered in hSPP1 compared to WT depending on the diet. In conclusion, we developed a versatile humanized model to study the action of OPN in vivo and to develop strategies that target human OPN in a variety of pathologies.
Collapse
Affiliation(s)
- Nicole G Grün
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Karina Zeyda
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; FH Campus Wien, University of Applied Sciences, Department Health, Section Biomedical Science, Vienna, Austria
| | - Veronica Moreno-Viedma
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Karin Strohmeier
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Maximilian Zeyda
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna Austria
| | - Thomas M Stulnig
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
35
|
Osteopontin induces autophagy to promote chemo-resistance in human hepatocellular carcinoma cells. Cancer Lett 2016; 383:171-182. [PMID: 27702661 DOI: 10.1016/j.canlet.2016.09.033] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 09/26/2016] [Accepted: 09/26/2016] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health burden worldwide for its high incidence and mortality. Osteopontin (OPN) is a chemokine-like, matricellular phosphoglycoprotein whose expression is elevated in various types of cancer including HCC. OPN has been shown to be involved in tumorigenesis, chemo-resistance, metastasis and sustaining stem-like properties of cancer cells. Autophagy is a cellular process by which cytoplasmic components are degraded and recycled for maintaining cellular homeostasis. There is increasing evidence supports that autophagy plays a critical role for stem-like properties and chemo-resistance of cancer cells. However, the relationship between OPN and autophagy in maintaining cancer stem-like properties and chemo-resistance is yet to be clarified. Herein, we found that secreted OPN induced autophagy via binding with its receptor integrin αvβ3 and sustaining FoxO3a stability. OPN-elicited autophagy could promote cancer cell survival and resistance to chemotherapy drugs, as well as stem-like properties. Our findings indicated that OPN was capable of promoting chemo-resistance of HCCs via autophagy, which might provide a new strategy for the treatment of HCC.
Collapse
|
|
36
|
Wang G, Zhao C, Chen S, Li X, Zhang L, Chang C, Xu C. A preliminary in vivo study of the effects of OPN on rat liver regeneration induced by partial hepatectomy. Mol Biol Rep 2016; 43:1371-1382. [PMID: 27585571 DOI: 10.1007/s11033-016-4071-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 08/25/2016] [Indexed: 01/15/2023]
Abstract
Osteopontin (OPN) is a member of Th1 cytokine secreted by activated lymphocytes and macrophages. However, it deserves to be studied whether OPN could promote cell activation or proliferation, and then facilitate hepatic self-repair during liver regeneration (LR). This study is designed to further reveal the effects of OPN on LR in vivo. Firstly, quantitative reverse transcription-PCR (qRT-PCR) and western blot (WB) were utilized to validate the expression profile of endogenous OPN in rat regenerating livers after partial hepatectomy (PH). Then OPN expression vector, two shRNA expression vectors and their respective test vectors were successfully constructed. Afterwards, test vectors were administrated into mouse livers via tail vein to find the more efficient shRNA. Furthermore, OPN expression vector and the more efficient shRNA expression vector were injected into rat regenerating livers, and then the changes in liver regeneration and hepatic microstructure were respectively detected by liver regeneration rate and HE staining, while the expressions of several marker genes were detected by qRT-PCR and WB. Endogenous OPN was strikingly up-regulated in both mRNA and protein level during LR, especially at 12 and 72 h after PH. The shRNA expression vector Opn(313) was found to be more efficient than Opn(887) in silencing the expression of Opn. Then OPN expression vector and Opn(313) were injected into rat remnant livers, and it showed that OPN overexpression aggravated hepatic necrosis and leukocytes infiltration, while OPN silencing inhibited liver regeneration rate and the expressions of PCNA and CCL2, but augmented that of BAX. In conclusion, OPN might enhance inflammation and cell proliferation, attenuate cell apoptosis, and ultimately facilitate liver regeneration at the termination stage of liver regeneration.
