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Qi H, Gao H, Li M, Sun T, Gu X, Wei L, Zhi M, Li Z, Fu D, Liu Y, Wei Z, Dou Y, Feng Q. Parvimonas micra promotes oral squamous cell carcinoma metastasis through TmpC-CKAP4 axis. Nat Commun 2025; 16:2305. [PMID: 40055343 PMCID: PMC11889085 DOI: 10.1038/s41467-025-57530-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/25/2025] [Indexed: 03/12/2025] Open
Abstract
Parvimonas micra (P. micra), an opportunistic oral pathogen associated with multiple cancers, has limited research on its role in oral squamous cell carcinoma (OSCC). This study shows that P. micra is enriched in OSCC tissues and positively correlated with tumor metastasis and stages. P. micra infection promotes OSCC metastasis by inducing hypoxia/HIF-1α, glycolysis, and autophagy. Mechanistically, P. micra surface protein TmpC binds to CKAP4, a receptor overexpressed in OSCC, facilitating bacterial attachment and invasion. This interaction activates HIF-1α and autophagy via CKAP4-RanBP2 and CKAP4-NBR1 pathways, driving metastasis. Targeting CKAP4 with masitinib or antibodies impairs P. micra attachment and abolishes P. micra-promoted OSCC metastasis in vitro and in vivo. Together, our findings identify P. micra as a pathogen that promotes OSCC metastasis and highlight that TmpC-CKAP4 interaction could be a potential therapeutic target for OSCC.
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Affiliation(s)
- Houbao Qi
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Haiting Gao
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Meihui Li
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Tianyong Sun
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Xiufeng Gu
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Li Wei
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Mengfan Zhi
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Zixuan Li
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, 210093, China
| | - Dachuan Fu
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Yiran Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Ziyi Wei
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Yu Dou
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Qiang Feng
- Department of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China.
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Demir T, Moloney C, Mahalingam D. Threading the Needle: Navigating Novel Immunotherapeutics in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2025; 17:715. [PMID: 40075563 PMCID: PMC11898821 DOI: 10.3390/cancers17050715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/08/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis. Currently, chemotherapy is the only option for most patients with advanced-stage PDAC. Further, conventional immunotherapies and targeted therapies improve survival outcomes only in rare PDAC patient subgroups. To date, combinatory immunotherapeutic strategies to overcome the immune-hostile PDAC tumor microenvironment (TME) have resulted in limited efficacy in clinical studies. However, efforts are ongoing to develop new treatment strategies for patients with PDAC with the evolving knowledge of the TME, molecular characterization, and immune resistance mechanisms. Further, the growing arsenal of various immunotherapeutic agents, including novel classes of immune checkpoint inhibitors and oncolytic, chimeric antigen receptor T cell, and vaccine therapies, reinforces these efforts. This review will focus on the place of immunotherapy and future possible strategies in PDAC.
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Affiliation(s)
| | | | - Devalingam Mahalingam
- Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; (T.D.); (C.M.)
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Haskell A, Pan S, Reese R, Powers A, Lopez MG, Lomeli S, Story C, Benton J, Blazier JC, Kaunas R, Gregory CA. Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental osteosarcoma. Sci Rep 2025; 15:1878. [PMID: 39805917 PMCID: PMC11730318 DOI: 10.1038/s41598-024-84037-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has been implicated in bone destruction, tumor survival and metastases during OS. We examined the role of Dkk-1 in OS disease progression and explored strategies for targeting its activity. Dkk-1 enhances OS survival by amplifying a non-canonical Wnt pathway that upregulates aldehyde dehydrogenase 1A1. Targeting of Dkk-1 transcription with a vivo morpholino (DkkMo) reduced OS survival and enhanced osteogenic activity of OS in vitro. DkkMo as a single agent slowed tumor expansion, increased tumor necrosis, inhibited metastases and preserved bone in a PDX model of OS. DkkMo also reduced the frequency of dividing tumor cells and reinitiated a regenerative osteogenic phenotype in tumors and stroma while reducing infiltration of inflammatory cells. These findings indicate that DkkMo has the potential to safely target osteosarcoma growth, survival, metastases and bone destruction.
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Affiliation(s)
- Andrew Haskell
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - Simin Pan
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - Robert Reese
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, College Station, TX, USA
| | - Anthony Powers
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, College Station, TX, USA
| | - Megan G Lopez
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - Sebastian Lomeli
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - Christopher Story
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - Joshua Benton
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
| | - J Chris Blazier
- Texas A&M Institute for Genome Sciences and Society, College Station, TX, USA
| | - Roland Kaunas
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, College Station, TX, USA
| | - Carl A Gregory
- Department of Medical Physiology, Texas A&M College of Medicine, Bryan, TX, 77807, USA.
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Despotidis M, Lyros O, Driva TS, Sarantis P, Kapetanakis EI, Mylonakis A, Mamilos A, Sakellariou S, Schizas D. DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target. Diagnostics (Basel) 2025; 15:85. [PMID: 39795613 PMCID: PMC11720708 DOI: 10.3390/diagnostics15010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/26/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
Esophageal adenocarcinoma (EAC) is an aggressive gastrointestinal (GI) malignancy with increasing incidence. Despite the recent progress in targeted therapies and surgical approaches, the survival rates of esophageal adenocarcinoma patients remain poor. The Dickkopf (DKK) proteins are secretory proteins known mainly as antagonists of the Wnt/β-catenin signaling pathway, which is considered an oncogene. However, it has been shown that in several GI cancers, including esophageal cancer, DKK1 may act as an oncogene itself through Wnt-independent signaling pathways. LRP5\6 and Kremen1/2 (Krm1/2) are transmembrane receptors to which the DKK proteins are mainly known to bind. CKAP4 (cytoskeleton-associated protein 4) is a novel receptor of DKK1, and the DKK1-CKAP4 pathway seems to be crucial in the role of DKK1 as an oncogene. The aim of this review is to feature the essential role of DKK1 and its receptors in carcinogenesis with a focus on EAC in an era of urgent need for specific biomarkers along with improved targeted therapies.
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Affiliation(s)
- Markos Despotidis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
| | - Orestis Lyros
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Tatiana S. Driva
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.S.D.); (S.S.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Emmanouil I. Kapetanakis
- Department of Thoracic Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Adam Mylonakis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
| | - Andreas Mamilos
- Institute of Pathology, University of Regensburg, 93053 Bavaria, Germany;
- Department of Pathology, German Oncology Center, Limassol 4108, Cyprus
| | - Stratigoula Sakellariou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.S.D.); (S.S.)
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
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Hsieh CC, Li TW, Li CC, Chen SH, Wei YL, Chiang NJ, Shen CH. DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer. Oncogenesis 2024; 13:34. [PMID: 39333078 PMCID: PMC11436992 DOI: 10.1038/s41389-024-00537-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/15/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.
