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Zheng S, Wang C, Fu J, Shao J. Investigating Overlapping Immune-related Genetic Markers in Cholangiocarcinoma and Inflammatory Bowel Disease for Predictive Prognosis. J Immunother 2025:00002371-990000000-00142. [PMID: 40384613 DOI: 10.1097/cji.0000000000000562] [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: 02/07/2025] [Accepted: 04/09/2025] [Indexed: 05/20/2025]
Abstract
This study aims to explore the common immune-related gene characteristics of cholangiocarcinoma (CHOL) and inflammatory bowel disease (IBD) to predict disease prognosis. By analyzing the gene expression data from the TCGA, GEO, and NGDC databases, differentially expressed immune-related genes (DE-IRGs) were screened, and a prognostic model was constructed. The results showed that CCR7, OSM, S100P, ACVR1C, OSMR, SPP1, and PIK3R3 were key immune-related genes, and their expressions were closely related to the occurrence and development of CHOL and IBD. Patients in the low immune risk score (IRS) group had more abundant antitumor immune cell infiltration, while those in the high IRS group had more macrophage infiltration. In addition, the model based on these genes had good predictive ability for the diagnosis and prognosis of CHOL and IBD, with an area under the ROC curve (AUC) value exceeding 0.7. This study also predicted potential small molecule drugs that might be effective for the treatment of CHOL, such as Umbralisib and Tamoxifen. In conclusion, this study provides new biomarkers and potential targets for diagnosis, prognosis assessment, and treatment of CHOL and IBD.
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Affiliation(s)
| | | | | | - Jinfan Shao
- Colorectal Surgery, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital
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Porreca V, Corbella E, Palmisano B, Peres M, Angelone P, Barbagallo C, Stella M, Mignogna G, Mennini G, Melandro F, Rossi M, Ragusa M, Corsi A, Riminucci M, Maras B, Mancone C. Pigment Epithelium-Derived Factor Inhibits Cell Motility and p-ERK1/2 Signaling in Intrahepatic Cholangiocarcinoma Cell Lines. BIOLOGY 2025; 14:155. [PMID: 40001923 PMCID: PMC11851717 DOI: 10.3390/biology14020155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/15/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025]
Abstract
Pigment epithelium-derived factor (PEDF) is a multifunctional soluble glycoprotein, primarily known for its potent anti-angiogenic properties. In recent years, its ability to counteract cell proliferation and motility has generated interest in PEDF as a potential tumor suppressor. In the intrahepatic Cholangiocarcinoma (iCCA), PEDF, Thrombospondin 1 (THBS1), and Thrombospondin 2 (THBS2) are expressed and released into the tumor microenvironment (TME), where they promote lymphangiogenesis at the expense of the neoangiogenic program, aiding the dissemination of cancer cells via lymphatic vessels. Recently, we demonstrated that THBS1 and THBS2 directly affect iCCA cells, exacerbating their malignant behavior, while the direct role of PEDF remains to be elucidated. In this study, through a cell-based assay and molecular analysis, we investigate the direct function of PEDF on two well-established iCCA cell lines. Our results show that PEDF affects cancer cell motility in a paracrine manner, reducing their migratory and invasive capabilities. Notably, our data suggest that the PEDF-induced inhibition of motility in iCCA cells occurs through the MAPK/ERK signaling pathway, as indicated by the reduced phosphorylation of ERK1/2. Overall, this study provides the first evidence of PEDF acting as a tumor suppressor in iCCA.
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Affiliation(s)
- Veronica Porreca
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Eleonora Corbella
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Biagio Palmisano
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Marco Peres
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Pietro Angelone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Cristina Barbagallo
- Department of Biomedical and Biotechnological Sciences-Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Michele Stella
- Department of Biomedical and Biotechnological Sciences-Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Giuseppina Mignogna
- Department of Biochemical Science, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Gianluca Mennini
- General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (G.M.); (F.M.); (M.R.)
| | - Fabio Melandro
- General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (G.M.); (F.M.); (M.R.)
| | - Massimo Rossi
- General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (G.M.); (F.M.); (M.R.)
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences-Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
| | - Bruno Maras
- Department of Biochemical Science, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (V.P.); (E.C.); (B.P.); (M.P.); (P.A.); (A.C.); (M.R.)
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Liu L, Niu K, Yang Z, Song J, Wei D, Zhang R, Tao K. Osteopontin: an indispensable component in common liver, pancreatic, and biliary related disease. J Cancer Res Clin Oncol 2024; 150:508. [PMID: 39572438 PMCID: PMC11582231 DOI: 10.1007/s00432-024-06038-0] [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: 09/09/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND The liver, gallbladder, and pancreas constitute a critically important system of digestive and endocrine organs in the human body, performing essential and complex physiological functions. At present, diseases of this digestive system have a high incidence in the world and is a more common disease. However, osteopontin (OPN) plays a crucial role in common liver, pancreatic, and biliary diseases, and its mechanisms of action merit further exploration and study. METHODS We performed an analysis to assess the role of osteopontin in liver, pancreatic, and biliary diseases, focusing on its significance in these conditions. RESULTS Osteopontin, a profoundly phosphorylated glycoprotein, can be utilized as a diagnostic marker for hepatocellular carcinoma and cholangiopathies. Additionally it assists in the treatment of non-alcoholic fatty liver disease and promotes the proliferation, migration, and invasion of pancreatic cancer cells. Furthermore, osteopontin regulates inflammatory responses in chronic pancreatitis. CONCLUSIONS This review offers a thorough analysis of the genetic and protein architecture of OPN, and elucidates the relationship between osteopontin and liver, pancreatic, and biliary diseases. Furthermore, exclusive focus is lavished on the potential utility of OPN as a biomarker and an innovative therapeutic target in the management of these disorder.
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Affiliation(s)
- Lu Liu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhipeng Yang
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Junbo Song
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Dan Wei
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ruohan Zhang
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
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Kustiawan PM, Siregar KAAK, Jauhar MM, Ramadhan D, Mardliyati E, Syaifie PH. Network pharmacology and bioinformatic integrative analysis reveals candidate gene targets and potential therapeutic of East Kalimantan propolis against hepatocellular carcinoma. Heliyon 2024; 10:e39142. [PMID: 39524833 PMCID: PMC11544044 DOI: 10.1016/j.heliyon.2024.e39142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/01/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Hepatocellular Carcinoma (HCC) is commonly treated with surgery, liver transplantation, and chemotherapy, but recurrence and metastasis remain challenges. Natural complementary therapies like propolis, known for its hepatoprotective properties, are gaining interest due to limited efficacy and toxicity of conventional chemotherapy. This study aims to identify core targets for HCC, assess the therapeutic potential of East Kalimantan propolis (EKP) from stingless bees, and analyze the molecular interactions. Methods EKP compounds were analyzed using target prediction tools related to HCC, alongside clinical data from the Gene Expression Omnibus (GEO) database, to identify overlapping genes with clinical relevance. The selected genes were then subjected to protein-protein interaction (PPI), GO and KEGG enrichment, immunohistochemical comparison and survival analysis to identify potential core targets and related pathways for HCC therapy. Furthermore, molecular docking and dynamics were conducted to verify the molecular interactions and stability of EKP compounds with targets. Results 108 genes have been selected as HCC potential targets, which mostly associated with MicroRNAs in cancer, chemical carcinogenesis, and viral carcinogenesis pathways. These targets were obtained by overlapping genes from GEO clinical databases and target predictors. PPI network analysis revealed 4 main targets of propolis in HCC. Furthermore, differential expression genes, survival analysis, and Immunohistochemical analysis from databases suggested that AKR1C3 and MAPK1 promote HCC progression and shorten survival rate of HCC patients. Molecular docking and dynamic studies confirmed strong binding affinity and stability of Baicalein, Chrysin, Quercetin, and Myricetin with receptor targets within simulation time. Conclusions This study provides insight into the mechanism of action of EKP on HCC and identifies AKR1C3 and MAPK1 as candidate target treatments for future drug development.
