|
1
|
Zhou S, Li D, Quan C, Yu Z, Feng Y, Wang S, Li Y, Qi T, Chen J. Pan-cancer profiling of FZD2 as a prognostic biomarker: integrative multi-omics analysis with experimental validation and functional characterization in gastric cancer. Front Pharmacol 2025; 16:1534974. [PMID: 40444048 PMCID: PMC12120476 DOI: 10.3389/fphar.2025.1534974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/21/2025] [Indexed: 06/02/2025] Open
Abstract
Background Frizzled class receptor 2 (FZD2), is a critical protein in the Wnt signaling pathway, which plays significant roles in various cancers. However, its role in cancer progression, prognosis, and diagnosis remains largely unexplored. This study investigates the correlation between FZD2 expression and clinical outcomes, as well as its underlying molecular mechanisms in pan-cancer. Methods A comprehensive bioinformatic analysis was performed using pan-cancer data from The Cancer Genome Atlas (TCGA), which included 33 cancer types. Gene set enrichment analysis (GSEA) was conducted to explore functional pathways, while a protein-protein interaction (PPI) network was constructed to further elucidate the role of FZD2 in tumor biology. The relationship between FZD2 expression and immune cell infiltration across 22 categories was assessed using CIBERSORT. Additionally, single-cell analysis was employed to examine FZD2 expression levels across different cell types. To investigate the functional impact of FZD2, loss-of-function experiments were carried out in gastric cancer cell lines using siRNA-mediated knockdown. Subsequent assays, including Polymerase Chain Reaction (PCR), Western blotting (WB), Cell Counting Kit-8 (CCK8), Flow Cytometry, wound healing, and transwell migration and invasion assays, were performed to assess cellular responses. A subcutaneous gastric cancer xenograft model was established in nude mice to investigate the effect of FZD2 knockdown on tumor growth in vivo. Results Our analysis revealed significant upregulation of FZD2 in multiple malignancies, including stomach adenocarcinoma (STAD), bladder cancer (BLCA), and cholangiocarcinoma (CHOL). FZD2 expression was correlated with various cancer characteristics, including stemness score, matrix score, immune score, tumor mutational burden (TMB), microsatellite instability (MSI), RNA modification genes, and drug sensitivity. Notably, FZD2 was associated with altered sensitivity to several anticancer agents, suggesting its role in modulating treatment responses. FZD2 knockdown was demonstrated by both in vitro and in vivo experiments to suppress tumor cell proliferation, migration, and invasion in gastric cancer cell lines, indicating its critical role in tumor progression. Furthermore, FZD2 exhibited significant correlations with other Wnt pathway genes (e.g., Wnt2, Wnt4, Wnt5B), indicating a complex interaction network contributing to tumorigenesis. Conclusion FZD2 is widely upregulated in various tumor types, with its expression closely associated with key clinical outcomes, including overall survival, disease-specific survival, disease-free interval, as well as tumor mutations, drug sensitivity, immune cell infiltration, and immunotherapy-related biomarkers such as TMB and MSI. These findings highlight the pivotal role of FZD2 in cancer prognosis and treatment, offering potential for novel therapeutic approaches and the development of personalized medicine strategies in oncology.
Collapse
Affiliation(s)
- Sijiang Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Da Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Chao Quan
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhu Yu
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Yue Feng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Shengyu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Yong Li
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
- Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tongtong Qi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| | - Junqiang Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, Nanning, China
- Guangxi Clinical Research Center for Enhanced Recovery after Surgery, Nanning, China
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, Nanning, China
| |
Collapse
|
|
2
|
Lee A, Lim J, Lim JS. Emerging roles of MITF as a crucial regulator of immunity. Exp Mol Med 2024; 56:311-318. [PMID: 38351314 PMCID: PMC10907664 DOI: 10.1038/s12276-024-01175-5] [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: 07/31/2023] [Revised: 11/15/2023] [Accepted: 12/03/2023] [Indexed: 02/19/2024] Open
Abstract
Microphthalmia-associated transcription factor (MITF), a basic helix-loop-helix leucine zipper transcription factor (bHLH-Zip), has been identified as a melanocyte-specific transcription factor and plays a critical role in melanocyte survival, differentiation, function, proliferation and pigmentation. Although numerous studies have explained the roles of MITF in melanocytes and in melanoma development, the function of MITF in the hematopoietic or immune system-beyond its function in melanin-producing cells-is not yet fully understood. However, there is convincing and increasing evidence suggesting that MITF may play multiple important roles in immune-related cells. Therefore, this review is focused on recent advances in elucidating novel functions of MITF in cancer progression and immune responses to cancer. In particular, we highlight the role of MITF as a central modulator in the regulation of immune responses, as elucidated in recent studies.