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Affiliation(s)
- Chi-Che Hsieh
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Ting-Wei Li
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- Department of Life Sciences, National Cheng Kung University, Tainan, 704, Taiwan
| | - Chun-Chun Li
- Department of Life Sciences, National Cheng Kung University, Tainan, 704, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan
| | - You-Lin Wei
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan
| | - Nai-Jung Chiang
- Department of Oncology, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
| | - Che-Hung Shen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
- Doctoral Program in Tissue Engineering and Regenerative Medicine, Biotechnology Center, National Chung Hsing University, Taichung, 402, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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Dişçi E, Peksöz R, Laloğlu E, Yıldırgan Mİ, Albayrak Y, Şirin MA, Ağırman E, Atamanalp SS. The Role of Serum Dickkopf1 and CKAP4 Levels in Diagnosing Colorectal Cancer and Measuring the Disease Severity: A Prospective Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:933. [PMID: 38929550 PMCID: PMC11205388 DOI: 10.3390/medicina60060933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/11/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024]
Abstract
Background and Objective: Colorectal cancer (CRC) is among the most common types of cancer. Although the disease is treatable in its early stages, five-year survival falls below 20% in the later stages. CEA and CA19-9 are tumor markers used in the diagnosis and follow-up of the disease in clinical practice; however, their diagnostic effectiveness is insufficient. Therefore, the identification of biomarkers that can be easily studied from serum and can diagnose CRC and determine its severity is highly important. In this context, dickkopf1 (DKK1) and cytoskeleton-associated protein 4 (CKAP4) are both promising biomarkers. Materials and Methods: Serum DKK1 and CKAP4 levels were measured in 55 patients with CRC and 40 healthy controls. The patients with CRC were divided into groups based on pathological stages and histological differentiation. The serum levels of both proteins in patients with CRC were measured preoperatively and 10 and 30 days postoperatively. Results: Serum DKK1 and CKAP4 were significantly higher in the CRC group than in the healthy controls (p < 0.05). Serum levels of both proteins rose in line with the disease stage and grade but decreased following surgical resection. A positive correlation was observed between tumor diameter and protein blood levels. The diagnostic efficacy of DKK1 and CKAP4 in CRC (approximately 95%) was higher than that of markers such as CEA and CA19-9. Conclusions: The DKK1 and CKAP4 serum values of patients with CRC are promising biomarkers. They can potentially be used in CRC management, namely, in the diagnosis and treatment of tumor response access and in tumor aggressiveness prediction.
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Affiliation(s)
- Esra Dişçi
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
| | - Rıfat Peksöz
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
| | - Esra Laloğlu
- Department Medical Biochemistry, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
| | - Mehmet İlhan Yıldırgan
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
| | - Yavuz Albayrak
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
| | - Mehmet Akif Şirin
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
| | - Enes Ağırman
- Department of General Surgery, Erzurum City Hospital, Erzurum 25240, Turkey
| | - Sabri Selçuk Atamanalp
- Department of General Surgery, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey; (E.D.); (R.P.); (M.İ.Y.)
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Abe M, Hasegawa T, Hongo H, Yamamoto T, Shi Y, Cui J, Liu X, Yao Q, Ishizu H, Maruoka H, Yoshino H, Haraguchi-Kitakamae M, Shimizu T, Amizuka N. Immunohistochemical and Morphometric Assessment on the Biological Function and Vascular Endothelial Cells in the Initial Process of Cortical Porosity in Mice With PTH Administration. J Histochem Cytochem 2024; 72:309-327. [PMID: 38725403 PMCID: PMC11107436 DOI: 10.1369/00221554241247883] [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: 12/02/2023] [Accepted: 03/29/2024] [Indexed: 05/18/2024] Open
Abstract
To clarify the cellular mechanism of cortical porosity induced by intermittent parathyroid hormone (PTH) administration, we examined the femoral cortical bone of mice that received 40 µg/kg/day (four times a day) human PTH (hPTH) (1-34). The PTH-driven cortical porosity initiated from the metaphyseal region and chronologically expanded toward the diaphysis. Alkaline phosphatase (ALP)-positive osteoblasts in the control mice covered the cortical surface, and endomucin-positive blood vessels were distant from these osteoblasts. In PTH-administered mice, endomucin-reactive blood vessels with TRAP-positive penetrated the ALP-positive osteoblast layer, invading the cortical bone. Statistically, the distance between endomucin-positive blood vessels and the cortical bone surface abated after PTH administration. Transmission electron microscopic observation demonstrated that vascular endothelial cells often pass through the flattened osteoblast layer and accompanied osteoclasts in the deep region of the cortical bone. The cell layers covering mature osteoblasts thickened with PTH administration and exhibited ALP, α-smooth muscle actin (αSMA), vascular cell adhesion molecule-1 (VCAM1), and receptor activator of NF-κB ligand (RANKL). Within these cell layers, osteoclasts were found near endomucin-reactive blood vessels. In PTH-administered femora, osteocytes secreted Dkk1, a Wnt inhibitor that affects angiogenesis, and blood vessels exhibited plasmalemma vesicle-associated protein, an angiogenic molecule. In summary, endomucin-positive blood vessels, when accompanied by osteoclasts in the ALP/αSMA/VCAM1/RANKL-reactive osteoblastic cell layers, invade the cortical bone, potentially due to the action of osteocyte-derived molecules such as DKK1.
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Affiliation(s)
- Miki Abe
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Tomoka Hasegawa
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Hiromi Hongo
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Tomomaya Yamamoto
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
- Hokkaido University, Sapporo, Japan, and Department of Dentistry, Japan Ground Self-Defense Force Camp Shinmachi, Takasaki, Japan
| | - Yan Shi
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Jiaxin Cui
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Xuanyu Liu
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Qi Yao
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Hotaka Ishizu
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine and Orthopedics, Graduate School of Medicine, Faculty of Medicine
| | - Haruhi Maruoka
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Hirona Yoshino
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | - Mai Haraguchi-Kitakamae
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
| | | | - Norio Amizuka
- Ultrastructure of Hard Tissue, Graduate School of Dental Medicine, Faculty of Dental Medicine
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Mourtada J, Thibaudeau C, Wasylyk B, Jung AC. The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer. Cells 2023; 13:75. [PMID: 38201279 PMCID: PMC10778571 DOI: 10.3390/cells13010075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/22/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.
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Affiliation(s)
- Jana Mourtada
- Laboratoire de Biologie Tumorale, Institut de Cancérologie Strasbourg Europe, 67200 Strasbourg, France; (J.M.); (C.T.)
- Laboratoire STREINTH (Stress Response and Innovative Therapies), INSERM U1113 IRFAC, Université de Strasbourg, 67200 Strasbourg, France
| | - Chloé Thibaudeau
- Laboratoire de Biologie Tumorale, Institut de Cancérologie Strasbourg Europe, 67200 Strasbourg, France; (J.M.); (C.T.)
- Laboratoire STREINTH (Stress Response and Innovative Therapies), INSERM U1113 IRFAC, Université de Strasbourg, 67200 Strasbourg, France
| | - Bohdan Wasylyk
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch Graffenstaden, France;
- Institut National de la Santé et de la Recherche Médicale (INSERM), U 1258, 67404 Illkirch Graffenstaden, France
- Centre Nationale de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch Graffenstaden, France
- Université de Strasbourg, 67000 Strasbourg, France
| | - Alain C. Jung
- Laboratoire de Biologie Tumorale, Institut de Cancérologie Strasbourg Europe, 67200 Strasbourg, France; (J.M.); (C.T.)
- Laboratoire STREINTH (Stress Response and Innovative Therapies), INSERM U1113 IRFAC, Université de Strasbourg, 67200 Strasbourg, France
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Liang Y, An Q, Song H, Tang Y, Xiao S, Wu J, Yan N, Yu B, Cao X, Lu M. AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity. J Med Chem 2023; 66:16579-16596. [PMID: 38069817 DOI: 10.1021/acs.jmedchem.3c00104] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure-activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.
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Affiliation(s)
- Ying Liang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Quanlin An
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Huaxin Song
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yigang Tang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shujun Xiao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jiale Wu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ni Yan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Xin Cao
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Min Lu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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10
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Hsu YC, Chang CC, Hsieh CC, Huang YT, Shih YH, Chang HC, Chang PJ, Lin CL. Dickkopf-1 Acts as a Profibrotic Mediator in Progressive Chronic Kidney Disease. Int J Mol Sci 2023; 24:ijms24087679. [PMID: 37108841 PMCID: PMC10143456 DOI: 10.3390/ijms24087679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open
Abstract
Chronic kidney disease (CKD) is a serious public health problem. Due to a high variability in the speed of CKD progression to end-stage renal disease (ESRD) and the critical involvement of Wnt/β-catenin signaling in CKD, we investigated the role of the Wnt antagonist Dickkopf-1 (DKK1) in CKD progression. Our data revealed that patients with CKD stages 4-5 had higher DKK1 levels in their serum and renal tissues than the control subjects. In an 8-year follow-up, the serum DKK1-high group in the enrolled CKD patients showed a faster progression to ESRD than the serum DKK1-low group. Using a rat model of 5/6 nephrectomy (Nx)-induced CKD, we consistently detected elevated serum levels and renal production of DKK1 in 5/6 Nx rats compared to sham-operated rats. Importantly, the knockdown of the DKK1 levels in the 5/6 Nx rats markedly attenuated the CKD-associated phenotypes. Mechanistically, we demonstrated that the treatment of mouse mesangial cells with recombinant DKK1 protein induced not only the production of multiple fibrogenic proteins, but also the expression of endogenous DKK1. Collectively, our findings suggest that DKK1 acts as a profibrotic mediator in CKD, and elevated levels of serum DKK1 may be an independent predictor of faster disease progression to ESRD in patients with advanced CKD.