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Affiliation(s)
- Paula Mariana Kustiawan
- Faculty of Pharmacy, Universitas Muhammadiyah Kalimantan Timur, Samarinda, East Kalimantan, 75124, Indonesia
| | - Khalish Arsy Al Khairy Siregar
- Faculty of Pharmacy, Universitas Muhammadiyah Kalimantan Timur, Samarinda, East Kalimantan, 75124, Indonesia
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, 15314, Indonesia
| | - Muhammad Miftah Jauhar
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, 15314, Indonesia
| | - Donny Ramadhan
- Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Bogor, Indonesia
| | - Etik Mardliyati
- Research Center for Vaccine and Drug, National Research and Innovation Agency (BRIN), Bogor, 16911, Indonesia
| | - Putri Hawa Syaifie
- Center of Excellence Life Sciences, Nano Center Indonesia, South Tangerang, 15314, Indonesia
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Li Z, Yang J, Sun Y, Han S, Gong J, Zhang Y, Feng Z, Yao H, Shi P. Schisandra chinensis Bee Pollen Extract Inhibits Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells via Ferroptosis-, Wnt-, and Focal Adhesion-Signaling Pathways. Drug Des Devel Ther 2024; 18:2745-2760. [PMID: 38974120 PMCID: PMC11227337 DOI: 10.2147/dddt.s461581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/18/2024] [Indexed: 07/09/2024] Open
Abstract
Purpose Bee pollen possesses favorable anticancer activities. As a medicinal plant source, Schisandra chinensis bee pollen (SCBP) possesses potential pharmacological properties, such as reducing cisplatin-induced liver injury, but its anti-liver cancer effect is still rarely reported. This paper aims to investigate the effect and mechanism of SCBP extract (SCBPE) on hepatocellular carcinoma HepG2 cells. Methods The effect of SCBPE on cell proliferation and migration of HepG2 cells was evaluated based on MTT assay, morphology observation, or scratching assay. Furthermore, tandem mass tag-based quantitative proteomics was used to study the effect mechanisms. The mRNA expression levels of identified proteins were verified by RT-qPCR. Results Tandem mass tag-based quantitative proteomics showed that 61 differentially expressed proteins were obtained in the SCBPE group compared with the negative-control group: 18 significantly downregulated and 43 significantly upregulated proteins. Bioinformatic analysis showed the significantly enriched KEGG pathways were predominantly ferroptosis-, Wnt-, and hepatocellular carcinoma-signaling ones. Protein-protein interaction network analysis and RT-qPCR validation revealed SCBPE also downregulated the focal adhesion-signaling pathway, which is abrogated by PF-562271, a well-known inhibitor of FAK. Conclusion This study confirmed SCBPE suppressed the cell proliferation and migration of hepatocellular carcinoma HepG2 cells, mainly through modulation of ferroptosis-, Wnt-, hepatocellular carcinoma-, and focal adhesion-signaling pathways, providing scientific data supporting adjuvant treatment of hepatocellular carcinoma using SCBP.
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Affiliation(s)
- Zhiliang Li
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Jiali Yang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Yang Sun
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Shuo Han
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Jietao Gong
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Yi Zhang
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
- College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Zhiyuan Feng
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China
| | - Peiying Shi
- College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
- State and Local Joint Engineering Laboratory of Natural Biotoxins, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China
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Ruan J, Tian Q, Li S, Zhou X, Sun Q, Wang Y, Xiao Y, Li M, Chang K, Yi X. The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial-mesenchymal transition by phosphorylating β-catenin. Cell Commun Signal 2024; 22:318. [PMID: 38858740 PMCID: PMC11163813 DOI: 10.1186/s12964-024-01683-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/27/2024] [Indexed: 06/12/2024] Open
Abstract
OBJECTIVES Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis. MATERIALS AND METHODS We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/β-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2. RESULTS We observed that ectopic milieu, characterized by ROS, TGF-β1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/β-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or β-catenin with siRNA, and β-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/β-catenin signaling. CONCLUSION Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/β-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs.
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Affiliation(s)
- Jingyao Ruan
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Qi Tian
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Siting Li
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Xiaoyu Zhou
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Qianzhi Sun
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Yuning Wang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China
| | - Yinping Xiao
- Department of Pathology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Kaikai Chang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
| | - Xiaofang Yi
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 419# Fangxie Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
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Cantallops Vilà P, Ravichandra A, Agirre Lizaso A, Perugorria MJ, Affò S. Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2024; 79:941-958. [PMID: 37018128 DOI: 10.1097/hep.0000000000000206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/25/2022] [Indexed: 04/06/2023]
Abstract
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
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Affiliation(s)
| | - Aashreya Ravichandra
- Medical Clinic and Polyclinic II, Klinikum Rechts Der Isar, Technical University Munich, Munich, Germany
| | - Aloña Agirre Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
- CIBERehd, Institute of Health Carlos III, Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Silvia Affò
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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Fu Y, Shen K, Wang H, Wang S, Wang X, Zhu L, Zheng Y, Zou T, Ci H, Dong Q, Qin LX. Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis. Signal Transduct Target Ther 2024; 9:63. [PMID: 38453934 PMCID: PMC10920868 DOI: 10.1038/s41392-024-01761-z] [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: 07/21/2023] [Revised: 01/03/2024] [Accepted: 01/29/2024] [Indexed: 03/09/2024] Open
Abstract
Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3β signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
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Affiliation(s)
- Yan Fu
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, 210009, Nanjing, China
| | - Keyu Shen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Hao Wang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Shun Wang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Xufeng Wang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Le Zhu
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Yan Zheng
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Tiantian Zou
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Hongfei Ci
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China
| | - Qiongzhu Dong
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China.
- Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission, Minhang Hospital, Fudan University, Shanghai, China.
| | - Lun-Xiu Qin
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, 200040, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China.
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9
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Bui KC, Nguyen TML, Barat S, Scholta T, Xing J, Bhuria V, Sipos B, Wilkens L, Nguyen LT, Le HS, Velavan TP, Bozko P, Plentz RR. Novel Adiponectin Receptor Agonist Inhibits Cholangiocarcinoma via Adenosine Monophosphate-activated Protein Kinase. Curr Med Chem 2024; 31:4534-4548. [PMID: 38361349 DOI: 10.2174/0109298673254969231122114107] [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: 03/25/2023] [Revised: 10/06/2023] [Accepted: 10/26/2023] [Indexed: 02/17/2024]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear. OBJECTIVES This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA. METHODS The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues. RESULTS AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05). CONCLUSIONS AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.
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Affiliation(s)
- Khac Cuong Bui
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
- Laboratory Animal Research Center, Vietnam Military Medical University, Hanoi, Vietnam
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
| | - Thi Mai Ly Nguyen
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Department of Biochemistry, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Samarpita Barat
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Tim Scholta
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Jun Xing
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Vikas Bhuria
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention-ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Bence Sipos
- Department of Internal Medicine VIII, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Ludwig Wilkens
- Institute of Pathology, Nordstadt Krankenhaus, Hannover, Germany
| | - Linh Toan Nguyen
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Huu Song Le
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Faculty of Tropical and Infectious Diseases, 108 Military Central Hospital, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Duy Tan University, Da Nang, Vietnam
| | - Przemyslaw Bozko
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Ruben R Plentz
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Department of Internal Medicine, Klinikum Bremen Nord, Bremen, Germany
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10
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Zhang Y, Yan HJ, Wu J. The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of Cholangiocarcinoma. Curr Cancer Drug Targets 2024; 24:681-700. [PMID: 38213139 DOI: 10.2174/0115680096267791231115101107] [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: 06/17/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 01/13/2024]
Abstract
Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.
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Affiliation(s)
- Ye Zhang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
| | - Hai-Jiao Yan
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou, 213003, China
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11
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Zhang Z, Zhu XQ, Yang F, Lai NN, Zhu L, Cole K, Hu BY, Li TE, Zhu Y, Zhang LM, Wang S, Zheng Y, Mao H, Zhao Y, Bruns C, Vago R, Tu B, Wong JWH, Fu DL, Qin LX, Dong QZ. Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma. MED 2023; 4:728-743.e7. [PMID: 37633269 DOI: 10.1016/j.medj.2023.07.010] [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: 10/15/2022] [Revised: 05/08/2023] [Accepted: 07/26/2023] [Indexed: 08/28/2023]
Abstract
BACKGROUND Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive. METHODS Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry. FINDINGS High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103+PD-1+CD39+ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73+ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC. CONCLUSIONS Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy. FUNDING This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.