Collapse
Affiliation(s)
- Gaiping Wang
- College of Life Science, Henan Normal University, No. 46, Construction East Road, Xinxiang, 453007, Henan, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Congcong Zhao
- College of Life Science, Henan Normal University, No. 46, Construction East Road, Xinxiang, 453007, Henan, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Shasha Chen
- College of Life Science, Henan Normal University, No. 46, Construction East Road, Xinxiang, 453007, Henan, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Xiaofang Li
- College of Life Science, Henan Normal University, No. 46, Construction East Road, Xinxiang, 453007, Henan, China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Ling Zhang
- Henan Academy of Fishery Science, Zhengzhou, 450044, Henan, China
| | - Cuifang Chang
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Cunshuan Xu
- College of Life Science, Henan Normal University, No. 46, Construction East Road, Xinxiang, 453007, Henan, China. .,State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang, 453007, Henan, China.
| |
Collapse
|
|
37
|
Wen Y, Jeong S, Xia Q, Kong X. Role of Osteopontin in Liver Diseases. Int J Biol Sci 2016; 12:1121-8. [PMID: 27570486 PMCID: PMC4997056 DOI: 10.7150/ijbs.16445] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.
Collapse
Affiliation(s)
- Yankai Wen
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
38
|
Zhang J, Yamada O, Kida S, Matsushita Y, Murase S, Hattori T, Kubohara Y, Kikuchi H, Oshima Y. Identification of brefelamide as a novel inhibitor of osteopontin that suppresses invasion of A549 lung cancer cells. Oncol Rep 2016; 36:2357-64. [DOI: 10.3892/or.2016.5006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 08/01/2016] [Indexed: 11/06/2022] Open
|
|
39
|
Comparative analysis of gene expression profiles of OPN signalling pathway in four kinds of liver diseases. J Genet 2016; 95:741-50. [DOI: 10.1007/s12041-016-0673-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
40
|
Ouyang J, Sun Y, Li W, Zhang W, Wang D, Liu X, Lin Y, Lian B, Xie L. dbPHCC: a database of prognostic biomarkers for hepatocellular carcinoma that provides online prognostic modeling. Biochim Biophys Acta Gen Subj 2016; 1860:2688-95. [PMID: 26940364 DOI: 10.1016/j.bbagen.2016.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/27/2016] [Accepted: 02/26/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a poor prognosis. For decades, more and more biomarkers were found to effect on HCC prognosis, but these studies were scattered and there were no unified identifiers. Therefore, we built the database of prognostic biomarkers and models for hepatocellular carcinoma (dbPHCC). METHODS dbPHCC focuses on biomarkers which were related to HCC prognosis by traditional experiments rather than high-throughput technology. All of the prognostic biomarkers came from literatures issued during 2002 to 2014 in PubMed and were manually selected. dbPHCC collects comprehensive information of candidate biomarkers and HCC prognosis. RESULTS dbPHCC mainly contains 567 biomarkers: 323 proteins, 154 genes, and 90 microRNAs. For each biomarker, the reference information, experimental conditions, and prognostic information are shown. Based on two available patient cohort data sets, an exemplified prognostic model was constructed using 15 phosphotransferases in dbPHCC. The web interface does not only provide a full range of browsing and searching, but also provides online analysis tools. dbPHCC is available at http://lifecenter.sgst.cn/dbphcc/ CONCLUSIONS dbPHCC provides a comprehensive and convenient search and analysis platform for HCC prognosis research. GENERAL SIGNIFICANCE dbPHCC is the first database to focus on experimentally verified individual biomarkers, which are related to HCC prognosis. Prognostic markers in dbPHCC have the potential to be therapeutic drug targets and may help in designing new treatments to improve survival of HCC patients. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.
Collapse
Affiliation(s)
- Jian Ouyang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Ying Sun
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
| | - Wei Li
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Wen Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of People Libration Army General Hospital, Beijing 100048, China
| | - Dandan Wang
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Xiangqiong Liu
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yong Lin
- Biomedical Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Baofeng Lian
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China; Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200240, China.
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China.