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Affiliation(s)
- Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Cheng-Chih Chang
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Ching-Chuan Hsieh
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Yu-Ting Huang
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Ya-Hsueh Shih
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Hsiu-Ching Chang
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Pey-Jium Chang
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 105, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
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11
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Doucet D, Brubaker C, Turner D, Gregory CA. Factors affecting the role of canonical Wnt inhibitor Dickkopf-1 in cancer progression. Front Oncol 2023; 13:1114822. [PMID: 37007131 PMCID: PMC10050559 DOI: 10.3389/fonc.2023.1114822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/01/2023] [Indexed: 03/17/2023] Open
Abstract
BackgroundThe canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has the capacity to modulate homeostasis between canonical and non-canonical Wnt pathways and also signal independently of Wnt. The specific effects of Dkk-1 activity on tumor physiology are therefore unpredictable with examples of Dkk-1 serving as either a driver or suppressor of malignancy. Given that Dkk-1 blockade may serve as a potential treatment for some types of cancer, we questioned whether it is possible to predict the role of Dkk-1 on tumor progression based on the tissue origin of the tumor.MethodsOriginal research articles that described Dkk-1 in terms a tumor suppressor or driver of cancer growth were identified. To determine the association between tumor developmental origin and the role of Dkk-1, a logistic regression was performed. The Cancer Genome Atlas database was interrogated for survival statistics based on tumor Dkk-1 expression.ResultsWe report that Dkk-1 is statistically more likely to serve as a suppressor in tumors arising from the ectoderm (p = 0.0198) or endoderm (p = 0.0334) but more likely to serve as a disease driver in tumors of mesodermal origin (p = 0.0155). Survival analyses indicated that in cases where Dkk-1 expression could be stratified, high Dkk-1 expression is usually associated with poor prognosis. This in part may be due to pro-tumorigenic role Dkk-1 plays on tumor cells but also through its influence on immunomodulatory and angiogenic processes in the tumor stroma.ConclusionDkk-1 has a context-specific dual role as a tumor suppressor or driver. Dkk-1 is significantly more likely to serve as a tumor suppressor in tumors arising from ectoderm and endoderm while the converse is true for mesodermal tumors. Patient survival data indicated high Dkk-1 expression is generally a poor prognostic indicator. These findings provide further support for the importance of Dkk-1 as a therapeutic cancer target in some cases.
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Affiliation(s)
- Dakota Doucet
- Medical Sciences Program, Texas A&M Health Science Center School of Medicine, Texas A&M University, Bryan, TX, United States
| | - Connor Brubaker
- Department of Statistics, Texas A&M University, College Station, TX, United States
| | - Donald Turner
- Department of Statistics, Texas A&M University, College Station, TX, United States
| | - Carl A. Gregory
- Department of Cell Biology and Genetics, Texas A&M Health Science Center School of Medicine, Texas A&M University, Bryan, TX, United States
- *Correspondence: Carl A. Gregory,
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12
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Li Y, Huang X, Meng X, Luo Y, Luo S, Wang J. Postoperative recurrence of mixed extragonadal germ cell tumor in the right shoulder: a case report. Diagn Pathol 2023; 18:26. [PMID: 36805679 PMCID: PMC9940327 DOI: 10.1186/s13000-023-01312-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Extragonadal germ cell tumours (EGGCTs) originated in Shoulder are extremely rare, with 1 case described in the literature. We report a case of a patient with a primary Right Shoulder mixed EGGCT. CASE PRESENTATION A 36-year-old male patient was hospitalized for 6 months due to progressive right shoulder swelling accompanied by pain. Subsequently, the right shoulder tumor was removed entirely. Gross pathological examination showed that the size of the tumor mass was about 14 × 10 × 6 cm.Mutations were observed in ENPEP (4q25), ZCCHC11, RREB1 (6p24.3), CKAP4 (12q23.3), and other genes were detected by whole exome sequencing. Histology revealed a mixed EGGCT of the Right Shoulder with immature teratoma and yolk sac tumour. The patient went through 6 cycles of chemotherapy. After 7 months of follow-up, the patient is recurrence. CONCLUSION The primary MEGCT of the shoulder is an extremely rare condition. However, the recurrence and metastasis rates are high. Therefore, further research is necessary to determine this rare disease's genetic and clinical characteristics to develop an effective treatment plan.
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Affiliation(s)
- Yao Li
- grid.413390.c0000 0004 1757 6938Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province P.R. China
| | - Xiang Huang
- grid.413390.c0000 0004 1757 6938Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province P.R. China
| | - Xue Meng
- grid.413390.c0000 0004 1757 6938Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province P.R. China
| | - Yuqing Luo
- grid.413390.c0000 0004 1757 6938Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province P.R. China
| | - Shuai Luo
- grid.413390.c0000 0004 1757 6938Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province P.R. China
| | - Jinjing Wang
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province, P.R. China.
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13
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Luo M, Chen YJ, Xie Y, Wang QR, Xiang YN, Long NY, Yang WX, Zhao Y, Zhou JJ. Dickkopf-related protein 1/cytoskeleton-associated protein 4 signaling activation by Helicobacter pylori-induced activator protein-1 promotes gastric tumorigenesis via the PI3K/AKT/mTOR pathway. World J Gastroenterol 2022; 28:6769-6787. [PMID: 36620343 PMCID: PMC9813938 DOI: 10.3748/wjg.v28.i47.6769] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/05/2022] [Accepted: 11/30/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignant tumor with high incidence and mortality rates globally, especially in East Asian countries. Helicobacter pylori (H. pylori) infection is a significant and independent risk factor for GC. However, its underlying mechanism of action is not fully understood. Dickkopf-related protein (DKK) 1 is a Wnt signaling antagonist, and cytoskeleton-associated protein (CKAP) 4 is a newly identified DKK1 receptor. Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 inde-pendent of Wnt signaling. We hypothesize that H. pylori-induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.
AIM To investigate the interaction of H. pylori infection, DKK1 and CAKP4 in GC, as well as the underlying molecular mechanisms.
METHODS RNA sequencing was used to identify differentially expressed genes (DEGs) between H. pylori-infected and uninfected primary GC cells. Gain- and loss-of-function experiments were performed to verify the H. pylori-induced upregulation of activator protein-1 (AP-1) in GC cells. A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4. Western blotting and immunohistochemistry detected the expression of DKK1, CKAP4, and phos-phatidylinositol 3-kinase (PI3K) pathway-related proteins in GC cells and tissues. Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells in vitro and in vivo.
RESULTS We identified 32 DEGs between primary GC cells with and without H. pylori infection, including JUN, fos-like antigen-1 (FOSL1), and DKK1, and confirmed that the three proteins and CKAP4 were highly expressed in H. pylori-infected GC cells, H. pylori-infected gerbil gastric tissues, and human GC tissues. JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter. Activated DKK1 bound to CKAP4, but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6, to promote GC cell growth, colony formation, migration, invasion, and xenograft tumor growth in nude mice. All these effects were driven by activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. Targeting the PI3K signaling pathway by LY294002 inhibited DKK1-mediated CKAP4/PI3K signaling activity and the malignant behavior of GC cells.