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Affiliation(s)
- Ze Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiao-Qiang Zhu
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
| | - Feng Yang
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Nan-Nan Lai
- Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China
| | - Le Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Kathryn Cole
- Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu-Min Zhang
- Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Huarong Mao
- Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China
| | - Yue Zhao
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Razi Vago
- Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Bo Tu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Jason W H Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China.
| | - De-Liang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China.
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12
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Yang L, Zhu Z, Zheng Y, Yang J, Liu Y, Shen T, Li M, He H, Huang H, Dai W. RAB6A functions as a critical modulator of the stem-like subsets in cholangiocarcinoma. Mol Carcinog 2023; 62:1460-1473. [PMID: 37278569 DOI: 10.1002/mc.23589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/08/2023] [Accepted: 05/25/2023] [Indexed: 06/07/2023]
Abstract
RAB6A is a member of RAB GTPase family and plays an important role in the targeted transport of neurotrophic receptors and inflammatory cytokines. RAB6A-mediated secretory pathway is involved in many physiological and pathological processes. Defects in RAB6A-mediated secretory pathway may lead to the development of many diseases, including cancer. However, its role in cholangiocarcinoma (CCA) has not yet been revealed. We explored the regulatory role of RAB6A in the stem-like subsets of CCA. We showed that RAB6A knockdown (KD) impedes cancer stem cells (CSCs) properties and epithelial-mesenchymal transition in vitro and that suppression of RAB6A inhibits tumor growth in vivo. We screened target cargos of RAB6A in CCA cells and identified a extracellular matrix component as the target cargo. RAB6A binds directly to OPN, and RAB6A KD suppressed OPN secretion and inhibited the interaction between OPN and αV integrin receptor. Moreover, RAB6A KD inhibited the AKT signaling pathway, which is a downstream effector of the integrin receptor signaling. In addition, shRNA targeting OPN blocked endogenous expression of OPN and consequently weakened CSCs properties in RAB6A-formed spheres. Similarly, inhibitor of AKT signaling, MK2206 also impedes oncogenic function of RAB6A in the stem-like subsets of CCA cells. In conclusion, our findings showed that RAB6A sustains CSCs phenotype maintenance by modulating the secretion of OPN and consequentially activating the downstream AKT signaling pathway. Targeting the RAB6A/OPN axis may be an effective strategy for CCA therapy.
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Affiliation(s)
- Liangfang Yang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhiwen Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yang Zheng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaqi Yang
- Institution of Plastic Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yuxin Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tingyun Shen
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Mingyi Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Huijuan He
- Clinical Research Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Haili Huang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Institution of Plastic Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wei Dai
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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13
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Xuan Z, Liu L, Zhang G, Zheng X, Jiang J, Wang K, Huang P. Novel cell subtypes of SPP1 + S100P+, MS4A1-SPP1 + S100P+ were key subpopulations in intrahepatic cholangiocarcinoma. Biochim Biophys Acta Gen Subj 2023; 1867:130420. [PMID: 37433400 DOI: 10.1016/j.bbagen.2023.130420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/25/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023]
Abstract
BACKGROUND In this study, we integrated single-cell RNA sequencing (scRNA-seq) data to investigate cell heterogeneity and utilized MSigDB and CIBERSORTx to explore the pathways of major cell types and the relationships between different cell subtypes. Subsequently, we explored the correlation of cell subtypes with survival and used Gene Set Enrichment Analysis (GSEA) analyses to assess the pathways associated with the infiltration of specific cell subtypes. Finally, multiplex immunohistochemistry in tissue microarray cohort were performed to validate differences in protein level and their correlation with survival. RESULTS iCCA presented a unique immune ecosystem, with increased proportions of Epi (epithelial)-SPP1-2, Epi-S100P-1, Epi-DN (double negative for SPP1 and S100P expression)-1, Epi-DN-2, Epi-DP (double positive for SPP1 and S100P expression)-1, Plasma B-3, Plasma B-2, B-HSPA1A-1, B-HSPA1A-2 cells, and decreased proportions of B-MS4A1. High level of Epi-DN-2, Epi-SPP1-1, Epi-SPP1-2, B-MS4A1, and low level of Epi-DB-1, Epi-S100P-1, and Epi-S100P-2 was significantly associated with longer overall survival (OS), and high level of B-MS4A1_Low_Epi-DN-2_Low was associated with the shortest OS. Moreover, the results of MsigDB and GSEA suggest that bile acid metabolism is a crucial process in iCCA. Finally, we found that S100P+, SPP1+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ were highly expressed, whereas MS4A1 was lowly expressed in iCCA, and patients with high level of S100P+, SPP1 + S100P+, and MS4A1-SPP1 + S100P+ exhibited shorter survival. CONCLUSIONS We identified the cell heterogeneity of iCCA, found that iCCA is a unique immune ecosystem with many cell subtypes, and showed that the novel cell subtypes of SPP1 + S100P+ and MS4A1-SPP1 + S100P+ were key subpopulations in iCCA.
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Affiliation(s)
- Zixue Xuan
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Linqing Liu
- International Medical Department, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Guobing Zhang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xiaowei Zheng
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jinying Jiang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Kai Wang
- Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China.
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
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14
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Zheng Y, Zhu L, Qin ZY, Guo Y, Wang S, Xue M, Shen KY, Hu BY, Wang XF, Wang CQ, Qin LX, Dong QZ. Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression. Cell Rep 2023; 42:112666. [PMID: 37347667 DOI: 10.1016/j.celrep.2023.112666] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 02/10/2023] [Accepted: 06/05/2023] [Indexed: 06/24/2023] Open
Abstract
Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.
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Affiliation(s)
- Yan Zheng
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Le Zhu
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission, Minhang Hospital, Fudan University, Shanghai, China
| | - Zhao-Yu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Yu Guo
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Min Xue
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Ke-Yu Shen
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Xu-Feng Wang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Chao-Qun Wang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission, Minhang Hospital, Fudan University, Shanghai, China.
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15
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Caligiuri A, Parola M, Marra F, Cannito S, Gentilini A. Cholangiocarcinoma tumor microenvironment highlighting fibrosis and matrix components. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Cholangiocarcinoma (CCA) is an extremely aggressive malignancy characterized by a very limited prognosis and scarce treatment options. The majority of patients are diagnosed at an advanced stage and do not qualify for potentially curative surgical treatments, making CCA an increasingly prevalent global challenge. CCA is characterized by a highly reactive desmoplastic stroma, with complex mechanisms underlying the mutual interactions between tumor cells and stromal compartment. This review focuses on the recent studies examining CCA’s biological features, with particular reference to the tumor reactive stroma (TRS) and its role in CCA progression, including matrix remodeling, angiogenesis and lymphangiogenesis, metastasis, and immune evasion. After giving a panoramic view of the relationship between the tumoral and stromal compartment (cancer-associated fibroblast, CAFs and tumor-associated macrophages, TAMs), this review also discusses the current therapeutic approaches to counteract CAFs and TAMs effects on CCA progression.
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16
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Golub A, Ordak M, Nasierowski T, Bujalska-Zadrozny M. Advanced Biomarkers of Hepatotoxicity in Psychiatry: A Narrative Review and Recommendations for New Psychoactive Substances. Int J Mol Sci 2023; 24:ijms24119413. [PMID: 37298365 DOI: 10.3390/ijms24119413] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
One of the factors that increase the effectiveness of the pharmacotherapy used in patients abusing various types of new psychoactive substances (NPSs) is the proper functioning of the liver. However, the articles published to date on NPS hepatotoxicity only address non-specific hepatic parameters. The aim of this manuscript was to review three advanced markers of hepatotoxicity in psychiatry, namely, osteopontin (OPN), high-mobility group box 1 protein (HMGB1) and glutathione dehydrogenase (GDH, GLDH), and, on this basis, to identify recommendations that should be included in future studies in patients abusing NPSs. This will make it possible to determine whether NPSs do indeed have a hepatotoxic effect or whether other factors, such as additional substances taken or hepatitis C virus (HCV) infection, are responsible. NPS abusers are at particular risk of HCV infection, and for this reason, it is all the more important to determine what factors actually show a hepatotoxic effect in them.