Collapse
Affiliation(s)
- Aram Lee
- Department of Biological Science and the Cellular Heterogeneity Research Center, Research Institute of Women's Health, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Jihyun Lim
- Department of Biological Science and the Cellular Heterogeneity Research Center, Research Institute of Women's Health, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Jong-Seok Lim
- Department of Biological Science and the Cellular Heterogeneity Research Center, Research Institute of Women's Health, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| |
Collapse
|
|
3
|
Vietor I, Cikes D, Piironen K, Vasakou T, Heimdörfer D, Gstir R, Erlacher MD, Tancevski I, Eller P, Demetz E, Hess MW, Kuhn V, Degenhart G, Rozman J, Klingenspor M, Hrabe de Angelis M, Valovka T, Huber LA. The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15). eLife 2023; 12:e88350. [PMID: 37603466 PMCID: PMC10468205 DOI: 10.7554/elife.88350] [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: 04/20/2023] [Accepted: 08/20/2023] [Indexed: 08/23/2023] Open
Abstract
Delta-like homolog 1 (Dlk1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Experimental data presented here identify two independent regulatory mechanisms, transcriptional and translational, by which Ifrd1 (TIS7) and its orthologue Ifrd2 (SKMc15) regulate Dlk1 levels. Mice deficient in both Ifrd1 and Ifrd2 (dKO) had severely reduced adipose tissue and were resistant to high-fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation, was significantly upregulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk1 inhibited the expression of adipogenesis regulators Pparg and Cebpa, and fatty acid transporter Cd36. Although both Ifrd1 and Ifrd2 contributed to this phenotype, they utilized two different mechanisms. Ifrd1 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk1. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of Dlk1 regulation in adipocyte differentiation involving Ifrd1 and Ifrd2 are based on experimental data presented here.
Collapse
Affiliation(s)
- Ilja Vietor
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
| | - Domagoj Cikes
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
- IMBA, Institute of MolecularBiotechnology of the Austrian Academy of SciencesViennaAustria
| | - Kati Piironen
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
- Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of HelsinkiHelsinkiFinland
| | - Theodora Vasakou
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
| | - David Heimdörfer
- Division of Genomics and RNomics, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
| | - Ronald Gstir
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
- ADSI – Austrian Drug Screening Institute GmbHInnsbruckAustria
| | | | - Ivan Tancevski
- Department of Internal Medicine II, Innsbruck Medical UniversityInnsbruckAustria
| | - Philipp Eller
- Department of Internal Medicine II, Innsbruck Medical UniversityInnsbruckAustria
| | - Egon Demetz
- Department of Internal Medicine II, Innsbruck Medical UniversityInnsbruckAustria
| | - Michael W Hess
- Division of Histology and Embryology, Innsbruck Medical UniversityInnsbruckAustria
| | - Volker Kuhn
- Department Trauma Surgery, Innsbruck Medical UniversityInnsbruckAustria
| | - Gerald Degenhart
- Department of Radiology, Medical University InnsbruckInnsbruckAustria
| | - Jan Rozman
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthNeuherbergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, School of Life SciencesWeihenstephanGermany
- EKFZ - Else Kröner Fresenius Center for Nutritional Medicine, Technical University of MunichFreisingGermany
- ZIEL - Institute for Food & Health, Technical University of MunichFreisingGermany
| | - Martin Hrabe de Angelis
- German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthNeuherbergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Chair of Experimental Genetics, Technical University of Munich, School of Life SciencesFreisingGermany
| | - Taras Valovka
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
| | - Lukas A Huber
- Institute of Cell Biology, Biocenter, Innsbruck Medical UniversityInnsbruckAustria
- ADSI – Austrian Drug Screening Institute GmbHInnsbruckAustria
| |
Collapse
|
|
4
|
Tigue ML, Loberg MA, Goettel JA, Weiss WA, Lee E, Weiss VL. Wnt Signaling in the Phenotype and Function of Tumor-Associated Macrophages. Cancer Res 2023; 83:3-11. [PMID: 36214645 PMCID: PMC9812914 DOI: 10.1158/0008-5472.can-22-1403] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/26/2022] [Accepted: 10/05/2022] [Indexed: 02/03/2023]
Abstract
Tumor-associated macrophages (TAM) play an important role in supporting tumor growth and suppressing antitumor immune responses, and TAM infiltration has been associated with poor patient prognosis in various cancers. TAMs can be classified as pro-inflammatory, M1-like, or anti-inflammatory, M2-like. While multiple factors within the tumor microenvironment affect the recruitment, polarization, and functions of TAMs, accumulating evidence suggests that Wnt signaling represents an important, targetable driver of an immunosuppressive, M2-like TAM phenotype. TAM production of Wnt ligands mediates TAM-tumor cross-talk to support cancer cell proliferation, invasion, and metastasis. Targeting TAM polarization and the protumorigenic functions of TAMs through inhibitors of Wnt signaling may prove a beneficial treatment strategy in cancers where macrophages are prevalent in the microenvironment.
Collapse
Affiliation(s)
- Megan L Tigue
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew A Loberg
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jeremy A Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William A Weiss
- Departments of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
| | - Ethan Lee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Vivian L Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| |
Collapse
|
|
5
|
Yahsi B, Gunaydin G. Immunometabolism - The Role of Branched-Chain Amino Acids. Front Immunol 2022; 13:886822. [PMID: 35812393 PMCID: PMC9259854 DOI: 10.3389/fimmu.2022.886822] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
Immunometabolism has been the focus of extensive research over the last years, especially in terms of augmenting anti-tumor immune responses. Regulatory T cells (Tregs) are a subset of CD4+ T cells, which have been known for their immunosuppressive roles in various conditions including anti-tumor immune responses. Even though several studies aimed to target Tregs in the tumor microenvironment (TME), such approaches generally result in the inhibition of the Tregs non-specifically, which may cause immunopathologies such as autoimmunity. Therefore, specifically targeting the Tregs in the TME would be vital in terms of achieving a successful and specific treatment. Recently, an association between Tregs and isoleucine, which represents one type of branched-chain amino acids (BCAAs), has been demonstrated. The presence of isoleucine seems to affect majorly Tregs, rather than conventional T cells. Considering the fact that Tregs bear several distinct metabolic features in the TME, targeting their immunometabolic pathways may be a rational approach. In this Review, we provide a general overview on the potential distinct metabolic features of T cells, especially focusing on BCAAs in Tregs as well as in their subtypes.