CONCLUSION H. pylori induces JUN and FOSL1 expression to form AP-1, which transcriptionally activates DKK1. Binding of DKK1 to KAKP4 contributes to gastric tumorigenesis via the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Mei Luo
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yuan-Jia Chen
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Qin-Rong Wang
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yi-Ning Xiang
- Department of Pathology of Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Ni-Ya Long
- Department of Neurology of Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Wen-Xiu Yang
- Department of Pathology of Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Jian-Jiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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14
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Jaschke NP, Pählig S, Sinha A, Adolph TE, Colunga ML, Hofmann M, Wang A, Thiele S, Schwärzler J, Kleymann A, Gentzel M, Tilg H, Wielockx B, Hofbauer LC, Rauner M, Göbel A, Rachner TD. Dickkopf1 fuels inflammatory cytokine responses. Commun Biol 2022; 5:1391. [PMID: 36539532 PMCID: PMC9765382 DOI: 10.1038/s42003-022-04368-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.
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Affiliation(s)
- Nikolai P Jaschke
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
| | - Sophie Pählig
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Anupam Sinha
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Maria Ledesma Colunga
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Maura Hofmann
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Andrew Wang
- Department of Medicine (Rheumatology, Allergy & Immunology), Yale University School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Sylvia Thiele
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Alexander Kleymann
- Division of Rheumatology, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Marc Gentzel
- Molecular Analysis - Mass Spectrometry, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Innsbruck Medical University, Innsbruck, Austria
| | - Ben Wielockx
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Andy Göbel
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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15
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Wang Q, Tian J, Li X, Liu X, Zheng T, Zhao Y, Li X, Zhong H, Liu D, Zhang W, Zhang M, Li M, Zhang M. Upregulation of Endothelial DKK1 (Dickkopf 1) Promotes the Development of Pulmonary Hypertension Through the Sp1 (Specificity Protein 1)/SHMT2 (Serine Hydroxymethyltransferase 2) Pathway. Hypertension 2022; 79:960-973. [PMID: 35249365 DOI: 10.1161/hypertensionaha.121.18672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Pulmonary hypertension (PH) is a cancer-like proliferative disease, which has no curative treatment options. The dysfunction of pulmonary artery endothelial cells plays a key role in PH. DKK1 (Dickkopf 1) is a secretory glycoprotein that exerts proproliferative effects on tumor cells. In the present study, we aimed to identify the role and underlying mechanism of DKK1 in the development of PH, which still remain unclear. METHODS AND RESULTS We found endothelial DKK1 expression was upregulated in serum and lung tissues obtained from patients with PH, mice with hypoxia-induced PH, and human pulmonary artery endothelial cells cultured under hypoxic conditions. Endothelium-specific DKK1-knockout (DKK1ECKO) mice significantly ameliorated hypoxia+Sugen5416 and hypoxia-induced PH. More importantly, neutralizing anti-DKK1 antibody treatment significantly attenuated established hypoxia+Sugen5416 PH. Results of proteome analysis of control and DKK1-knockdown human pulmonary artery endothelial cells identified a significantly differentially expressed protein, SHMT2 (serine hydroxymethyltransferase 2), a key metabolic enzyme in one-carbon metabolism, as a novel DKK1 target. DKK1 knockdown in human pulmonary artery endothelial cells cultured under hypoxic conditions decreased the cellular NADPH/NADP+ ratio, increased reactive oxygen species levels and the extent of mitochondrial DNA damage, and inhibited mitochondrial membrane hyperpolarization. In the context of this altered redox defense and mitochondrial disorder, DKK1 induced a proproliferative and antiapoptotic phenotype in endothelial cells. Furthermore, we confirmed that DKK1 regulated SHMT2 transcription through the AKT-Sp1 (specificity protein 1) signaling axis. CONCLUSIONS Our data provide robust evidence and molecular explanations for the associations between DKK1, redox defense, mitochondrial disorders, and PH and reveal a novel target for PH treatment.
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Affiliation(s)
- Qianqian Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Jingjing Tian
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Xuan Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Xiaolin Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Tengfei Zheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Yachao Zhao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Xiao Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Hongyu Zhong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Dongdong Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Wencheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Meng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Mengmeng Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Mei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, China
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16
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Jiang H, Zhang Z, Yu Y, Chu HY, Yu S, Yao S, Zhang G, Zhang BT. Drug Discovery of DKK1 Inhibitors. Front Pharmacol 2022; 13:847387. [PMID: 35355709 PMCID: PMC8959454 DOI: 10.3389/fphar.2022.847387] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/21/2022] [Indexed: 12/24/2022] Open
Abstract
Dickkopf-1 (DKK1) is a well-characterized Wnt inhibitor and component of the Wnt/β-catenin signaling pathway, whose dysregulation is associated with multiple abnormal pathologies including osteoporosis, Alzheimer's disease, diabetes, and various cancers. The Wnt signaling pathway has fundamental roles in cell fate determination, cell proliferation, and survival; thus, its mis-regulation can lead to disease. Although DKK1 is involved in other signaling pathways, including the β-catenin-independent Wnt pathway and the DKK1/CKAP4 pathway, the inhibition of DKK1 to propagate Wnt/β-catenin signals has been validated as an effective way to treat related diseases. In fact, strategies for developing DKK1 inhibitors have produced encouraging clinical results in different pathological models, and many publications provide detailed information about these inhibitors, which include small molecules, antibodies, and nucleic acids, and may function at the protein or mRNA level. However, no systematic review has yet provided an overview of the various aspects of their development and prospects. Therefore, we review the DKK1 inhibitors currently available or under study and provide an outlook on future studies involving DKK1 and drug discovery.
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Affiliation(s)
- Hewen Jiang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Zongkang Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yuanyuan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hang Yin Chu
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Sifan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Shanshan Yao
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ge Zhang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.,Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.,Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Bao-Ting Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
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Ahn HS, Ryu JS, Lee J, Mun SJ, Hong YH, Shin Y, Chung KS, Son MJ. Generation of An Induced Pluripotent Stem Cell Line from Human Liver Fibroblasts from A Patient with Combined Hepatocellular-Cholangiocarcinoma. CELL JOURNAL 2022; 24:133-139. [PMID: 35451583 PMCID: PMC9035233 DOI: 10.22074/cellj.2022.7765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/13/2020] [Indexed: 11/08/2022]
Abstract
Objective Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of primary liver cancer with characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The pathogenesis of cHCCCC is poorly understood due to a shortage of suitable in vitro models. Due to scarce availability of human liver tissue, induced pluripotent stem cells (iPSCs) are a useful alternative source to produce renewable liver cells. For use in the development of liver pathology models, here we successfully developed and evaluated iPSCs from liver fibroblasts of a patient with cHCC-CC. Materials and Methods In this experimental study, human liver fibroblasts (HLFs) were obtained from the liver biopsy of a 69-year-old male patient with cHCC-CC and transduced with a retroviral cocktail that included four factors - OCT4, SOX2, KLF4, and c-MYC (OSKM). Pluripotency of the iPSCs was determined by alkaline phosphatase (AP) staining, quantitative real-time polymerase chain reaction (PCR), and immunofluorescence. We induced in vitro embryoid body (EB) formation and performed an in vivo teratoma assay to confirm their differentiation capacity into the three germ layers. Results HLF iPSCs derived from the cHCC-CC patient displayed typical iPSC-like morphology and pluripotency marker expression. The proficiency of the iPSCs to differentiate into three germ layers was assessed both in vitro and in vivo. Compared to normal control iPSCs, differentiated HLF iPSCs showed increased expressions of HCC markers alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) and the CC marker cytokeratin 7 (CK7), and a decreased expression of the CC tumour suppressor SRY-related HMG-box 17 (SOX17). Conclusion We established HLF iPSCs using liver fibroblasts from a patient with cHCC-CC for the first time. The HLF iPSCs maintained marker expression in the patient when differentiated into EBs. Therefore, HLF iPSCs may be a sustainable cell source for modelling cHCC-CC and beneficial for understanding liver cancer pathology and developing therapies for cHCC-CC treatment.