| |
Collapse
|
|
41
|
Ma X, Hui H, Jin Y, Dong D, Liang X, Yang X, Tan K, Dai Z, Cheng Z, Tian J. Enhanced immunotherapy of SM5-1 in hepatocellular carcinoma by conjugating with gold nanoparticles and its in vivo bioluminescence tomographic evaluation. Biomaterials 2016; 87:46-56. [PMID: 26897539 DOI: 10.1016/j.biomaterials.2016.02.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 01/01/2016] [Accepted: 02/04/2016] [Indexed: 02/07/2023]
Abstract
SM5-1 is a humanized mouse monoclonal antibody, targeting an over-expressed membrane protein of approximately 230 kDa in hepatocellular carcinoma (HCC). SM5-1 can be used for target therapy in hepatocellular carinoma due to its ability of inhibiting cell growth and inducing apoptosis. However, the tumor inhibition efficacy of SM5-1 in HCC cancer treatment remains low. In this study, we synthesized SM5-1-conjugated gold nanoparticles (Au-SM5-1 NPs) and investigated their anticancer efficacy in HCC both in vitro and in vivo. The tumor inhibition rates of Au-SM5-1 NPs for subcutaneous tumor mice were 40.10% ± 4.34%, 31.37% ± 5.12%, and 30.63% ± 4.87% on day 12, 18, and 24 post-treatment as determined by bioluminescent intensity. In addition, we investigated the antitumor efficacy of Au-SM5-1 NPs in orthotopic HCC tumor models. The results showed that the inhibition rates of Au-SM5-1 NPs can reach up to 39.64% ± 4.87% on day 31 post-treatment determined by the bioluminescent intensity of the abdomen in tumor-bearing mice. Furthermore, three-dimensional reconstruction results of the orthotopic tumor revealed that Au-SM5-1 NPs significantly inhibited tumor growth compared with SM5-1 alone. Our results suggested that the developed Au-SM5-1 NPs has great potential as an antibody-based nano-drug for HCC therapy.
Collapse
Affiliation(s)
- Xibo Ma
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Molecular Imaging Program at Stanford (MIPS), Bio-X Program, Department of Radiology, Stanford University, CA, 94305-5344, USA; Beijing Key Laboratory of Molecular Imaging, Beijing, 100190, China
| | - Hui Hui
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Beijing Key Laboratory of Molecular Imaging, Beijing, 100190, China
| | - Yushen Jin
- Nanomedicine and Biosensor Laboratory, School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Di Dong
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Beijing Key Laboratory of Molecular Imaging, Beijing, 100190, China
| | - Xiaolong Liang
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China
| | - Xin Yang
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Beijing Key Laboratory of Molecular Imaging, Beijing, 100190, China
| | - Ke Tan
- Educational Technology Center, The Chinese PLA General Hospital, 100853, Beijing, China
| | - Zhifei Dai
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China
| | - Zhen Cheng
- Molecular Imaging Program at Stanford (MIPS), Bio-X Program, Department of Radiology, Stanford University, CA, 94305-5344, USA.
| | - Jie Tian
- Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China; Beijing Key Laboratory of Molecular Imaging, Beijing, 100190, China.
| |
Collapse
|
|
42
|
Gene expression profiles predict the possible regulatory role of OPN-mediated signaling pathways in rat liver regeneration. Gene 2016; 576:782-90. [DOI: 10.1016/j.gene.2015.11.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 11/03/2015] [Accepted: 11/08/2015] [Indexed: 12/28/2022]
|
|
43
|
Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB-HIF-1α pathway. Oncotarget 2016; 6:6627-40. [PMID: 25749383 PMCID: PMC4466639 DOI: 10.18632/oncotarget.3113] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 01/08/2015] [Indexed: 12/18/2022] Open
Abstract
There is increasing evidence to suggest that hepatocellular carcinomas (HCCs) are sustained by a distinct subpopulation of self-renewing cells known as cancer stem cells. However, the precise signals required for maintenance of stemness-like properties of these cells are yet to be elucidated. Here, we demonstrated that the level of oncoprotein osteopontin (OPN) in tumor cells of the edge of bulk tumors was significantly correlated with the clinical prognosis of patients with HCC. OPN was highly expressed in side population fractions of HCC cell lines, as well as in dormant cells, spheroids and chemo-resistant cancer cells, all of which are considered as having stemness-like cellular features. Depletion of OPN in HCC cell lines resulted in a reduction in the proportion of side population fractions, formation of hepato-spheroids, expression of stem-cell-associated genes and decreased tumorigenecity in immunodeficient mice. Mechanistically, OPN was demonstrated to bind to integrin αvβ3 and activate the transcription factor NF-κB, which resulted in upregulation of HIF-1α transcription and its downstream gene, BMI1, to mediate maintenance of the stemness-like phenotype. Suppression of the αvβ3–NF-κB–HIF-1α pathway decreased OPN-mediated self-renewal capabilities. Levels of OPN protein expression were significantly correlated with HIF-1α protein levels in HCC tumor tissue samples. OPN might promote a cancer stem cell-like phenotype via the αvβ3–NF-κB–HIF-1α pathway. Our findings offer strong support for OPN requirement in maintaining stem-like properties in HCC cells.