Collapse
Affiliation(s)
- Berkay Yahsi
- School of Medicine, Hacettepe University, Ankara, Turkey
| | - Gurcan Gunaydin
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey
| |
Collapse
|
|
6
|
Rozhkova AV, Dmitrieva VG, Nosova EV, Dergunov AD, Limborska SA, Dergunova LV. Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis. J Cardiovasc Dev Dis 2021; 8:jcdd8120170. [PMID: 34940525 PMCID: PMC8707585 DOI: 10.3390/jcdd8120170] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.
Collapse
Affiliation(s)
- Alexandra V. Rozhkova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Veronika G. Dmitrieva
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Elena V. Nosova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Alexander D. Dergunov
- Laboratory of Structural Fundamentals of Lipoprotein Metabolism, National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia
- Correspondence:
| | - Svetlana A. Limborska
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Liudmila V. Dergunova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| |
Collapse
|
|
7
|
Huangfu N, Wang Y, Xu Z, Zheng W, Tao C, Li Z, Hu Y, Chen X. TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages. Front Cell Dev Biol 2021; 9:687169. [PMID: 34291051 PMCID: PMC8287832 DOI: 10.3389/fcell.2021.687169] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/07/2021] [Indexed: 12/18/2022] Open
Abstract
Objective Atherosclerosis (AS), characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease. Transactive response DNA-binding protein∼43 kDa (TDP43) has recently been identified as an independent driver of neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 is involved in AS development, especially in macrophages-mediated-foam cell formation and inflammatory responses. Methods Transactive response DNA-binding protein∼43 kDa expressions in oxidized low-density lipoprotein (oxLDL)-treated macrophages and peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) were detected by real time-polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence. Gene gain or loss of function was used to investigate the effects of TDP43 on macrophages-mediated lipid untake and inflammation with ELISA, protein immunoprecipitation, RT-PCR, Western blot, and immunofluorescence. Macrophage TDP43 specific knockout mice with ApoE-/- background were fed with western diet for 12 weeks to establish AS model, and used to explore the role of TDP43 on AS progression. Results Transactive response DNA-binding protein∼43 kDa expression increases in oxLDL-treated macrophages and PBMCs from patients with CAD. Furthermore, we find that TDP43 promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cGAS-STING signaling. Moreover, TDP43 strengthens lipid uptake of macrophages through regulating β-catenin and PPAR-γ complex to promote scavenger receptor gene CD36 transcription. Finally, using macrophage TDP43 specific knockout mice with ApoE-/- background fed with western diet for 12 weeks to establish AS model, we find that specific knockout of TDP43 in macrophages obviously alleviates western diet-induced AS progression in mice. Conclusions Transactive response DNA-binding protein∼43 kDa exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug.
Collapse
Affiliation(s)
- Ning Huangfu
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Yong Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Zhenyu Xu
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Wenyuan Zheng
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Chunlan Tao
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Zhenwei Li
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Yewen Hu
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| | - Xiaomin Chen
- Department of Cardiology, Ningbo First Hospital, Ningbo, China
| |
Collapse
|
|
8
|
Zhou M, Sun X, Zhu Y. Analysis of the role of Frizzled 2 in different cancer types. FEBS Open Bio 2021; 11:1195-1208. [PMID: 33565732 PMCID: PMC8016138 DOI: 10.1002/2211-5463.13111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/28/2021] [Accepted: 01/30/2021] [Indexed: 01/02/2023] Open
Abstract
Frizzled 2 (FZD2) is an important receptor in the Wnt pathway, which is highly expressed in malignant tumors and helps regulate multiple tumor behaviors. Its expression level is related to prognosis. Here, bioinformatic analysis was performed to understand the expression of FZD2 in different tumors. We examined FZD2 expression using pan‐cancer data of 33 cancer types from The Cancer Genome Atlas (TCGA). Differential expression analysis (Wilcoxon's test) was used to compare tumor and normal tissues. Univariate Cox proportional hazard regression was performed to compare gene expression and overall patient survival. COSMIC, cBioPortal, and CCLE were used to examine FZD2 mutations in human cancers. Dryness index was calculated using one‐class logistic regression (OCLR). Spearman's correlation was performed based on gene expression and dryness score and used to analyze the correlation between gene expression and stemness score, matrix score, immune score, estimated score, tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity. STRING website was used to construct an FZD2 protein interaction network and identify genes that interact with FZD2. We report that FZD2 is highly expressed in most tumors, differing between cancer types. Expression was related to patient overall survival (OS), disease‐specific survival, disease‐free interval (DFI), mutations, drug sensitivity, tumor microenvironment, immune cell infiltration, immune checkpoint gene expression, immunotherapy indicators (TMB, MSI), and tumor cell stemness. FZD2 influenced drug sensitivities, including cobimetinib (r = −0.553, P < 0.001), selumetinib (r = −0.539, P < 0.001), bafetinib (r = −0.538, P < 0.001), tamoxifen (r = −0.523, P < 0.001), alvespimycin (r = −0.520, P < 0.001), and nilotinib (r = −0.502, P < 0.001). FZD2 has the most significant correlation with ROR2 (r = 0.4, P < 0.001), Wnt2 (r = 0.37, P < 0.001), and Wnt4A (r = 0.34, P < 0.001). The results confirm the importance of FZD2 expression in cancer prognosis and treatment, and provide new clues for treatment strategies.