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Affiliation(s)
- Hyo-Suk Ahn
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea
| | - Jae-Sung Ryu
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea
| | - Jaeseo Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea
| | - Seon Ju Mun
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea,Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon, Republic of Korea
| | - Yeon-Hwa Hong
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea,Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon, Republic of Korea
| | - Yongbo Shin
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea,Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon, Republic of Korea
| | - Kyung-Sook Chung
- Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon, Republic of Korea ,Biomedical Translational Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea ,Department of Functional GenomicsKorea University of Science and Technology (UST)217 GajungroYuseong-guDaejeonRepublic of KoreaStem Cell Convergence Research CenterKorea Research Institute of Bioscience and Biotechnology (KRIBB)125 Gwahak-roYuseong-guDaejeonRepublic of Korea
Emails:,
| | - Myung Jin Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro,
Yuseong-gu, Daejeon, Republic of Korea,Biomedical Translational Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea ,Department of Functional GenomicsKorea University of Science and Technology (UST)217 GajungroYuseong-guDaejeonRepublic of KoreaStem Cell Convergence Research CenterKorea Research Institute of Bioscience and Biotechnology (KRIBB)125 Gwahak-roYuseong-guDaejeonRepublic of Korea
Emails:,
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18
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DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma. Blood Adv 2021; 5:3656-3667. [PMID: 34470047 DOI: 10.1182/bloodadvances.2021004315] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/12/2021] [Indexed: 01/16/2023] Open
Abstract
Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.
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19
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Luo T, Ding K, Ji J, Zhang X, Yang X, Chen A, Huang B, Zhang D, Wang J, Li X. Cytoskeleton-associated protein 4 (CKAP4) promotes malignant progression of human gliomas through inhibition of the Hippo signaling pathway. J Neurooncol 2021; 154:275-283. [PMID: 34476666 DOI: 10.1007/s11060-021-03831-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 08/16/2021] [Indexed: 12/22/2022]
Abstract
PURPOSE Gliomas are the most common and aggressive malignant brain tumors and are associated with high mortality and incidence in humans. Despite rigorous multi-modal therapy, including surgery, chemotherapy and radiotherapy, patients with malignant glioma survive an average of 12-15 months following primary diagnosis. Therefore, new molecular biomarkers are urgently needed for diagnosis and targeted therapy. Here, we find that suppression of CKAP4 might inhibit glioma growth through regulation of Hippo signaling. METHODS We examined the expression levels of CKAP4 through analysis of RNA sequencing data from GEPIA and CGGA databases. Then, Lentivirus was used to construct stable cell lines with knockout or overexpression of CKAP4. Next, the function of CKAP4 on glioma was investigated in vitro and in an orthotopic brain tumor model in mice. Lastly, luciferase reporter assay, immunofluorescence and immunoblotting were performed to explore the potential mechanism of how CKAP4 affects gliomas. RESULTS CKAP4 is highly upregulated in glioma and high CKAP4 expressing tumors were associated with poor patient survival. And CKAP4 promotes malignant progression of gliomas via inhibiting Hippo signaling. CONCLUSION CKAP4 has potential as a promising biomarker and can predict the prognosis of patients with gliomas. And targeting CKAP4 expression may be an effective therapeutic strategy for the treatment of human gliomas.
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Affiliation(s)
- Tao Luo
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Kaikai Ding
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Jianxiong Ji
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Xin Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Xiaobing Yang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Anjing Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China.,School of Medicine, Shandong University, Shandong, China
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Di Zhang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China
| | - Jian Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China.,Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway.,Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Cheeloo College of Medicine, Shandong University, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China. .,Key Laboratory of Brain Functional Remodeling, Shandong, 250012, Jinan, China. .,Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, 107# Wenhua Xi Road, Shandong, 250012, Jinan, China.
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20
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Xiao Y, Amaral TF, Ross PJ, Soto DA, Diffenderfer KE, Pankonin AR, Jeensuk S, Tríbulo P, Hansen PJ. Importance of WNT-dependent signaling for derivation and maintenance of primed pluripotent bovine embryonic stem cells†. Biol Reprod 2021; 105:52-63. [PMID: 33899086 DOI: 10.1093/biolre/ioab075] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/24/2021] [Accepted: 04/09/2021] [Indexed: 12/23/2022] Open
Abstract
The WNT signaling system plays an important but paradoxical role in the regulation of pluripotency. In the cow, IWR-1, which inhibits canonical WNT activation and has WNT-independent actions, promotes the derivation of primed pluripotent embryonic stem cells from the blastocyst. Here, we describe a series of experiments to determine whether derivation of embryonic stem cells could be generated by replacing IWR-1 with other inhibitors of WNT signaling. Results confirm the importance of inhibition of canonical WNT signaling for the establishment of pluripotent embryonic stem cells in cattle and indicate that the actions of IWR-1 can be mimicked by the WNT secretion inhibitor IWP2 but not by the tankyrase inhibitor XAV939 or WNT inhibitory protein dickkopf 1. The role of Janus kinase-mediated signaling pathways for the maintenance of pluripotency of embryonic stem cells was also evaluated. Maintenance of pluripotency of embryonic stem cells lines was blocked by a broad inhibitor of Janus kinase, even though the cells did not express phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Further studies with blastocysts indicated that IWR-1 blocks the activation of pSTAT3. A likely explanation is that IWR-1 blocks differentiation of embryonic stem cells into a pSTAT3+ lineage. In conclusion, results presented here indicate the importance of inhibition of WNT signaling for the derivation of pluripotent bovine embryonic stem cells, the role of Janus kinase signaling for maintenance of pluripotency, and the participation of IWR-1 in the inhibition of activation of STAT3.
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Affiliation(s)
- Yao Xiao
- Department of Animal Sciences, Donald Henry Barron Reproductive and Perinatal Biology Research Program, and Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Thiago F Amaral
- Department of Animal Sciences, Donald Henry Barron Reproductive and Perinatal Biology Research Program, and Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Pablo J Ross
- Department of Animal Science, University of California, Davis, CA, USA
| | - Delia A Soto
- Department of Animal Science, University of California, Davis, CA, USA
| | | | - Aimee R Pankonin
- Stem Cell Core, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Surawich Jeensuk
- Department of Animal Sciences, Donald Henry Barron Reproductive and Perinatal Biology Research Program, and Genetics Institute, University of Florida, Gainesville, FL, USA.,Department of Livestock Development, Bureau of Biotechnology in Livestock Production, Pathum Thani, Thailand
| | - Paula Tríbulo
- Department of Animal Sciences, Donald Henry Barron Reproductive and Perinatal Biology Research Program, and Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Peter J Hansen
- Department of Animal Sciences, Donald Henry Barron Reproductive and Perinatal Biology Research Program, and Genetics Institute, University of Florida, Gainesville, FL, USA
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21
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Li SX, Li J, Dong LW, Guo ZY. Cytoskeleton-Associated Protein 4, a Promising Biomarker for Tumor Diagnosis and Therapy. Front Mol Biosci 2021; 7:552056. [PMID: 33614703 PMCID: PMC7892448 DOI: 10.3389/fmolb.2020.552056] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022] Open
Abstract
Cytoskeleton-associated protein 4 (CKAP4) is located in the rough endoplasmic reticulum (ER) and plays an important role in stabilizing the structure of ER. Meanwhile, CKAP4 is also found to act as an activated receptor at the cell surface. The multifunction of CKAP4 was gradually discovered with growing research evidence. In addition to the involvement in various physiological events including cell proliferation, cell migration, and stabilizing the structure of ER, CKAP4 has been implicated in tumorigenesis. However, the role of CKAP4 is still controversial in tumor biology, which may be related to different signal transduction pathways mediated by binding to different ligands in various microenvironments. Interestingly, CKAP4 has been recently recognized as a serological marker of several tumors and CKAP4 is expected to be a tumor therapeutic target. Therefore, deciphering the gene status, expression regulation, functions of CKAP4 in different diseases may shed new light on CKAP4-based cancer diagnosis and therapeutic strategy. This review discusses the publications that describe CKAP4 in various diseases, especially on tumor promotion and suppression, and provides a detailed discussion on the discrepancy.