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Affiliation(s)
- Aniela Golub
- Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
| | - Michal Ordak
- Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
| | - Tadeusz Nasierowski
- Department of Psychiatry, Faculty of Pharmacy, Medical University of Warsaw, Nowowiejska 27 Str., 00-665 Warsaw, Poland
| | - Magdalena Bujalska-Zadrozny
- Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
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17
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Keenan BP, McCarthy EE, Ilano A, Yang H, Zhang L, Allaire K, Fan Z, Li T, Lee DS, Sun Y, Cheung A, Luong D, Chang H, Chen B, Marquez J, Sheldon B, Kelley RK, Ye CJ, Fong L. Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis. Cell Rep 2022; 40:111384. [PMID: 36130508 PMCID: PMC10060099 DOI: 10.1016/j.celrep.2022.111384] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/20/2022] [Accepted: 08/29/2022] [Indexed: 01/17/2023] Open
Abstract
Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14+ monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14CTX) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14CTX can directly suppress CD4+ T cells and induce SOCS3 expression in CD4+ T cells, rendering them functionally unresponsive. The CD14CTX gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance.
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Affiliation(s)
- Bridget P Keenan
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Elizabeth E McCarthy
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA
| | - Arielle Ilano
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Hai Yang
- Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Li Zhang
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Kathryn Allaire
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Zenghua Fan
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Tony Li
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - David S Lee
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Yang Sun
- Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Alexander Cheung
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Diamond Luong
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Hewitt Chang
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Brandon Chen
- Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Jaqueline Marquez
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA
| | - Brenna Sheldon
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Robin K Kelley
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Chun Jimmie Ye
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; J. David Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
| | - Lawrence Fong
- Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
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18
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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19
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Param NJ, Bramel ER, Sia D. The Molecular Pathogenesis and Targeted Therapies for Cholangiocarcinoma. Surg Pathol Clin 2022; 15:529-539. [PMID: 36049834 DOI: 10.1016/j.path.2022.05.006] [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] [Indexed: 06/15/2023]
Abstract
Cholangiocarcinoma (CCA) is a group of malignancies of the bile ducts with high mortality rates and limited treatment options. In the past decades, remarkable efforts have been dedicated toward elucidating the specific molecular signaling pathways and oncogenic loops driving cholangiocarcinogenesis to ultimately develop more effective therapies. Despite some recent advances, an extensive intra- and inter-tumor heterogeneity together with a poorly understood immunosuppressive microenvironment significantly compromises the efficacy of available treatments. Here, we provide a concise review of the latest advances and current knowledge of the molecular pathogenesis of CCA focusing on clinically relevant aberrations as well as future research avenues.
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Affiliation(s)
- Nesteene Joy Param
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA
| | - Emily R Bramel
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA
| | - Daniela Sia
- Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, 11th Floor Room 70-E, New York, NY 10029, USA.
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20
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Macias RIR, Cardinale V, Kendall TJ, Avila MA, Guido M, Coulouarn C, Braconi C, Frampton AE, Bridgewater J, Overi D, Pereira SP, Rengo M, Kather JN, Lamarca A, Pedica F, Forner A, Valle JW, Gaudio E, Alvaro D, Banales JM, Carpino G. Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions. Gut 2022; 71:1669-1683. [PMID: 35580963 DOI: 10.1136/gutjnl-2022-327099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.
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Affiliation(s)
- Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) group, University of Salamanca, IBSAL, Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Matias A Avila
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Maria Guido
- Department of Medicine - DIMED, University of Padua, Padua, Italy
| | - Cedric Coulouarn
- UMR_S 1242, COSS, Centre de Lutte contre le Cancer Eugène Marquis, INSERM University of Rennes 1, Rennes, France
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Adam E Frampton
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford, Surrey, UK
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Stephen P Pereira
- Institute for Liver & Digestive Health, University College London, London, UK
| | - Marco Rengo
- Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy
| | - Jakob N Kather
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Angela Lamarca
- Medical Oncology/Institute of Cancer Sciences, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Alejandro Forner
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- BCLC group, Liver Unit, Hospital Clínic Barcelona. IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Juan W Valle
- Medical Oncology/Institute of Cancer Sciences, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Jesus M Banales
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
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21
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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22
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Umapathy D, Karthikeyan MC, Ponnuchamy K, Kannan MK, Ganeshan M, Arockiam AJV. The absence of cellular glucose triggers oncogene AEG-1 that instigates VEGFC in HCC: A possible genetic root cause of angiogenesis. Gene X 2022; 826:146446. [PMID: 35337853 DOI: 10.1016/j.gene.2022.146446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 03/02/2022] [Accepted: 03/18/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Astrocyte Elevated Gene-1 (AEG-1) is the master and multi-regulator of the various transcriptional factor primarily regulating chemoresistance, angiogenesis, metastasis, and invasion under the pathological condition, including liver cancer. This study was focused on investigating the process of tumor angiogenesis in liver carcinoma by studying the role of AEG-1 under GD/2DG conditions. METHOD AND RESULTS The PCR and western blot analysis revealed that glucose depletion (GD) induces the overexpression of AEG-1. Further, it leads to the constant expression of VEGFC through the activation of HIF-1α/CCR7 via the stimulations of PI3K/Akt signaling pathways. GLUT2 is the major transporter of a glucose molecule that is highly participating under GD through the expression of AEG-1 and constantly expresses glucokinase (GCK). The obtained data suggest that AEG-1 act as an angiogenesis and glycolysis regulator by modulating the expression of GCK through HIF-1α and GLUT2. 2-deoxy-D-glucose (2DG) is a glycolysis inhibitor that induces impaired glycolysis and cellular apoptosis by cellular oxidative stress. The administration of 2DG has led to the chemoresistance of AEG-1. CONCLUSION The total findings of the study judged that disruption of cellular energy metabolism induced by the absence of glucose or the presence of mutant glucose moiety (2DG) promotes the overexpression of AEG-1. The GD/2DG activates the VEGFC by inducing the HIF-1α and CCR7. Moreover, AEG-1 induces the expression of OPN, which regulates metastasis, angiogenesis, and actively participates in protective autophagy by promoting LC3 a/b.
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Affiliation(s)
- Devan Umapathy
- Department of Biochemistry, Molecular Oncology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Mano Chitra Karthikeyan
- Department of Biochemistry, Molecular Oncology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Kumar Ponnuchamy
- Department of Animal Health and Management, Food Chemistry and Molecular Cancer Biology Laboratory, Alagappa University, Karaikudi 630 003, Tamil Nadu, India
| | - Mahesh Kumar Kannan
- Department of Biochemistry, Molecular Oncology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Mathan Ganeshan
- Cancer Biology Laboratory, Department of Biomedical Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Antony Joseph Velanganni Arockiam
- Department of Biochemistry, Molecular Oncology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India.
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23
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Song G, Shi Y, Meng L, Ma J, Huang S, Zhang J, Wu Y, Li J, Lin Y, Yang S, Rao D, Cheng Y, Lin J, Ji S, Liu Y, Jiang S, Wang X, Zhang S, Ke A, Wang X, Cao Y, Ji Y, Zhou J, Fan J, Zhang X, Xi R, Gao Q. Single-cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma. Nat Commun 2022; 13:1642. [PMID: 35347134 PMCID: PMC8960779 DOI: 10.1038/s41467-022-29164-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1- iCCAphl has significantly reduced levels of infiltrating CD4+ T cells, CD56+ NK cells, and increased CCL18+ macrophages and PD1+CD8+ T cells compared to S100P-SPP1 + iCCApps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCApps has significantly more SPP1+ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1- iCCAphl. Moreover, S100P-SPP1 + iCCApps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.