Collapse
Affiliation(s)
| | - Xuezhu Sun
- West Anhui Health Vocational College, Anhui, China
| | - Yunhao Zhu
- West Anhui Health Vocational College, Anhui, China
| |
Collapse
|
|
9
|
Li X, Zhang T, Geng J, Wu Z, Xu L, Liu J, Tian J, Zhou Z, Nie J, Bai X. Advanced Oxidation Protein Products Promote Lipotoxicity and Tubulointerstitial Fibrosis via CD36/β-Catenin Pathway in Diabetic Nephropathy. Antioxid Redox Signal 2019; 31:521-538. [PMID: 31084358 DOI: 10.1089/ars.2018.7634] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Aims: Diabetic nephropathy (DN) is the principal cause of mortality and morbidity in diabetic patients, the progression of which correlates best with tubulointerstitial fibrosis (TIF). Advanced oxidation protein products (AOPPs) have been detected in patients with chronic renal failure, causing injuries to proximal tubular epithelial cells. CD36, a known receptor for AOPP, is an important modulator of lipid homeostasis, predisposing to renal tubular damage. However, whether AOPPs induce lipotoxicity via the CD36 receptor pathway remains unknown. Herein, we tested the hypothesis that AOPPs accumulation in diabetes incurs lipotoxicity, causing renal TIF via the CD36 signaling pathway. Results: In DN patients and diabetic mice in vivo, AOPPs overload induces lipogenesis (upregulation of CD36 and sterol regulatory element-binding protein 1), fibrosis (upregulation of Fibronectin), and renal function decline (increased serum creatinine and N-acetyl-β-d-glucosaminidase, decreased estimated glomerular filtration rate). In HK-2 cells in vitro, high glucose stimulated AOPPs-induced lipotoxicity, apoptosis, and fibrosis via the CD36 receptor pathway. In addition, apocynin abrogated AOPPs-induced lipid accumulation and CD36 inhibition significantly mitigated AOPPs-induced mitochondrial injuries, lipotoxicity, and renal fibrosis. Further, we provide mechanistic evidence that AOPPs overload induces the enrichment of β-catenin binding the CD36 promoter region. Innovation and Conclusion: Our data reveal a major role of AOPPs in triggering lipotoxicity and fibrosis via CD36-dependent Wnt/β-catenin activation, providing new evidence for understanding the role of lipid accumulation in DN.
Collapse
Affiliation(s)
- Xiao Li
- 1Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ting Zhang
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jian Geng
- 3Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhuguo Wu
- 4Department of Internal Medicine, the Second Clinical Medical College, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China
| | - Liting Xu
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jixing Liu
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jianwei Tian
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhanmei Zhou
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jing Nie
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiaoyan Bai
- 2Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| |
Collapse
|
|
10
|
Huangfu N, Wang Y, Cheng J, Xu Z, Wang S. Metformin protects against oxidized low density lipoprotein-induced macrophage apoptosis and inhibits lipid uptake. Exp Ther Med 2018; 15:2485-2491. [PMID: 29456653 PMCID: PMC5795518 DOI: 10.3892/etm.2018.5704] [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: 07/11/2017] [Accepted: 12/28/2017] [Indexed: 12/31/2022] Open
Abstract
Oxidized low density lipoprotein (ox-LDL)-induced macrophage apoptosis contributes to the formation of atherosclerosis. Metformin, an antidiabetic drug, has been reported to attenuate lipid accumulation in macrophages. In this study, the effects of metformin on ox-LDL-induced macrophage apoptosis were investigated and the mechanisms involved in this process were examined. By performing flow cytometry analysis, it was demonstrated that metformin inhibited ox-LDL-induced macrophage apoptosis. Increased expression of endoplasmic reticulum (ER) stress marker proteins, including C/EBP-homologous protein, eukaryotic translation initiation factor 2A, and glucose-regulated protein 78 kDa, induced by ox-LDL was also reversed by metformin. Furthermore, ox-LDL-induced cytochrome c (cyto-c) release and mitochondrial membrane potential loss were inhibited by metformin. As lipid uptake in macrophages contributed to ER stress, cyto-c release and mitochondrial membrane potential loss, the mechanisms involved in metformin-inhibited macrophage lipid uptake were investigated. Expression of scavenger receptors, including scavenger receptor A, cluster of differentiation 36 and lectin-type oxidized LDL receptor 1 was examined in the presence or absence of metformin with ox-LDL treatment. Additionally, the upstream regulatory mechanism of scavenger receptors by metformin was also analyzed. In conclusion, metformin protects against ox-LDL-induced macrophage apoptosis and inhibits macrophage lipid uptake.