Collapse
|
|
44
|
Lee SH, Park JW, Go DM, Kim HK, Kwon HJ, Han SU, Kim DY. Ablation of osteopontin suppresses N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric cancer development in mice. Carcinogenesis 2015; 36:1550-60. [PMID: 26438603 DOI: 10.1093/carcin/bgv144] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 09/27/2015] [Indexed: 12/14/2022] Open
Abstract
Several clinical studies have reported increased expression of osteopontin (OPN) in various types of human cancer, including gastric cancer. However, the precise mechanisms underlying tumor development remain unclear. In the present study, we investigated the pathogenic roles of OPN in Helicobacter pylori-induced gastric cancer development. Wild-type (WT) and OPN knockout (KO) mice were treated with N-methyl-N-nitrosourea (MNU) and infected with H.pylori. Mice were killed 50 weeks after treatment, and stomach tissues were assessed by histopathological examination, immunohistochemistry, quantitative real-time RT-PCR and western blotting. To clarify the carcinogenic effects of OPN, we also conducted an in vitro study using AGS human gastric cancer cell line and THP-1 human monocytic cell line. The overall incidence of gastric tumors was significantly decreased in OPN KO mice compared with WT mice. Apoptotic cell death was significantly enhanced in OPN KO mice and was accompanied by upregulation of signal transducer and activator of transcription 1 (STAT1) and inducible nitric oxide synthase (iNOS). In vitro study, OPN suppression also caused STAT1 upregulation and iNOS overexpression in AGS and THP-1 cells, which resulted in apoptosis of AGS cells. In addition, a negative correlation was clearly identified between expression of OPN and iNOS in human gastric cancer tissues. Our data demonstrate that loss of OPN decreases H.pylori-induced gastric carcinogenesis by suppressing proinflammatory immune response and augmenting STAT1 and iNOS-mediated apoptosis of gastric epithelial cells. An important implication of these findings is that OPN actually contributes to the development of gastric cancer.
Collapse
Affiliation(s)
| | - Jun-Won Park
- Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea
| | | | - Hark Kyun Kim
- Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea
| | - Hyo-Jung Kwon
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 305-764, South Korea and
| | - Sang-Uk Han
- Department of Surgery, Ajou University Medical Center, Ajou University School of Medicine, Suwon 443-749, South Korea
| | | |
Collapse
|
|
45
|
Higher Matrix Stiffness Upregulates Osteopontin Expression in Hepatocellular Carcinoma Cells Mediated by Integrin β1/GSK3β/β-Catenin Signaling Pathway. PLoS One 2015; 10:e0134243. [PMID: 26280346 PMCID: PMC4539226 DOI: 10.1371/journal.pone.0134243] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 07/07/2015] [Indexed: 12/13/2022] Open
Abstract
Increased stromal stiffness is associated with hepatocellular carcinoma (HCC) development and progression. However, the molecular mechanism by which matrix stiffness stimuli modulate HCC progress is largely unknown. In this study, we explored whether matrix stiffness-mediated effects on osteopontin (OPN) expression occur in HCC cells. We used a previously reported in vitro culture system with tunable matrix stiffness and found that OPN expression was remarkably upregulated in HCC cells with increasing matrix stiffness. Furthermore, the phosphorylation level of GSK3β and the expression of nuclear β-catenin were also elevated, indicating that GSK3β/β-catenin pathway might be involved in OPN regulation. Knock-down analysis of integrin β1 showed that OPN expression and p-GSK3β level were downregulated in HCC cells grown on high stiffness substrate compared with controls. Simultaneously, inhibition of GSK-3β led to accumulation of β-catenin in the cytoplasm and its enhanced nuclear translocation, further triggered the rescue of OPN expression, suggesting that the integrin β1/GSK-3β/β-catenin pathway is specifically activated for matrix stiffness-mediated OPN upregulation in HCC cells. Tissue microarray analysis confirmed that OPN expression was positively correlated with the expression of LOX and COL1. Taken together, high matrix stiffness upregulated OPN expression in HCC cells via the integrin β1/GSK-3β/β-catenin signaling pathway. It highlights a new insight into a pathway involving physical mechanical signal and biochemical signal molecules which contributes to OPN expression in HCC cells.