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Affiliation(s)
- Guohe Song
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yang Shi
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China
| | - Lu Meng
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Jiaqiang Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Siyuan Huang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Juan Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yingcheng Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Jiaxin Li
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Youpei Lin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Shuaixi Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Dongning Rao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yifei Cheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Jian Lin
- Department of Cancer Center, Jin Shan Hospital, Fudan University, Shanghai, China
| | - Shuyi Ji
- Department of Cancer Center, Jin Shan Hospital, Fudan University, Shanghai, China
| | - Yuming Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Shan Jiang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoliang Wang
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Aiwu Ke
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Xiaoying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Xiaoming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
| | - Ruibin Xi
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
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24
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Baj J, Bryliński Ł, Woliński F, Granat M, Kostelecka K, Duda P, Flieger J, Teresiński G, Buszewicz G, Furtak-Niczyporuk M, Portincasa P. Biomarkers and Genetic Markers of Hepatocellular Carcinoma and Cholangiocarcinoma-What Do We Already Know. Cancers (Basel) 2022; 14:1493. [PMID: 35326644 PMCID: PMC8946081 DOI: 10.3390/cancers14061493] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an increasing worldwide mortality rate. Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In both types of cancers, early detection is very important. Biomarkers are a relevant part of diagnosis, enabling non-invasive detection and control of cancer recurrence, as well as in the application of screening tests in high-risk groups. Furthermore, some of these biomarkers are useful in controlling therapy and treatment selection. Detection of some markers presents higher sensitivity and specificity in combination with other markers when compared with a single detection. Some gene aberrations are also prognostic markers in the two types of cancers. In the following review, we discuss the most common biomarkers and genetic markers currently being used in the diagnosis of hepatocellular carcinoma and cholangiocarcinoma.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Łukasz Bryliński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Filip Woliński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Michał Granat
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Katarzyna Kostelecka
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Piotr Duda
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Grzegorz Teresiński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | | | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
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25
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Wu Q, Xuan YF, Su AL, Bao XB, Miao ZH, Wang YQ. TNKS inhibitors potentiate proliferative inhibition of BET inhibitors via reducing β-Catenin in colorectal cancer cells. Am J Cancer Res 2022; 12:1069-1087. [PMID: 35411247 PMCID: PMC8984892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/16/2022] [Indexed: 06/14/2023] Open
Abstract
Colorectal cancer (CRC) is an aggressive malignancy with limited options for treatment. Targeting the bromodomain and extra terminal domain (BET) proteins by using BET inhibitors (BETis) could effectively interrupt the interaction with acetylated histones, inhibit genes transcription and have shown a certain effect on CRC inhibition. To improve the efficacy, the inhibitors of Tankyrases, which cause accumulation of AXIN through dePARsylation, in turn facilitate the degradation of β-Catenin and suppress the growth of adenomatous polyposis coli (APC)-mutated CRCs, were tested together with BETi as a combination treatment. We examined the effects of BETi and Tankyrases inhibitor (TNKSi) together on the proliferation, cell cycle and apoptosis of human CRCs cell lines with APC or CTNNB1 mutation, and elucidated the underlying molecular mechanisms affected by the double treatment. The result showed that the TNKSi could sensitize all tested CRC cell lines to BETi, and the synergistic effect was not only seen in cell proliferation inhibition, but also confirmed in decreased colony-forming ability and weaken EdU incorporation compared with monotherapy. Combined treatment resulted in enhanced G1 cell cycle arrest and increased apoptosis. In addition, we found β-Catenin was potentially inhibited by the combination and revealed that both BETi-induced transcriptional inhibition and TNKSi-mediated protein degradation all reduced the β-Catenin accumulation. In all, the synergistic effects suggest that combination of BETi and TNKSi could provide novel treatment opportunities for CRC, but both TNKSi and combination strategy need to be optimized.
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Affiliation(s)
- Qian Wu
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, China
| | - Yi-Fei Xuan
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, China
| | - Ai-Ling Su
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, China
| | - Xu-Bin Bao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
| | - Ze-Hong Miao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, China
| | - Ying-Qing Wang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences501 Haike Road, Shanghai 201203, China
- University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, China
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26
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Chatterjee A, Paul S, Bisht B, Bhattacharya S, Sivasubramaniam S, Paul MK. Advances in targeting the WNT/β-catenin signaling pathway in cancer. Drug Discov Today 2022; 27:82-101. [PMID: 34252612 DOI: 10.1016/j.drudis.2021.07.007] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/27/2021] [Accepted: 07/06/2021] [Indexed: 01/05/2023]
Abstract
WNT/β-catenin signaling orchestrates various physiological processes, including embryonic development, growth, tissue homeostasis, and regeneration. Abnormal WNT/β-catenin signaling is associated with various cancers and its inhibition has shown effective antitumor responses. In this review, we discuss the pathway, potential targets for the development of WNT/β-catenin inhibitors, available inhibitors, and their specific molecular interactions with the target proteins. We also discuss inhibitors that are in clinical trials and describe potential new avenues for therapeutically targeting the WNT/β-catenin pathway. Furthermore, we introduce emerging strategies, including artificial intelligence (AI)-assisted tools and technology-based actionable approaches, to translate WNT/β-catenin inhibitors to the clinic for cancer therapy.
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Affiliation(s)
- Avradip Chatterjee
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sayan Paul
- Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012, India; Centre for Cardiovascular Biology and Disease, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India
| | - Bharti Bisht
- Department of Thoracic Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
| | - Shelley Bhattacharya
- Environmental Toxicology Laboratory, Department of Zoology (Centre for Advanced Studies), Visva Bharati (A Central University), Santiniketan 731235, India
| | - Sudhakar Sivasubramaniam
- Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012, India
| | - Manash K Paul
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
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27
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Matricellular proteins in intrahepatic cholangiocarcinoma. Adv Cancer Res 2022; 156:249-281. [DOI: 10.1016/bs.acr.2022.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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28
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Dabravolski SA, Bezsonov EE, Orekhov AN. The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression. Biomed Pharmacother 2021; 142:112041. [PMID: 34411916 DOI: 10.1016/j.biopha.2021.112041] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023] Open
Abstract
Senescence is a crucial player in several metabolic disorders and chronic inflammatory diseases. Recent data prove the involvement of hepatocyte senescence in the development of NAFLD (non-alcoholic fatty liver disease). As the main energy and ROS (reactive oxygen species) producing organelle, mitochondria play the central role in accelerated senescence and diseases development. In this review, we focus on the role of regulation of mitochondrial Ca2+ homeostasis, NAD+/NADH ratio, UPRmt (mitochondrial unfolded protein response), phospholipids and fatty acid oxidation in hepatic senescence, lifespan and NAFLD disease susceptibility. Additionally, the involvement of mitochondrial and nuclear mutations in lifespan-modulation and NAFLD development is discussed. While nuclear and mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) can be used as effective diagnostic markers and targets for treatments, advanced age should be considered as an independent risk factor for NAFLD development.
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Affiliation(s)
- Siarhei A Dabravolski
- Department of Clinical Diagnostics, Vitebsk State Academy of Veterinary Medicine [UO VGAVM], 7/11 Dovatora str., 210026 Vitebsk, Belarus.
| | - Evgeny E Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.
| | - Alexander N Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia; Laboratory of Angiopathology, The Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia; Department of Basic Research, Institute for Atherosclerosis Research, Moscow 121609, Russia.
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29
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Zhou M, Wang C, Lu S, Xu Y, Li Z, Jiang H, Ma Y. Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target. EBioMedicine 2021; 67:103375. [PMID: 33993051 PMCID: PMC8134032 DOI: 10.1016/j.ebiom.2021.103375] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/21/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and activated in the CCA microenvironment, especially at the tumor invasive front and perivascular sites. TAMs create a favorable environment that benefits CCA growth by closely interacting with CCA cells and other stromal cells via releasing multiple protumor factors. In addition, TAMs exert immunosuppressive and antichemotherapeutic effects, thus intensifying the malignancy. Targeting TAMs may provide an improved understanding of, and novel therapeutic approaches for, CCA. This review focuses on revealing the interplay between TAMs and CCA.