Collapse
Affiliation(s)
- Ning Huangfu
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Yong Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Jingsong Cheng
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Zhenyu Xu
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Shenghuang Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| |
Collapse
|
|
11
|
Linde N, Casanova-Acebes M, Sosa MS, Mortha A, Rahman A, Farias E, Harper K, Tardio E, Reyes Torres I, Jones J, Condeelis J, Merad M, Aguirre-Ghiso JA. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun 2018; 9:21. [PMID: 29295986 PMCID: PMC5750231 DOI: 10.1038/s41467-017-02481-5] [Citation(s) in RCA: 317] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/04/2017] [Indexed: 02/07/2023] Open
Abstract
Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.
Collapse
Affiliation(s)
- Nina Linde
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Merck KGaA, Frankfurter Str. 250, Postcode: A025/301, Darmstadt, 64293, Germany
| | - Maria Casanova-Acebes
- Department of Oncological Sciences, The Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Maria Soledad Sosa
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Arthur Mortha
- Department of Oncological Sciences, The Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, USA
| | - Adeeb Rahman
- Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Eduardo Farias
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kathryn Harper
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ethan Tardio
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ivan Reyes Torres
- Department of Oncological Sciences, The Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Joan Jones
- Department of Anatomy and Structural Biology, Integrated Imaging Program, Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - John Condeelis
- Department of Anatomy and Structural Biology, Integrated Imaging Program, Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Miriam Merad
- Department of Oncological Sciences, The Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Julio A Aguirre-Ghiso
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| |
Collapse
|
|
12
|
Huangfu N, Xu Z, Zheng W, Wang Y, Cheng J, Chen X. LncRNA MALAT1 regulates oxLDL-induced CD36 expression via activating β-catenin. Biochem Biophys Res Commun 2017; 495:2111-2117. [PMID: 29258822 DOI: 10.1016/j.bbrc.2017.12.086] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 12/15/2017] [Indexed: 01/19/2023]
Abstract
The expression of scavenger receptors in macrophages regulating lipid uptake plays an important role in foam cell formation and the subsequent atherosclerotic plaque formation. Long non-coding RNA MALAT1 is abundantly expressed in THP-1-derived macrophages, and oxidized low-density lipoprotein promotes its transcription by qRT-PCR and RNA FISH detection. Through chemical inhibitor treatments and by performing a dual luciferase reporter analysis, we found that oxLDL induces MALAT1 transcription through the NF-κB pathway. The knockdown of MALAT1 using siRNA transfection affects lipid uptake in macrophages. To understand the details, we checked the scavenger receptors, which mainly control lipid uptake, and found that MALAT1 knockdown decreased CD36 expression. Additionally, we also incubated macrophages with actinomycin D, combined with a dual luciferase reporter analysis, and we found that MALAT1 influenced CD36 expression at the transcription level. We aim to investigate the detailed mechanism by which MALAT1 promotes CD36 transcription, and thus, we designed and synthesized biotin-TEG labeled oligonucleotides to precipitate the MALAT1 RNA-DNA-protein complex in vivo. Combined with SDS-PAGE electrophoresis and a subsequent mass spectra analysis, β-catenin, a transcription factor that promotes CD36 transcription, was found in the complex. By performing R-IPs, we validated that β-catenin was bound to MALAT1 under the oxLDL treatment. In addition, using VAX939, a chemical inhibitor of β-catenin, MALAT1 was demonstrated to promote CD36 transcription partly via β-catenin. We also performed chips to detect whether MALAT1 affects β-catenin accumulation in the binding sites of the CD36 promoter and found that MALAT1 knockdown decreases β-catenin binding to the CD36 promoter and vice versa. In conclusion, oxLDL induced MALAT1 transcription and MALAT1 recruits β-catenin to binding sites on the CD36 promoter to induce CD36 expression, which enhances lipid uptake in macrophages.
Collapse
Affiliation(s)
- Ning Huangfu
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China
| | - Zhenyu Xu
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China
| | - Wenyuan Zheng
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China
| | - Yong Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China
| | - Jingsong Cheng
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China
| | - Xiaomin Chen
- Department of Cardiology, Ningbo First Hospital, Ningbo, PR China.
| |
Collapse
|
|
13
|
Wallace J, Lutgen V, Avasarala S, St Croix B, Winn RA, Al-Harthi L. Wnt7a induces a unique phenotype of monocyte-derived macrophages with lower phagocytic capacity and differential expression of pro- and anti-inflammatory cytokines. Immunology 2017; 153:203-213. [PMID: 28872671 DOI: 10.1111/imm.12830] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 08/24/2017] [Accepted: 08/26/2017] [Indexed: 12/25/2022] Open
Abstract
The variation of macrophage functions suggests the involvement of multiple signalling pathways in fine tuning their differentiation. Macrophages that originate from monocytes in the blood migrate to tissue in response to homeostatic or 'danger' signals and undergo substantial morphological and functional modifications to meet the needs of the dominant signals in the microenvironment. Wnts are secreted glycoproteins that play a significant role in organ and cell differentiation, yet their impact on monocyte differentiation is not clear. In this study, we assessed the role of Wnt1 and Wnt7a on the differentiation of monocytes and the subsequent phenotype and function of monocyte-derived macrophages (MDMs). We show that Wnt7a decreased the expression of CD14, CD11b, CD163 and CD206, whereas Wnt1 had no effect. The Wnt7a effect on CD11b was also observed in the brain and spleen of Wnt7a-/- adult brain mouse tissue and in embryonic Wnt7a-/- tissue. Wnt7a reduced the phagocytic capacity of M-MDMs, decreased interleukin-10 (IL-10) and IL-12 secretion and increased IL-6 secretion. Collectively, these findings demonstrate that Wnt7a generates an MDM phenotype with both pro-inflammatory and alternative MDM cytokine profiles and reduced phagocytic capacity. As such, Wnt7a can have a significant impact on macrophage responses in health and disease.