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Affiliation(s)
- Shuang-Xi Li
- Department of Nephrology, Changhai Hospital, The Navy Military Medical University, Shanghai, China
| | - Juan Li
- Department of Nephrology, Changhai Hospital, The Navy Military Medical University, Shanghai, China
| | - Li-Wei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Navy Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Zhi-Yong Guo
- Department of Nephrology, Changhai Hospital, The Navy Military Medical University, Shanghai, China
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22
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Summers ME, Richmond BW, Kropski JA, Majka SA, Bastarache JA, Hatzopoulos AK, Bylund J, Ghosh M, Petrache I, Foronjy RF, Geraghty P, Majka SM. Balanced Wnt/Dickkopf-1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function. Am J Physiol Cell Physiol 2021; 320:C119-C131. [PMID: 33085496 PMCID: PMC7846975 DOI: 10.1152/ajpcell.00277.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/29/2020] [Accepted: 10/12/2020] [Indexed: 02/08/2023]
Abstract
The well-described Wnt inhibitor Dickkopf-1 (DKK1) plays a role in angiogenesis as well as in regulation of growth factor signaling cascades in pulmonary remodeling associated with chronic lung diseases (CLDs) including emphysema and fibrosis. However, the specific mechanisms by which DKK1 influences mesenchymal vascular progenitor cells (MVPCs), microvascular endothelial cells (MVECs), and smooth muscle cells (SMCs) within the microvascular niche have not been elucidated. In this study, we show that knockdown of DKK1 in Abcg2pos lung mouse adult tissue resident MVPCs alters lung stiffness, parenchymal collagen deposition, microvessel muscularization and density as well as loss of tissue structure in response to hypoxia exposure. To complement the in vivo mouse modeling, we also identified cell- or disease-specific responses to DKK1, in primary lung chronic obstructive pulmonary disease (COPD) MVPCs, COPD MVECs, and SMCs, supporting a paradoxical disease-specific response of cells to well-characterized factors. Cell responses to DKK1 were dose dependent and correlated with varying expressions of the DKK1 receptor, CKAP4. These data demonstrate that DKK1 expression is necessary to maintain the microvascular niche whereas its effects are context specific. They also highlight DKK1 as a regulatory candidate to understand the role of Wnt and DKK1 signaling between cells of the microvascular niche during tissue homeostasis and during the development of chronic lung diseases.
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Affiliation(s)
- Megan E Summers
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Bradley W Richmond
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Jonathan A Kropski
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Sarah A Majka
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Antonis K Hatzopoulos
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Jeffery Bylund
- Division of Allergy, Pulmonary and Critical Care Medicine or Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Moumita Ghosh
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Irina Petrache
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Robert F Foronjy
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York
| | - Patrick Geraghty
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York
| | - Susan M Majka
- Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
- Department of Medicine, Pulmonary & Critical Care Medicine, Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado
- Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado
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23
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Mukherjee S, Biswas D, Gadre R, Jain P, Syed N, Stylianou J, Zeng Q, Mahadevan A, Epari S, Shetty P, Moiyadi A, Roy Ball G, Srivastava S. Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers. Front Oncol 2020; 10:1600. [PMID: 32974197 PMCID: PMC7482667 DOI: 10.3389/fonc.2020.01600] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/23/2020] [Indexed: 12/29/2022] Open
Abstract
Meningiomas are one of the most prevalent primary brain tumors. Our study aims to obtain mechanistic insights of meningioma pathobiology using mass spectrometry-based label-free quantitative proteome analysis to identifying druggable targets and perturbed pathways for therapeutic intervention. Label-free based proteomics study was done from peptide samples of 21 patients and 8 non-tumor controls which were followed up with Phosphoproteomics to identify the kinases and phosphorylated components of the perturbed pathways. In silico approaches revealed perturbations in extracellular matrix remodeling and associated cascades. To assess the extent of influence of Integrin and PI3K-Akt pathways, we used an Integrin Linked Kinase inhibitor on patient-derived meningioma cell line and performed a transcriptomic analysis of the components. Furthermore, we designed a Targeted proteomics assay which to the best of our knowledge for very first-time enables identification of peptides from 54 meningioma patients via SRM assay to validate the key proteins emerging from our study. This resulted in the identification of peptides from CLIC1, ES8L2, and AHNK many of which are receptors and kinases and are difficult to be characterized using conventional approaches. Furthermore, we were also able to monitor transitions for proteins like NEK9 and CKAP4 which have been reported to be associated with meningioma pathobiology. We believe, this study can aid in designing peptide-based validation assays for meningioma patients as well as IHC studies for clinical applications.
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Affiliation(s)
- Shuvolina Mukherjee
- Proteomics Lab, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India
| | - Deeptarup Biswas
- Proteomics Lab, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India
| | - Rucha Gadre
- Proteomics Lab, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India
| | - Pooja Jain
- Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Nelofer Syed
- Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom
| | - Julianna Stylianou
- Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom
| | - Qingyu Zeng
- Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom
| | - Anita Mahadevan
- Department of Neuropathology, Human Brain Tissue Repository (Brain Bank), NIMHANS, Bengaluru, India
| | - Sridhar Epari
- Department of Pathology, Tata Memorial Centre, Mumbai, India
| | - Prakash Shetty
- Department of Neurosurgery, Tata Memorial Centre, Mumbai, India
| | | | - Graham Roy Ball
- School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Sanjeeva Srivastava
- Proteomics Lab, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India
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24
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Jaschke N, Hofbauer LC, Göbel A, Rachner TD. Evolving functions of Dickkopf-1 in cancer and immunity. Cancer Lett 2020; 482:1-7. [PMID: 32251706 DOI: 10.1016/j.canlet.2020.03.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/23/2020] [Accepted: 03/31/2020] [Indexed: 12/17/2022]
Abstract
Dickkopf-1 (DKK-1) is a well-established inhibitor of canonical Wnt-signaling that critically participates in the regulation of bone formation and has been implicated in the development and progression of bone metastases. While the skeleton was originally considered the sole site of DKK-1 synthesis, it has now become clear that the molecule is also highly expressed in T-cells, platelets and multiple cancer cells. In the past years, several new functions of DKK-1 in angiogenesis, cancer cell biology, immune homeostasis and inflammation have been revealed. These novel insights have paved the way for clinical trials investigating the efficacy of anti-DKK-1 antibodies in a variety of different malignancies, most of which are currently still ongoing. In this review, we discuss the evolution and recent advances in DKK-1 research and highlight clinical implications of the available knowledge on the molecule, especially in cancer. Finally, we emphasize outstanding questions and provide an outlook on potential future studies that will aid in further improving our understanding of the pleiotropic roles of DKK-1 in health and disease.