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Affiliation(s)
- Menghua Zhou
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Chaoqun Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Shounan Lu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Yanan Xu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zihao Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Hongchi Jiang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
| | - Yong Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
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30
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Wang L, Liu D, Wei J, Yuan L, Zhao S, Huang Y, Ma J, Yang Z. MiR-543 Inhibits the Migration and Epithelial-To-Mesenchymal Transition of TGF-β-Treated Endometrial Stromal Cells via the MAPK and Wnt/β-Catenin Signaling Pathways. Pathol Oncol Res 2021; 27:1609761. [PMID: 34257616 PMCID: PMC8262167 DOI: 10.3389/pore.2021.1609761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/07/2021] [Indexed: 11/13/2022]
Abstract
Intrauterine adhesion (IUA) is one of the most prevalent reproductive system diseases in females. MicroRNAs (miRNAs) are reported to be master regulators in a variety of diseases, including IUA, but the role of microRNA-543 (miR-543) in IUA remains to be elucidated. In this study, we observed that miR-543 was downregulated in transforming growth factor-beta (TGF-β)-treated endometrial stromal cells (ESCs). Functionally, we observed that miR-543 suppressed the migration, epithelial-to-mesenchymal transition (EMT), and inhibited expression of extracellular matrix (ECM) proteins in TGF-β-treated ESCs. Mechanistically, MAPK1 is targeted by miR-543 after prediction and screening. A luciferase reporter assay demonstrated that miR-543 complementarily binds with the 3' untranslated region of mitogen-activated protein kinase 1 (MAPK1), and western blot analysis indicated that miR-543 negatively regulates MAPK1 protein levels. In addition, results from rescue assays showed that miR-543 inhibits the migration and EMT of TGF-β-treated ESCs by targeting MAPK1. In addition, we observed that miR-543 inactivates the Wnt/β-catenin signaling pathway through inhibiting the phosphorylation of MAPK1 and β-catenin. Finally, we confirmed that miR-543 represses migration, EMT and inhibits levels of ECM proteins in TGF-β-treated ESCs by targeting the Wnt/β-catenin signaling pathway. Our results demonstrated that miR-543 suppresses migration and EMT of TGF-β-treated ESCs by targeting the MAPK and Wnt/β-catenin pathways.
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Affiliation(s)
- Linlin Wang
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China.,Medical Experimental Center, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Dan Liu
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China.,Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China.,Key Laboratory of Ministry of Education for Fertility Preservation and Maintenance, Ningxia Medical University, Yinchuan, China
| | - Jun Wei
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Liwei Yuan
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China.,Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Shiyun Zhao
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China.,Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yani Huang
- College of Clinical Medicine, Ningxia Medical University, Yinchuan, China.,Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Jingwen Ma
- Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Zhijuan Yang
- Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, China
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31
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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma. Vaccines (Basel) 2021; 9:vaccines9050422. [PMID: 33922362 PMCID: PMC8146949 DOI: 10.3390/vaccines9050422] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
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32
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Song Z, Chen W, Athavale D, Ge X, Desert R, Das S, Han H, Nieto N. Osteopontin Takes Center Stage in Chronic Liver Disease. Hepatology 2021; 73:1594-1608. [PMID: 32986864 PMCID: PMC8106357 DOI: 10.1002/hep.31582] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022]
Abstract
Osteopontin (OPN) was first identified in 1986. The prefix osteo- means bone; however, OPN is expressed in other tissues, including liver. The suffix -pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well-established physiological roles, multiple "omics" analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non-alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.
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Affiliation(s)
- Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL,Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL
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33
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Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis. Oncogene 2021; 40:2910-2922. [PMID: 33742120 DOI: 10.1038/s41388-021-01705-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/26/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.
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34
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Tokuda K, Morine Y, Miyazaki K, Yamada S, Saito Y, Nishi M, Tokunaga T, Ikemoto T, Imura S, Shimada M. The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma. Oncotarget 2021; 12:333-343. [PMID: 33659044 PMCID: PMC7899554 DOI: 10.18632/oncotarget.27881] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cancer-tumor associated macrophage (TAM)-cancer associated fibroblast (CAF) interactions are an important factor in the tumor microenvironment of hepatocellular carcinoma. MATERIALS AND METHODS Hepatic stellate cells (HSCs) were cultured with cancer cell-conditioned medium (Ca.-CM), TAM-CM and CAF-CM, and the expression of CAF markers were evaluated by RT-PCR. Whether HSCs cultured with Ca.-CM, TAM-CM and CAF-CM contributed to the enhanced malignancy of cancer cells was examined using proliferation, invasion and migration assays. Furthermore, the differences between these three types of CM were evaluated using cytokine arrays. RESULTS HSCs cultured with Ca.-CM, TAM-CM and CAF-CM showed significantly increased mRNA expression of αSMA, FAP and IL-6. All HSCs cultured with each CM exhibited significantly increased proliferation, invasion and migration of cancer cells. The osteopontin concentration was significantly higher in HSCs cultured with TAM-CM than the other CAF-CMs. Osteopontin inhibition significantly reduced osteopontin secretion from HSCs cultured with TAM-CM and suppressed the proliferation and invasion of cancer cells enhanced by HSCs cultured with TAM-CM. CONCLUSIONS We observed enhanced osteopontin secretion from TAMs, and this increased osteopontin further promoted osteopontin secretion from HSCs cultured with TAM-CM, leading to increased malignancy. For the first time, we demonstrated the importance of cancer-TAM-CAF interactions via osteopontin in hepatocellular carcinoma.
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Affiliation(s)
- Kazunori Tokuda
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Katsuki Miyazaki
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Shinichiro Yamada
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yu Saito
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Masaaki Nishi
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Takuya Tokunaga
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Satoru Imura
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
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35
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Chen Z, Lin T, Liao X, Li Z, Lin R, Qi X, Chen G, Sun L, Lin L. Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma. Chin Med 2021; 16:13. [PMID: 33478536 PMCID: PMC7818939 DOI: 10.1186/s13020-021-00423-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Background Cholangiocarcinoma refers to an epithelial cell malignancy with poor prognosis. Yinchenhao decoction (YCHD) showed positive effects on cancers, and associations between YCHD and cholangiocarcinoma remain unclear. This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma. Methods By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC50 values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods. Results 32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC50 values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions. Conclusions As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effectsthrough multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.
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Affiliation(s)
- Zhiqiang Chen
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Tong Lin
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Xiaozhong Liao
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Zeyun Li
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Ruiting Lin
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Xiangjun Qi
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Guoming Chen
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese Medicine, 510405, Guangzhou, China
| | - Lingling Sun
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Jichang Road, Baiyun District, 510405, Guangzhou, China
| | - Lizhu Lin
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Jichang Road, Baiyun District, 510405, Guangzhou, China.
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Fabris L, Sato K, Alpini G, Strazzabosco M. The Tumor Microenvironment in Cholangiocarcinoma Progression. Hepatology 2021; 73 Suppl 1:75-85. [PMID: 32500550 PMCID: PMC7714713 DOI: 10.1002/hep.31410] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/07/2020] [Accepted: 05/16/2020] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree. A typical hallmark of CCA is that cancer cells are embedded into a dense stroma containing fibrogenic cells, lymphatics and a variety of immune cells. Functional roles of the reactive tumor stroma are not fully elucidated; however, recent studies suggest that the tumor microenvironment plays a key role in the progression and invasiveness of CCA. CCA cells exchange autocrine/paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment. This crosstalk is under the control of signals mediated by various cytokines, chemokines, and growth factors. In addition, extracellular vesicles (EVs), exosomes and microvesicles, containing cargo mediators, such as proteins and RNAs, play a key role in cell-to-cell communication, and particularly in epigenetic regulation thanks to their content in miRNAs. Both cytokine- and EV-mediated communications between CCA cells and other liver cells provide a potential novel target for the management of CCA. This review summarizes current understandings of the tumor microenvironment and intercellular communications in CCA and their role in tumor progression.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy,Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Keisaku Sato
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT,Correspondence: Mario Strazzabosco MD, PhD, Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA,
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Gómez‐Santos B, Saenz de Urturi D, Nuñez‐García M, Gonzalez‐Romero F, Buque X, Aurrekoetxea I, Gutiérrez de Juan V, Gonzalez‐Rellan MJ, García‐Monzón C, González‐Rodríguez Á, Mosteiro L, Errazti G, Mifsut P, Gaztambide S, Castaño L, Martin C, Nogueiras R, Martinez‐Chantar ML, Syn W, Aspichueta P. Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease. Aging Cell 2020; 19:e13183. [PMID: 32638492 PMCID: PMC7431823 DOI: 10.1111/acel.13183] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 04/14/2020] [Accepted: 06/06/2020] [Indexed: 12/17/2022] Open
Abstract
Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of age-related hepatosteatosis.