Collapse
Affiliation(s)
- Jennillee Wallace
- Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL, USA
| | - Victoria Lutgen
- Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL, USA
| | - Sreedevi Avasarala
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Brad St Croix
- Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD, USA
| | - Robert A Winn
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Lena Al-Harthi
- Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL, USA
| |
Collapse
|
|
14
|
Vergara D, Stanca E, Guerra F, Priore P, Gaballo A, Franck J, Simeone P, Trerotola M, De Domenico S, Fournier I, Bucci C, Salzet M, Giudetti AM, Maffia M. β-Catenin Knockdown Affects Mitochondrial Biogenesis and Lipid Metabolism in Breast Cancer Cells. Front Physiol 2017; 8:544. [PMID: 28798698 PMCID: PMC5529387 DOI: 10.3389/fphys.2017.00544] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 07/12/2017] [Indexed: 12/27/2022] Open
Abstract
β-catenin plays an important role as regulatory hub in several cellular processes including cell adhesion, metabolism, and epithelial mesenchymal transition. This is mainly achieved by its dual role as structural component of cadherin-based adherens junctions, and as a key nuclear effector of the Wnt pathway. For this dual role, different classes of proteins are differentially regulated via β-catenin dependent mechanisms. Here, we applied a liquid chromatography-mass spectrometry (LC-MS/MS) approach to identify proteins modulated after β-catenin knockdown in the breast cancer cell line MCF-7. We used a label free analysis to compare trypsin-digested proteins from CTR (shCTR) and β-catenin knockout cells (shβcat). This led to the identification of 98 differentially expressed proteins, 53 of them were up-regulated and 45 down-regulated. Loss of β-catenin induced morphological changes and a significant modulation of the expression levels of proteins associated with primary metabolic processes. In detail, proteins involved in carbohydrate metabolism and tricarboxylic acid cycle were found to be down-regulated, whereas proteins associated to lipid metabolism were found up-regulated in shβcat compared to shCTR. A loss of mitochondrial mass and membrane potential was also assessed by fluorescent probes in shβcat cells with respect to the controls. These data are consistent with the reduced expression of transcriptional factors regulating mitochondrial biogenesis detected in shβcat cells. β-catenin driven metabolic reprogramming resulted also in a significant modulation of lipogenic enzyme expression and activity. Compared to controls, β-catenin knockout cells showed increased incorporation of [1-14C]acetate and decreased utilization of [U-14C]glucose for fatty acid synthesis. Our data highlight a role of β-catenin in the regulation of metabolism and energy homeostasis in breast cancer cells.
Collapse
Affiliation(s)
- Daniele Vergara
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy.,Laboratory of Clinical Proteomic, "Giovanni Paolo II" HospitalLecce, Italy
| | - Eleonora Stanca
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy.,Laboratory of Clinical Proteomic, "Giovanni Paolo II" HospitalLecce, Italy
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy
| | - Paola Priore
- CNR NANOTEC - Institute of NanotechnologyLecce, Italy
| | | | - Julien Franck
- University of Lille, Institut national de la santé et de la recherche médicale, U-1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISMLille, France
| | - Pasquale Simeone
- Unit of Cytomorphology, CeSI-MeT and Department of Medicine and Aging Sciences, School of Medicine and Health Sciences, University "G. d'Annunzio"Chieti, Italy
| | - Marco Trerotola
- Unit of Cancer Pathology, CeSI-MeT and Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio"Chieti, Italy
| | | | - Isabelle Fournier
- University of Lille, Institut national de la santé et de la recherche médicale, U-1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISMLille, France
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy
| | - Michel Salzet
- University of Lille, Institut national de la santé et de la recherche médicale, U-1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISMLille, France
| | - Anna M Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy
| | - Michele Maffia
- Department of Biological and Environmental Sciences and Technologies, University of SalentoLecce, Italy.,Laboratory of Clinical Proteomic, "Giovanni Paolo II" HospitalLecce, Italy
| |
Collapse
|
|
15
|
Saul MC, Seward CH, Troy JM, Zhang H, Sloofman LG, Lu X, Weisner PA, Caetano-Anolles D, Sun H, Zhao SD, Chandrasekaran S, Sinha S, Stubbs L. Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice. Genome Res 2017; 27:959-972. [PMID: 28356321 PMCID: PMC5453329 DOI: 10.1101/gr.214221.116] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 03/24/2017] [Indexed: 12/22/2022]
Abstract
Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.