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Affiliation(s)
- Nikolai Jaschke
- Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Austria
| | - Lorenz C Hofbauer
- Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andy Göbel
- Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilman D Rachner
- Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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25
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Liu R, Wang Y, Li B, Wang H, Guan F, Tan Z, Li X. Screening differentially expressed proteins from co-cultured hematopoietic cells and bone marrow-derived stromal cells by quantitative proteomics (SILAC) method. Clin Proteomics 2019; 16:32. [PMID: 31360146 PMCID: PMC6637644 DOI: 10.1186/s12014-019-9249-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/04/2019] [Indexed: 02/06/2023] Open
Abstract
Background Bone marrow stromal cells protect hematopoietic cells and provide drug resistance by delivering bunch of variable proteins. Thus, alterations of protein expression are typically associated with cell–cell signal transduction and regulation of cellular functions. Methods Co-culture models of bone marrow stromal cells and hematopoietic cells are often used in studies of their crosstalk. Studies of altered protein expression initiated by stromal cell/hematopoietic cell interactions are an important new trend in microenvironmental research. There has been no report to date of global quantitative proteomics analysis of crosstalk between hematopoietic cells and stromal cells. In this study, we analyzed quantitative proteomes in a co-culture system of stromal HS5 cells and hematopoietic KG1a cells, and simultaneously tracked differentially expressed proteins in two types of cells before and after co-culture by stable isotope labeling by amino acids in cell culture (SILAC) method. Results We have shown that in co-cultured KG1a, 40 proteins (including CKAP4, LMNA, and SERPINB2) were upregulated and 64 proteins (including CD44, CD99, and NCAM1) were downregulated relative to KG1a alone. We utilized IPA analysis to discover that the NOD-like receptor signaling pathway was upregulated, whereas platelet activation was downregulated in co-cultured KG1a cells. Furthermore, 95 proteins (including LCP1, ARHGAP4, and UNCX) were upregulated and 209 proteins (including CAPG, FLNC, and MAP4) were downregulated in co-cultured HS5 relative to HS5 alone. The tight junction pathway was downregulated and glycolysis/gluconeogenesis pathway was dysfunctional in co-cultured HS5. Most importantly, the significantly differentially expressed proteins can also be confirmed using different co-cultured cell lines. Conclusion Altogether, we recommend such quantitative proteomics approach for the studies of the hematopoietic–stroma cross-talk, differentially expressed proteins and related signaling pathways identification. The differentially expressed proteins identified from this current SILAC method will provide a useful basis for ongoing studies of crosstalk between stromal cells and hematopoietic cells in co-culture systems. All these result suggested our ongoing studies can focus on the mechanisms underlying CKAP4 increase and CD44 decrease in co-cultured hematopoietic cells, and the increase of LCP1 and decrease of CAPG in co-cultured stromal cell. The proteomic profiles from the KG1a/stromal cell co-culture system give new molecular insights into the roles of these cells in MDS pathophysiology and related bone disease. Electronic supplementary material The online version of this article (10.1186/s12014-019-9249-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Rui Liu
- 1Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, 710069 Shaanxi China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, Shaanxi China
| | - Bingxin Li
- 1Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, 710069 Shaanxi China
| | - Hui Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, Shaanxi China
| | - Feng Guan
- 1Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, 710069 Shaanxi China
| | - Zengqi Tan
- 1Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, 710069 Shaanxi China
| | - Xiang Li
- 1Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, 229 Taibai North Road, Xi'an, 710069 Shaanxi China.,3Wuxi School of Medicine, Jiangnan University, Wu'xi, China
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Awad AE, Ebrahim MA, Eissa LA, El-Shishtawy MM. Dickkopf-1 and Amphiregulin as Novel Biomarkers and Potential Therapeutic Targets in Hepatocellular Carcinoma. Int J Hematol Oncol Stem Cell Res 2019; 13:153-163. [PMID: 31649806 PMCID: PMC6801323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a highly fatal tumor which represents a major health problem worldwide. Due to asymptomatic nature of HCC, most patients present with the progressive stage of disease, so, unfortunately, there are no effective therapies. Existing techniques for HCC surveillance and diagnosis lack the required accuracy. Therefore, searching for new diagnostic and/or therapeutic tools could improve patient survival. This study aimed to estimate the diagnostic role of Dickkopf-1 (DKK1) and amphiregulin (AREG) and to find out their correlation with different clinicopathological parameters in HCC patients. Materials and Methods: Serum levels of DKK1 and AREG in 55 HCC patients, 20 cirrhotic patients, and 15 healthy subjects as control group were measured using the ELISA technique. Results: Both of DKK1 and AREG showed a significant increase in the HCC group compared to cirrhotic and healthy groups. DKK1 at a cutoff point of 8.92 ng/ml showed that the area under the curve (AUC) was 0.826 with 87.3% sensitivity and 82.9% specificity. DKK1 showed a significant correlation with tumor size, liver dysfunction, and poor performance status in HCC patients. AREG at a cutoff point of 8.74 pg/ml showed a sensitivity of 74.5% but low specificity (47.1%). AREG showed a significant correlation with portal vein thrombosis and tumor metastasis in HCC patients. Conclusion: Serum DKK1 could be a diagnostic biomarker for HCC. Both of DKK1 and AREG may play significant roles in tumor progression and may offer promising therapeutic targets in HCC patients.
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Affiliation(s)
- Abeer E. Awad
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mohamed A. Ebrahim
- Oncology Centre, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Laila A. Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mamdouh M. El-Shishtawy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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Lyros O, Lamprecht AK, Nie L, Thieme R, Götzel K, Gasparri M, Haasler G, Rafiee P, Shaker R, Gockel I. Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett's associated esophageal adenocarcinoma. Am J Cancer Res 2019; 9:330-346. [PMID: 30906632 PMCID: PMC6405970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/24/2018] [Indexed: 06/09/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett's and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC.
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Affiliation(s)
- Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University HospitalLeipzig, Germany
| | - Ann-Kristin Lamprecht
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University HospitalLeipzig, Germany
| | - Linghui Nie
- Division of Gastroenterology and Hepatology, Medical College of WisconsinMilwaukee, Wisconsin, USA
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University HospitalLeipzig, Germany
| | - Katharina Götzel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University HospitalLeipzig, Germany
| | - Mario Gasparri
- Division of Cardiothoracic Surgery, Medical College of WisconsinMilwaukee, Wisconsin, USA
| | - George Haasler
- Division of Cardiothoracic Surgery, Medical College of WisconsinMilwaukee, Wisconsin, USA
| | - Parvaneh Rafiee
- Department of Surgery of Medical College of WisconsinMilwaukee, Wisconsin, USA
| | - Reza Shaker
- Division of Gastroenterology and Hepatology, Medical College of WisconsinMilwaukee, Wisconsin, USA
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University HospitalLeipzig, Germany
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Igbinigie E, Guo F, Jiang SW, Kelley C, Li J. Dkk1 involvement and its potential as a biomarker in pancreatic ductal adenocarcinoma. Clin Chim Acta 2019; 488:226-234. [PMID: 30452897 DOI: 10.1016/j.cca.2018.11.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 11/12/2018] [Accepted: 11/14/2018] [Indexed: 02/05/2023]
Abstract
Dickkopf-1 (Dkk1)'s dysregulation has been implicated in the pathogenesis of a variety of cancers. It is part of the Dkk family of proteins that includes Dkk2, Dkk3 and Dkk4. This family of secreted proteins shares similar conserved cysteine domains and inhibits the Wnt/b-catenin pathway by causing proteasomal B-catenin degradation, inducing apoptosis, and preventing cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer mortality in the United States due to the late stage of diagnosis and the limited effectiveness of current therapy. Dkk1 is found increased in PADC patients' specimens and serum. Dkk1 can be a promising biomarker specific to PDAC, which has the potential to increase PDAC survival rates through improving early stage detection and monitoring progression compared to current biomarker gold standards. In addition, recent studies suggest that Dkk1 could be an excellent target for cancer immunotherapy. Interestingly, Dkk1-CKAP4-PI3K/AKT signal pathway also plays role in pancreatic cancer cell proliferation. In this review, we present the multiple mechanisms of Dkk1 in PDAC studied thus far and explore its function, regulation, and clinical applications in gynecological cancers including pancreatic ductal adenocarcinoma (PDAC), breast, ovarian, cervical, and endometrial cancer. Further research into Dkk1's mechanism and use as a diagnostic tool, alone or in combination with other biomarkers, could prove clinically useful for better understanding the pathology of PDAC and improving its early detection and treatment.