Collapse
|
|
46
|
Zhang J, Du J, Liu Q, Zhang Y. Down-regulation of STAT3 expression using vector-based RNA interference promotes apoptosis in Hepatocarcinoma cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2015; 44:1201-5. [PMID: 26134753 DOI: 10.3109/21691401.2015.1029628] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In this study, we followed a DNA vector-based RNAi approach to silence the signal transducer and activator of transcription 3 (STAT3) expression in Bel-7402 cells, to explore how the Janus kinase (JAK)/STAT3 signaling pathway influences the apoptosis of hepatocarcinoma cells. According to GenBank's STAT3 cDNA, the plasmid pGCsi.U6/neoRFP STAT3, which was designed for expression of STAT3 small interfering RNA (siRNA), was constructed and synthesized, and then transfected into Bel-7402 cells using Lipofectamine 2000. Cells with or without siRNA transfection were treated in wells. The apoptotic rate was detected by flow cytometry (FCM) and by staining with the Annexin V/propidium iodide (PI) apoptosis detection kit. Simultaneously, the mitochondrial membrane potential (ΔΨm) was visualized by JC-1 fluorescence staining and observed using the inverted fluorescence microscope. Furthermore, the expression of caspase-3 protein was analyzed by Western blotting. The results showed that treatment with STAT3 siRNA displayed effects in the Bel-7402 cells, causing a significantly increased apoptotic ratio (P < 0.05). The mitochondrial membrane potential of the STAT3 siRNA group, observed by the JC-1 fluorescence staining, decreased significantly. The protein expression of active caspase-3 increased with STAT3 siRNA treatment, and was significantly higher than that of the control group (P < 0.05). STAT3 gene-silencing significantly improves the apoptotic effect against Bel-7402 cells.
Collapse
Affiliation(s)
- Junwei Zhang
- a Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University , Jinan , P.R. China.,b Department of Oncology , The Central Hospital of Panjin , Panjin , P.R. China
| | - Jiajun Du
- c Department of thoracic surgery , Provincial Hospital Affiliated to Shandong University, Shandong University , Jinan , P.R. China
| | - Qi Liu
- a Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University , Jinan , P.R. China
| | - Yi Zhang
- d Department of General Surgery , The Central Hospital of Panjin , Panjin , P.R. China
| |
Collapse
|
|
47
|
Ferrín G, Aguilar-Melero P, Rodríguez-Perálvarez M, Montero-Álvarez JL, de la Mata M. Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility. Hepat Med 2015; 7:1-10. [PMID: 25926760 PMCID: PMC4403743 DOI: 10.2147/hmer.s50161] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Because of the high prevalence and associated-mortality of hepatocellular carcinoma (HCC), early diagnosis of the disease is vital for patient survival. In this regard, tumor size is one of the two main prognostic factors for surgical resection, which constitutes the only curative treatment for HCC along with liver transplantation. However, techniques for HCC surveillance and diagnosis that are currently used in clinical practice have certain limitations that may be inherent to the tumor development. Thus, it is important to continue efforts in the search for biomarkers that increase diagnostic accuracy for HCC. In this review, we focus on different biological sources of candidate biomarkers for HCC diagnosis. Although those biomarkers identified from biological samples obtained by noninvasive methods have greater diagnostic value, we have also considered those obtained from liver tissue because of their potential therapeutic value. To date, sorafenib is the only US Food and Drug Administration-approved antineoplastic for HCC. However, this therapeutic agent shows very low tumor response rates and frequently causes acquired resistance in HCC patients. We discuss the use of HCC biomarkers as therapeutic targets themselves, or as targets to increase sensitivity to sorafenib treatment.