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Affiliation(s)
- Beatriz Gómez‐Santos
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Diego Saenz de Urturi
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Maitane Nuñez‐García
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Francisco Gonzalez‐Romero
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Xabier Buque
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Igor Aurrekoetxea
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Virginia Gutiérrez de Juan
- Liver Disease Lab, Center for Cooperative Research in Bioscience (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) e Derio Bizkaia Spain
| | - Maria J. Gonzalez‐Rellan
- Department of Physiology CIMUS University of Santiago de Compostela‐Instituto de Investigación Sanitaria Santiago de Compostela Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) Madrid Spain
| | - Carmelo García‐Monzón
- Liver Research Unit Santa Cristina University Hospital Instituto de Investigación Sanitaria Princesa Madrid Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Águeda González‐Rodríguez
- Liver Research Unit Santa Cristina University Hospital Instituto de Investigación Sanitaria Princesa Madrid Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Lorena Mosteiro
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Gaizka Errazti
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Patricia Mifsut
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Sonia Gaztambide
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Luis Castaño
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Cesar Martin
- Department of Biochemistry and Molecular Biology Biofisika Institute (UPV/EHU, CSIC) UPV/EHU Spain
| | - Rubén Nogueiras
- Department of Physiology CIMUS University of Santiago de Compostela‐Instituto de Investigación Sanitaria Santiago de Compostela Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) Madrid Spain
| | - María L. Martinez‐Chantar
- Liver Disease Lab, Center for Cooperative Research in Bioscience (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) e Derio Bizkaia Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Wing‐Kin Syn
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Section of Gastroenterology Ralph H Johnson VAMC Charleston SC USA
- Division of Gastroenterology and Hepatology Medical University of South Carolina Charleston SC USA
| | - Patricia Aspichueta
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
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Fabris L, Cadamuro M, Cagnin S, Strazzabosco M, Gores GJ. Liver Matrix in Benign and Malignant Biliary Tract Disease. Semin Liver Dis 2020; 40:282-297. [PMID: 32162285 DOI: 10.1055/s-0040-1705109] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the "desmoplastic matrix" of cholangiocarcinoma along with their pro-oncogenic effects.
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Affiliation(s)
- Luca Fabris
- Department of Molecular Medicine, University of Padua, Padua, Italy.,Liver Center, Department of Medicine, Yale University, New Haven, Connecticut
| | | | - Silvia Cagnin
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, Connecticut
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Michigan
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Zhang B, Zhou BH, Xiao M, Li H, Guo L, Wang MX, Yu SH, Ye QH. KDM5C Represses FASN-Mediated Lipid Metabolism to Exert Tumor Suppressor Activity in Intrahepatic Cholangiocarcinoma. Front Oncol 2020; 10:1025. [PMID: 32714863 PMCID: PMC7344276 DOI: 10.3389/fonc.2020.01025] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/22/2020] [Indexed: 01/03/2023] Open
Abstract
Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown. Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C. Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells. Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.
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Affiliation(s)
- Bo Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Bing-Hai Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Min Xiao
- Shanghai Ji Ai Genetics and IVF Institute, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Lei Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
| | - Meng-Xi Wang
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shan-He Yu
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing-Hai Ye
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
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40
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Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts. Br J Cancer 2020; 122:986-994. [PMID: 32015511 PMCID: PMC7109053 DOI: 10.1038/s41416-020-0744-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/15/2020] [Indexed: 12/11/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis. Methods We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo. Results CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups. Conclusions Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.
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Zhang Z, Li TE, Chen M, Xu D, Zhu Y, Hu BY, Lin ZF, Pan JJ, Wang X, Wu C, Zheng Y, Lu L, Jia HL, Gao S, Dong QZ, Qin LX. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. Br J Cancer 2020; 122:209-220. [PMID: 31819189 PMCID: PMC7052272 DOI: 10.1038/s41416-019-0658-4] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 11/08/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear. METHODS The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo. RESULTS Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1. CONCLUSIONS Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
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Affiliation(s)
- Ze Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Mo Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Da Xu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhi-Fei Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jun-Jie Pan
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xuan Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Wu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Song Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
- Cancer Metastasis Institute, Fudan University, Shanghai, China.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
- Cancer Metastasis Institute, Fudan University, Shanghai, China.
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Zhou KQ, Liu WF, Yang LX, Sun YF, Hu J, Chen FY, Zhou C, Zhang XY, Peng YF, Yu L, Zhou J, Fan J, Wang Z. Circulating osteopontin per tumor volume as a prognostic biomarker for resectable intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr 2019; 8:582-596. [PMID: 31929985 DOI: 10.21037/hbsn.2019.03.14] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background The role of osteopontin (OPN) in intrahepatic cholangiocarcinoma (ICC) remains controversial. This study aimed to explore the prognostic value of OPN in patients with ICC undergoing curative resection. Methods Patients undergoing curative resection from 2005 to 2016 were identified for inclusion in this retrospective study. The expression level of OPN in tumors was measured in each of the 228 patients by immunohistochemistry. Circulating OPN in serum was tested in 124 patients by ELISA. Tumor volume was calculated according to preoperative imaging or operation record. Proliferation assay, wound healing assay, and invasion assay were performed to investigate the biological function. Results Low expression of OPN in tissue was associated with lymph node metastasis (P=0.009) and shorter overall survival (OS) (P=0.001). A low level of circulating OPN/volume was associated with multiple tumors (P<0.001), vascular invasion (P=0.027), visceral peritoneal perforation (P=0.001), and lymph node metastasis (P=0.002). It was also able to predict the invasive behavior, lymph node metastasis, and early recurrence with the area under the receiver operating curve (AUC) of being 0.719, 0.708 and 0.622 respectively. Patients with a low level of circulating OPN/volume had shorter OS (P=0.028) and disease-free survival (DFS) (P=0.004) and could benefit from adjuvant chemotherapy (P=0.011). Compared with negative controlled cells, ICC cell lines, which expressed more OPN, showed a decelerated proliferation rate, the weaker ability of migration and invasion, while the opposite was true for the cells expressed less OPN. MMP1, MMP10, and CXCR4 were negatively regulated by OPN. Conclusions A low level of circulating OPN/volume could indicate aggressive characteristics, along with poor prognosis and efficacy of adjuvant chemotherapy in ICC patients. Over expression of OPN may inhibit phenotypes facilitating ICC metastasis by negatively regulating MMP1, MMP10, and CXCR4.
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Affiliation(s)
- Kai-Qian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Wei-Feng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Liu-Xiao Yang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Yun-Fan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jie Hu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Fei-Yu Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Cheng Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Xiang-Yu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Yuan-Fei Peng
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lei Yu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Zheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Wnt Signaling in the Regulation of Immune Cell and Cancer Therapeutics. Cells 2019; 8:cells8111380. [PMID: 31684152 PMCID: PMC6912555 DOI: 10.3390/cells8111380] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/21/2019] [Accepted: 11/01/2019] [Indexed: 12/17/2022] Open
Abstract
Wnt signaling is one of the important pathways to play a major role in various biological processes, such as embryonic stem-cell development, tissue regeneration, cell differentiation, and immune cell regulation. Recent studies suggest that Wnt signaling performs an essential function in immune cell modulation and counteracts various disorders. Nonetheless, the emerging role and mechanism of action of this signaling cascade in immune cell regulation, as well as its involvement in various cancers, remain debatable. The Wnt signaling in immune cells is very diverse, e.g., the tolerogenic role of dendritic cells, the development of natural killer cells, thymopoiesis of T cells, B-cell-driven initiation of T-cells, and macrophage actions in tissue repair, regeneration, and fibrosis. The purpose of this review is to highlight the current therapeutic targets in (and the prospects of) Wnt signaling, as well as the potential suitability of available modulators for the development of cancer immunotherapies. Although there are several Wnt inhibitors relevant to cancer, it would be worthwhile to extend this approach to immune cells.