Collapse
Affiliation(s)
- Michael C Saul
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Christopher H Seward
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Joseph M Troy
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Illinois Informatics Institute, Urbana, Illinois 61801, USA
| | - Huimin Zhang
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Laura G Sloofman
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Xiaochen Lu
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Patricia A Weisner
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Derek Caetano-Anolles
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Hao Sun
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Sihai Dave Zhao
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Sriram Chandrasekaran
- Harvard Society of Fellows, Harvard University, Cambridge, Massachusetts 02138, USA
- Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
| | - Saurabh Sinha
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Computer Science
- Department of Entomology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Lisa Stubbs
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| |
Collapse
|
|
16
|
Yousefipour Z, Chug N, Marek K, Nesbary A, Mathew J, Ranganna K, Newaz MA. Contribution of PPARγ in modulation of acrolein-induced inflammatory signaling in gp91 phox knock-out mice. Biochem Cell Biol 2017; 95:482-490. [PMID: 28376311 DOI: 10.1139/bcb-2016-0198] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Oxidative stress and inflammation are major contributors to acrolein toxicity. Peroxisome proliferator activated receptor gamma (PPARγ) has antioxidant and anti-inflammatory effects. We investigated the contribution of PPARγ ligand GW1929 to the attenuation of oxidative stress in acrolein-induced insult. Male gp91phox knock-out (KO) mice were treated with acrolein (0.5 mg·(kg body mass)-1 by intraperitoneal injection for 7 days) with or without GW1929 (GW; 0.5 mg·(kg body mass)-1·day-1, orally, for 10 days). The livers were processed for further analyses. Acrolein significantly increased 8-isoprostane and reduced PPARγ activity (P < 0.05) in the wild type (WT) and KO mice. GW1929 reduced 8-isoprostane (by 32% and 40% in WT and KO mice, respectively) and increased PPARγ activity (by 81% and 92% in WT and KO, respectively). Chemokine activity was increased (by 63%) in acrolein-treated WT mice, and was reduced by GW1929 (by 65%). KO mice exhibited higher xanthine oxidase (XO). Acrolein increased XO and COX in WT mice and XO in KO mice. GW1929 significantly reduced COX in WT and KO mice and reduced XO in KO mice. Acrolein significantly reduced the total antioxidant status in WT and KO mice (P < 0.05), which was improved by GW1929 (by 75% and 74%). The levels of NF-κB were higher in acrolein-treated WT mice. GW1929 reduced NF-κB levels (by 51%) in KO mice. Acrolein increased CD36 in KO mice (by 43%), which was blunted with GW1929. Data confirms that the generation of free radicals by acrolein is mainly through NAD(P)H, but other oxygenates play a role too. GW1929 may alleviate the toxicity of acrolein by attenuating NF-κB, COX, and CD36.
Collapse
Affiliation(s)
- Zivar Yousefipour
- a College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Neha Chug
- b College of Pharmacy, Chicago State University, Chicago, IL 60503, USA
| | - Katarzyna Marek
- b College of Pharmacy, Chicago State University, Chicago, IL 60503, USA
| | - Alicia Nesbary
- b College of Pharmacy, Chicago State University, Chicago, IL 60503, USA
| | - Joseph Mathew
- a College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Kasturi Ranganna
- a College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, USA
| | - Mohammad A Newaz
- b College of Pharmacy, Chicago State University, Chicago, IL 60503, USA
| |
Collapse
|
|
17
|
Yan H, Wang S, Li Z, Sun Z, Zan J, Zhao W, Pan Y, Wang Z, Wu M, Zhu J. Rspo2 suppresses CD36-mediated apoptosis in oxidized low density lipoprotein-induced macrophages. Mol Med Rep 2016; 14:2945-52. [PMID: 27571704 PMCID: PMC5042761 DOI: 10.3892/mmr.2016.5642] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 06/22/2016] [Indexed: 01/12/2023] Open
Abstract
Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R-spondin 2 (Rspo2), a member of the cysteine-rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R-spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox-LDL-induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL-induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry. In addition, Rspo2 was observed to suppress oxLDL-induced ER stress and reactive oxygen species production as demonstrated by western blotting. Furthermore, analysis of the role of Rspo2 in macrophage lipid uptake identified that Rspo2 negatively regulated the Dil-oxLDL uptake by inhibiting the expression of cluster of differentiation (CD)36, through the transcription factor, peroxisome proliferator-activated receptor (PPAR)-γ. The manipulation of Rspo2 had a direct effect on PPAR-γ nuclear translocation. In addition, chromatin immunoprecipitation analysis revealed that Rspo2 manipulation led to regulation of the direct binding between PPAR-γ and CD36. In conclusion, Rspo2 was found to have a negative regulatory effect during oxLDL-induced macrophage apoptosis by regulating lipid uptake.
Collapse
Affiliation(s)
- Hui Yan
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Shuai Wang
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhenwei Li
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Zewei Sun
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Jie Zan
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Wenting Zhao
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Yanyun Pan
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhen Wang
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Mingjie Wu
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Jianhua Zhu
- Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| |
Collapse
|
|
18
|
Mahon RN, Hafner R. Immune Cell Regulatory Pathways Unexplored as Host-Directed Therapeutic Targets for Mycobacterium tuberculosis: An Opportunity to Apply Precision Medicine Innovations to Infectious Diseases. Clin Infect Dis 2016; 61Suppl 3:S200-16. [PMID: 26409283 DOI: 10.1093/cid/civ621] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The lack of novel antimicrobial drugs in development for tuberculosis treatment has provided an impetus for the discovery of adjunctive host-directed therapies (HDTs). Several promising HDT candidates are being evaluated, but major advancement of tuberculosis HDTs will require understanding of the master or "core" cell signaling pathways that control intersecting immunologic and metabolic regulatory mechanisms, collectively described as "immunometabolism." Core regulatory pathways conserved in all eukaryotic cells include poly (ADP-ribose) polymerases (PARPs), sirtuins, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) signaling. Critical interactions of these signaling pathways with each other and their roles as master regulators of immunometabolic functions will be addressed, as well as how Mycobacterium tuberculosis is already known to influence various other cell signaling pathways interacting with them. Knowledge of these essential mechanisms of cell function regulation has led to breakthrough targeted treatment advances for many diseases, most prominently in oncology. Leveraging these exciting advances in precision medicine for the development of innovative next-generation HDTs may lead to entirely new paradigms for treatment and prevention of tuberculosis and other infectious diseases.