Collapse
Affiliation(s)
- Gustavo Ferrín
- Liver Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain ; Centro de Investigación Biomédica en Red (CIBER), Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Aguilar-Melero
- Liver Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Manuel Rodríguez-Perálvarez
- Liver Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain ; Centro de Investigación Biomédica en Red (CIBER), Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - José Luis Montero-Álvarez
- Liver Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain ; Centro de Investigación Biomédica en Red (CIBER), Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel de la Mata
- Liver Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain ; Centro de Investigación Biomédica en Red (CIBER), Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
48
|
Fan X, He C, Jing W, Zhou X, Chen R, Cao L, Zhu M, Jia R, Wang H, Guo Y, Zhao J. Intracellular Osteopontin inhibits toll-like receptor signaling and impedes liver carcinogenesis. Cancer Res 2014; 75:86-97. [PMID: 25398438 DOI: 10.1158/0008-5472.can-14-0615] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Osteopontin (OPN) has been implicated widely in tumor growth and metastasis, but the range of its contributions is not yet fully understood. In this study, we show that genetic ablation of Opn in mice sensitizes them to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Opn-deficient mice (Opn(-/-) mice) exhibited enhanced production of proinflammatory cytokines and compensatory proliferation. Administering OPN antibody or recombinant OPN protein to wild-type or Opn(-/-) mice-derived macrophages, respectively, had little effect on cytokine production. In contrast, overexpression of intracellular OPN (iOPN) in Opn-deficient macrophages strongly suppressed production of proinflammatory cytokines. In addition, we found that iOPN was able to interact with the pivotal Toll-like receptor (TLR) signaling protein MyD88 in macrophages after stimulation with cellular debris, thereby disrupting TLR signaling in macrophages. Our results indicated that iOPN was capable of functioning as an endogenous negative regulator of TLR-mediated immune responses, acting to ameliorate production of proinflammatory cytokines and curtail DEN-induced hepatocarcinogenesis. Together, our results expand the important role of OPN in inflammation-associated cancers and deepen its relevance for novel treatment strategies in liver cancer.
Collapse
Affiliation(s)
- Xiaoyu Fan
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China
| | - Chunyan He
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China
| | - Wei Jing
- Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Xuyu Zhou
- Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Rui Chen
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China
| | - Lei Cao
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China
| | - Minhui Zhu
- Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Rongjie Jia
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China
| | - Hao Wang
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China
| | - Yajun Guo
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, China.
| | - Jian Zhao
- International Joint Cancer Institute, The Second Military Medical University, Shanghai, China. School of Pharmacy, Liaocheng University, Liaocheng, Shandong, China. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, China.
| |
Collapse
|
|
49
|
Nabih MI, Aref WM, Fathy MM. Significance of plasma osteopontin in diagnosis of hepatitis C virus-related hepatocellular carcinoma. Arab J Gastroenterol 2014; 15:103-7. [PMID: 25249230 DOI: 10.1016/j.ajg.2014.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 05/20/2014] [Accepted: 08/03/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND STUDY AIMS Alfa fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with liver cirrhosis (LC). However, the clinical use of AFP has been shown to present some important limitations in sensitivity and specificity. Osteopontin (OPN) is a secreted matrix glycoprotein that is emerging as a significant protein in the biology of HCC. The aim of this study was to assess the diagnostic value of plasma OPN compared with that of AFP in the diagnosis of HCC among hepatitis C virus (HCV)-related LC. PATIENTS AND METHODS Plasma levels of OPN and AFP were measured in 69 Egyptian patients with HCV-related LC (35 with HCC and 34 without HCC) and 20 healthy controls. RESULTS Both median AFP and OPN levels were significantly higher in the HCC group compared to LC and healthy control groups (p<0.001 in each) and in LC compared to the control group (p<0.001). In the HCC group, both OPN and AFP levels were significantly higher in patients with Child-Pugh class C and B compared to class A (p<0.05 in each). There was no correlation between OPN and AFP levels. The OPN level was significantly higher in patients with multiple focal lesions than in those with single lesions (p<0.05) and in patients with portal vein invasion compared to patients without portal vein invasion (p<0.05). Receiver operator characteristic (ROC) curves showed that the area under the curve (AUC) for OPN and AFP was 0.824 and 0.730, respectively. CONCLUSION OPN is a promising tumour marker which could be used as a screening test for the diagnosis of HCC in patients with LC and, hence, improves the prognosis and survival rate of these patients. The association of OPN with the multiplicity of focal lesions and portal vein invasion suggests an additional prognostic value.
Collapse
Affiliation(s)
- Mona I Nabih
- Department of Internal Medicine, Cairo University, Giza, Egypt.
| | - Wael M Aref
- Department of Internal Medicine, Cairo University, Giza, Egypt
| | - Mona M Fathy
- Department of Chemical Pathology, Cairo University, Giza, Egypt
| |
Collapse
|
|
50
|
Hsu KH, Tsai HW, Lin PW, Hsu YS, Lu PJ, Shan YS. Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors. World J Surg Oncol 2014; 12:189. [PMID: 24947165 PMCID: PMC4080696 DOI: 10.1186/1477-7819-12-189] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/12/2014] [Indexed: 01/04/2023] Open
Abstract
Background Osteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs. Methods The expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance. Results Up-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically. Conclusions Our study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.
Collapse
Affiliation(s)
| | | | | | | | | | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan.
| |
Collapse
|