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Affiliation(s)
- Eseosaserea Igbinigie
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Fengbiao Guo
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA; Department of Histology and Embryology, Shantou University Medical College, Shantou 515000, China.
| | - Shi-Wen Jiang
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Cullen Kelley
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Jinping Li
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Florida Campus, Jacksonville, FL 32224, USA.
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Dunn J, Ferluga S, Sharma V, Futschik M, Hilton DA, Adams CL, Lasonder E, Hanemann CO. Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism. EBioMedicine 2018; 40:77-91. [PMID: 30594554 PMCID: PMC6412084 DOI: 10.1016/j.ebiom.2018.12.048] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/20/2018] [Accepted: 12/20/2018] [Indexed: 12/26/2022] Open
Abstract
Background Meningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is hampered by poor knowledge of their proteomic signature. There is an urgent need to identify new therapeutic targets and biomarkers of meningioma. Methods We performed proteomic profiling of grade I, II and III frozen meningioma specimens and three normal healthy human meninges using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. We validated differential expression of proteins and phosphoproteins by Western blot on a meningioma validation set and by immunohistochemistry. Findings We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades and normal meninges. Bioinformatics analysis revealed commonly upregulated proteins and phosphoproteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation studies confirmed significant overexpression of proteins such as EGFR and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation of the total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Novel proteins identified and validated in meningioma included the nuclear proto-oncogene SET, the splicing factor SF2/ASF and the higher-grade specific protein, HK2, involved in cellular metabolism. Interpretation Overall, we generated a proteomic thesaurus of meningiomas for the identification of potential biomarkers and therapeutic targets. Fund This study was supported by Brain Tumour Research.
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Affiliation(s)
- Jemma Dunn
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, John Bull Building, Plymouth Science Park, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - Sara Ferluga
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, John Bull Building, Plymouth Science Park, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - Vikram Sharma
- School of Biomedical Science, Faculty of Medicine and Dentistry, University of Plymouth, Derriford Research Facility, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - Matthias Futschik
- School of Biomedical Science, Faculty of Medicine and Dentistry, University of Plymouth, Derriford Research Facility, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - David A Hilton
- Cellular and Anatomical Pathology, Plymouth Hospitals NHS Trust, Derriford Road, Plymouth PL6 8DH, UK
| | - Claire L Adams
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, John Bull Building, Plymouth Science Park, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - Edwin Lasonder
- School of Biomedical Science, Faculty of Medicine and Dentistry, University of Plymouth, Derriford Research Facility, Research Way, Derriford, Plymouth PL6 8BU, UK
| | - C Oliver Hanemann
- Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, John Bull Building, Plymouth Science Park, Research Way, Derriford, Plymouth PL6 8BU, UK.
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30
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Abstract
Wnt/β-catenin signaling is crucial for adult homeostasis and stem cell maintenance, and its dysregulation is strongly associated to cancer. Upon Wnt binding, Wnt receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The assembly and regulation of these signalosomes remains largely elusive. Here, we use internally tagged Wnt ligands as a tool to isolate and analyze the composition and regulation of endogenous Wnt receptor complexes. We identify a positive regulator of Wnt signaling that facilitates signalosome formation by promoting intramembrane receptor interactions. Our results reveal that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps and involves regulated intramembrane interactions. Wnt/β-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target genes. Upon Wnt binding, the receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The molecular basis of signalosome formation and regulation remains elusive, largely due to the lack of tools to analyze its endogenous components. Here, we use internally tagged Wnt3a proteins to isolate and characterize activated, endogenous Wnt receptor complexes by mass spectrometry-based proteomics. We identify the single-span membrane protein TMEM59 as an interactor of FZD and LRP6 and a positive regulator of Wnt signaling. Mechanistically, TMEM59 promotes the formation of multimeric Wnt–FZD assemblies via intramembrane interactions. Subsequently, these Wnt–FZD–TMEM59 clusters merge with LRP6 to form mature Wnt signalosomes. We conclude that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions.
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31
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Sun CM, Geng J, Yan Y, Yao X, Liu M. Overexpression of CKAP4 is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma and Functions via Cyclin B Signaling. J Cancer 2017; 8:4018-4026. [PMID: 29187877 PMCID: PMC5706004 DOI: 10.7150/jca.21226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 09/29/2017] [Indexed: 11/15/2022] Open
Abstract
Aim: We aimed to study the role of CKAP4 in clear cell renal cell carcinoma (ccRCC), which is not reported previously. Method: In silico exploration and validation using immunohistochemistry in ccRCC samples were used to identify the impact of CKAP4 expression on clinicopathological parameters. In vitro and in vivo studies were carried out to recapitulate the role of CKAP4 in ccRCC cell lines and animal models. Results: Overexpression of CKAP4 occurred in 5% of ccRCC patients, who had significantly worsened prognosis. Increased CKAP4 expression was significantly associated with TNM staging and Fuhrman grade. Pathway analysis for genes coexpressed with CKAP4 in ccRCC unanimously revealed significant cell cycle progression at G2/M phase. Expressions of CCNB1 and CCNB2 were correlated with CKAP4 expression. Genetic upregulation of CKAP4 significantly increased proliferation, cell invasion and migration in ccRCC cell lines, and vice versa for CKAP4 silencing. CKAP4 silencing also significantly increased cell population at G2/M phase, while not influencing cell apoptosis. Silencing or upregulation of CKAP4 resulted in decreased or increased CCNB1/2 expressions, respectively. CCNB1/CDK1 inhibitor significantly inhibited colony formation ability and in vivo tumor growth of RCC cells with CKAP4 overexpression. Conclusion: Upregulation of CKAP4 was associated with worsened characteristics of ccRCC. CKAP4 was related with CCNB signaling in ccRCC, which supported a role for CCNB/CDK inhibitor for ccRCC with such genotype.
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Affiliation(s)
- Chen-Min Sun
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Jiang Geng
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Yang Yan
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Min Liu
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
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Shao YC, Wei Y, Liu JF, Xu XY. The role of Dickkopf family in cancers: from Bench to Bedside. Am J Cancer Res 2017; 7:1754-1768. [PMID: 28979801 PMCID: PMC5622213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 07/24/2017] [Indexed: 06/07/2023] Open
Abstract
Numerous epidemiological studies indicate that cancer will be responsible for millions of deaths in one year. Although multiple therapeutic strategies exist, and vast research efforts are being focused on developing newer and better regimens, cancer-related morbidity and mortality remain high. Metastasis and recurrence are prominent causes of treatment failure in cancers. Moreover, early diagnosis and treatment initiation are difficult to achieve in clinical practice. Fortunately, targeted therapy, which exerts its function at the molecular level, has proved to be greatly beneficial in several human diseases including cancers. The Wnt signaling pathway is a crucial regulator of embryogenesis and development in humans, and its dysfunction has been implicated in the incidence and development of cancers and other diseases. The Dickkopf family (Dkks) is a widely studied Wnt signaling pathway antagonist and plays multiple roles in human physiological and pathological process through both Wnt pathway-dependent and -independent manners. However, the precise roles of Dkks in tumorigenesis and the causal mechanisms have not been clearly elucidated. We discuss the pleiotropic roles of Dkks, with a specific focus on the underlying mechanisms, in cancer biology. We review recent literature to explore the potential use of Dkks as a tumor diagnosis biomarker and therapeutic target.
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Affiliation(s)
- You-Cheng Shao
- Department of Pathophysiology, College of Basic Medical Science, China Medical UniversityShenyang 110122, Liaoning, P. R. China
| | - Yan Wei
- Department of Pathophysiology, College of Basic Medical Science, China Medical UniversityShenyang 110122, Liaoning, P. R. China
| | - Jin-Fang Liu
- Department of Pathophysiology, College of Basic Medical Science, China Medical UniversityShenyang 110122, Liaoning, P. R. China
| | - Xiao-Yan Xu
- Department of Pathophysiology, College of Basic Medical Science, China Medical UniversityShenyang 110122, Liaoning, P. R. China
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