Collapse
Affiliation(s)
- Robert N Mahon
- Division of AIDS-Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Contractor to the National Institute of Allergy and Infectious Diseases, National Institutes of Health
| | - Richard Hafner
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
19
|
Abstract
Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.
Collapse
Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
| |
Collapse
|
|
20
|
Maiese K. Erythropoietin and diabetes mellitus. World J Diabetes 2015; 6:1259-1273. [PMID: 26516410 PMCID: PMC4620106 DOI: 10.4239/wjd.v6.i14.1259] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/25/2015] [Accepted: 09/28/2015] [Indexed: 02/05/2023] Open
Abstract
Erythropoietin (EPO) is a 30.4 kDa growth factor and cytokine that governs cell proliferation, immune modulation, metabolic homeostasis, vascular function, and cytoprotection. EPO is under investigation for the treatment of variety of diseases, but appears especially suited for the treatment of disorders of metabolism that include diabetes mellitus (DM). DM and the complications of this disease impact a significant portion of the global population leading to disability and death with currently limited therapeutic options. In addition to its utility for the treatment of anemia, EPO can improve cardiac function, reduce fatigue, and improve cognition in patients with DM as well as regulate cellular energy metabolism, obesity, tissue repair and regeneration, apoptosis, and autophagy in experimental models of DM. Yet, EPO can have adverse effects that involve the vasculature system and unchecked cellular proliferation. Critical to the cytoprotective capacity and the potential for a positive clinical outcome with EPO are the control of signal transduction pathways that include protein kinase B, the mechanistic target of rapamycin, Wnt signaling, mammalian forkhead transcription factors of the O class, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), and AMP activated protein kinase. Therapeutic strategies that can specifically target and control EPO and its signaling pathways hold great promise for the development of new and effective clinical treatments for DM and the complications of this disorder.
Collapse
|
|
21
|
Maiese K. Stem cell guidance through the mechanistic target of rapamycin. World J Stem Cells 2015; 7:999-1009. [PMID: 26328016 PMCID: PMC4550632 DOI: 10.4252/wjsc.v7.i7.999] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 06/29/2015] [Accepted: 07/17/2015] [Indexed: 02/06/2023] Open
Abstract
Stem cells offer great promise for the treatment of multiple disorders throughout the body. Critical to this premise is the ability to govern stem cell pluripotency, proliferation, and differentiation. The mechanistic target of rapamycin (mTOR), 289-kDa serine/threonine protein kinase, that is a vital component of mTOR Complex 1 and mTOR Complex 2 represents a critical pathway for the oversight of stem cell maintenance. mTOR can control the programmed cell death pathways of autophagy and apoptosis that can yield variable outcomes in stem cell survival and be reliant upon proliferative pathways that include Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and trophic factors. mTOR also is a necessary component for the early development and establishment of stem cells as well as having a significant impact in the regulation of the maturation of specific cell phenotypes. Yet, as a proliferative agent, mTOR can not only foster cancer stem cell development and tumorigenesis, but also mediate cell senescence under certain conditions to limit invasive cancer growth. mTOR offers an exciting target for the oversight of stem cell therapies but requires careful consideration of the diverse clinical outcomes that can be fueled by mTOR signaling pathways.
Collapse
|
|
22
|
Maiese K. Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease. Neural Regen Res 2015; 10:518-28. [PMID: 26170801 PMCID: PMC4424733 DOI: 10.4103/1673-5374.155427] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2015] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus affects almost 350 million individuals throughout the globe resulting in significant morbidity and mortality. Of further concern is the growing population of individuals that remain undiagnosed but are susceptible to the detrimental outcomes of this disorder. Diabetes mellitus leads to multiple complications in the central and peripheral nervous systems that include cognitive impairment, retinal disease, neuropsychiatric disease, cerebral ischemia, and peripheral nerve degeneration. Although multiple strategies are being considered, novel targeting of trophic factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1, and stem cell tissue regeneration are considered to be exciting prospects to overcome the cellular mechanisms that lead to neuronal injury in diabetes mellitus involving oxidative stress, apoptosis, and autophagy. Pathways that involve insulin-like growth factor-1, fibroblast growth factor, epidermal growth factor, and erythropoietin can govern glucose homeostasis and are intimately tied to Wnt signaling that involves Wnt1 and Wnt1 inducible signaling pathway protein 1 (CCN4) to foster control over stem cell proliferation, wound repair, cognitive decline, β-cell proliferation, vascular regeneration, and programmed cell death. Ultimately, cellular metabolism through Wnt signaling is driven by primary metabolic pathways of the mechanistic target of rapamycin and AMP activated protein kinase. These pathways offer precise biological control of cellular metabolism, but are exquisitely sensitive to the different components of Wnt signaling. As a result, unexpected clinical outcomes can ensue and therefore demand careful translation of the mechanisms that govern neural repair and regeneration in diabetes mellitus.
Collapse
Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101, USA
| |
Collapse
|