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44
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Gouesse RJ, Lavoie M, Dianati E, Wade MG, Hales BF, Robaire B, Plante I. Gestational and Lactational Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants Downregulates Junctional Proteins, Thyroid Hormone Receptor α1 Expression, and the Proliferation-Apoptosis Balance in Mammary Glands Post Puberty. Toxicol Sci 2019; 171:13-31. [PMID: 31241157 PMCID: PMC6735962 DOI: 10.1093/toxsci/kfz147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/11/2019] [Accepted: 06/11/2019] [Indexed: 12/21/2022] Open
Abstract
Mammary gland development requires hormonal regulation during puberty, pregnancy, and lactation. Brominated flame retardants (BFRs) are endocrine disruptors; they are added to consumer products to satisfy flammability standards. Previously, we showed that gestational and lactational exposure to an environmentally relevant mixture of BFRs disrupts proteins of the adherens junctions in rat dam mammary glands at weaning. Here, we hypothesize that perinatal exposure to the same BFR mixture also disrupts junctional proteins and signaling pathways controlling mammary gland development in pups. Dams were exposed through diet to a BFR mixture based on the substances in house dust; doses of the mixture used were 0, 0.06, 20, or 60 mg/kg/day. Dams were exposed continuously beginning prior to mating until pups' weaning; female offspring were euthanized on postnatal day (PND) 21, 46, and 208. The lowest dose of BFRs significantly downregulated adherens junction proteins, E-cadherin, and β-catenin, and the gap junction protein p-Cx43, as well as thyroid hormone receptor alpha 1 protein at PND 46. No effects were observed on estrogen or progesterone receptors. The low dose also resulted in a decrease in cleaved caspase-3, a downward trend in PARP levels, proteins involved in apoptosis, and an upward trend in proliferating cell nuclear antigen, a marker of proliferation. No effects were observed on ductal elongation or on the numbers of terminal end buds. Together, our results indicate that gestational and lactational exposure to an environmentally relevant mixture of BFRs disrupts cell-cell interactions, thyroid hormone homeostasis and the proliferation-apoptosis balance at PND 46, a critical stage for mammary gland development.
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Affiliation(s)
| | - Mélanie Lavoie
- INRS, Centre Armand-Frappier Santé Bioscience, Laval, Quebec, Canada
| | - Elham Dianati
- INRS, Centre Armand-Frappier Santé Bioscience, Laval, Quebec, Canada
| | - Mike G Wade
- Health Canada, Environmental Health Science and Research Bureau, Ottawa, Ontario, Canada
| | | | - Bernard Robaire
- Department of Pharmacology & Therapeutics
- Department of Obstetrics & Gynecology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Isabelle Plante
- INRS, Centre Armand-Frappier Santé Bioscience, Laval, Quebec, Canada
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Ghosh N, Hossain U, Mandal A, Sil PC. The Wnt signaling pathway: a potential therapeutic target against cancer. Ann N Y Acad Sci 2019; 1443:54-74. [PMID: 31017675 DOI: 10.1111/nyas.14027] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/05/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
The role of the evolutionarily conserved Wnt signaling pathway is well documented in several cellular processes, such as cell proliferation, differentiation, cell motility, and maintenance of the stem cell niche. The very first indication that aberrant Wnt signaling can cause carcinogenesis came from a finding that the mutation of the adenomatous polyposis coli gene (APC) predisposes a person to colorectal carcinoma. Later, with progressing research it became clear that abnormal activation or mutation of the genes related to this pathway could drive tumorigenesis. Here, we review recent advances in research regarding Wnt signaling regulation and its role in several cancer subtypes. Additionally, the utility of Wnt pathway-targeted cancer therapy intervention is also highlighted, with an overview of current approaches to target the Wnt pathway in oncogenesis and the future scopes and challenges associated with them.
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Affiliation(s)
- Noyel Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Uday Hossain
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Ankita Mandal
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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Chen L, Guo P, Zhang H, Li W, Gao C, Huang Z, Fan J, Zhang Y, Li X, Liu X, Wang F, Wang S, Li Q, He Z, Li H, Chen S, Wu X, Ye L, Li Q, Tang H, Wang Q, Dong G, Xiao Y, Chen W, Li D. Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1. J Biol Chem 2018; 294:2486-2499. [PMID: 30567741 DOI: 10.1074/jbc.ra118.006319] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/14/2018] [Indexed: 12/21/2022] Open
Abstract
Chronic benzene exposure is associated with hematotoxicity and the development of aplastic anemia and leukemia. However, the signaling pathways underlying benzene-induced hematotoxicity remain to be defined. Here, we investigated the role of protein phosphatase 2A (PP2A) in the regulation of benzene-induced hematotoxicity in a murine model. Male mice with a hepatocyte-specific homozygous deletion of the Ppp2r1a gene (encoding PP2A Aα subunit) (HO) and matched wildtype (WT) mice were exposed to benzene via inhalation at doses of 1, 10, and 100 ppm for 28 days. Peripheral white blood cell counts and activation of bone marrow progenitors were attenuated in the HO mice, indicating that Ppp2r1a deletion protects against benzene-induced hematotoxicity. Moreover, elevation of urinary S-phenyl mercapturic acid, a benzene metabolite, was much greater in WT mice than in HO mice. Real-time exhalation analysis revealed more exhaled benzene but fewer benzene metabolites in HO mice than in WT mice, possibly because of the down-regulation of Cyp2e1, encoding cytochrome P4502E1, in hepatocytes of the HO mice. Loss-of-function screening disclosed that PP2A complexes containing the B56α subunit participate in regulating Cyp2e1 expression. Notably, PP2A-B56α suppression in HepG2 cells resulted in persistent β-catenin phosphorylation at Ser33-Ser37-Thr41 in response to CYP2E1 agonists. In parallel, nuclear translocation of β-catenin was inhibited, concomitant with a remarkable decrease of Cyp2e1 expression. These findings support the notion that a regulatory cascade comprising PP2A-B56α, β-catenin, and Cyp2e1 is involved in benzene-induced hematotoxicity, providing critical insight into the role of PP2A in responses to the environmental chemicals.
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Affiliation(s)
- Liping Chen
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Ping Guo
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Haiyan Zhang
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Wenxue Li
- the Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou 510440
| | - Chen Gao
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Zhenlie Huang
- the Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou 510515
| | - Junling Fan
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Yuling Zhang
- the Institute of Mass Spectrometer and Atmospheric Environment, Jinan University, Guangzhou 510632, and
| | - Xue Li
- the Institute of Mass Spectrometer and Atmospheric Environment, Jinan University, Guangzhou 510632, and
| | - Xiaoling Liu
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Fangping Wang
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Shan Wang
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Qingye Li
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Zhini He
- the Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou 510515
| | - Huiyao Li
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Shen Chen
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Xiaonen Wu
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Lizhu Ye
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Qiong Li
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Huanwen Tang
- the Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Qing Wang
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Guanghui Dong
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Yongmei Xiao
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Wen Chen
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080
| | - Daochuan Li
- From the Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080,
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Faria M, Shepherd P, Pan Y, Chatterjee SS, Navone N, Gustafsson JÅ, Strom A. The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling. Oncotarget 2018; 9:36273-36288. [PMID: 30555629 PMCID: PMC6284737 DOI: 10.18632/oncotarget.26345] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/31/2018] [Indexed: 12/28/2022] Open
Abstract
Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.
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Affiliation(s)
- Michelle Faria
- University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA
| | - Peter Shepherd
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yinghong Pan
- University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA
| | - Sujash S Chatterjee
- University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA
| | - Nora Navone
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jan-Åke Gustafsson
- University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA.,Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden
| | - Anders Strom
- University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA
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