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Galifi CA, Dikdan RJ, Kantak D, Bulatowicz JJ, Maingrette K, Gunderson SI, Wood TL. Identifying antisense oligonucleotides for targeted inhibition of insulin receptor isoform A. Front Oncol 2025; 15:1563985. [PMID: 40303997 PMCID: PMC12038057 DOI: 10.3389/fonc.2025.1563985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/10/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction The insulin receptor (IR) is alternatively spliced into two isoforms, IR-A and IR-B. IR-B is primarily associated with metabolic signaling, whereas IR-A is highly expressed during embryogenesis. IR-A specifically has been associated with several aggressive cancers; however, selective targeting of IR-A has proven difficult due to its homology with IR-B. Methods We generated several antisense oligonucleotides (ASOs) that target the exon 10-12 splice junction site present in IR-A, but not IR-B, mRNA. To test the efficacy of the ASOs, we performed lipofectamine transfections of MDA-MB-231 breast cancer, 22Rv1 prostate carcinoma, and Hs822.T Ewing sarcoma cell lines. We also incubated the MDA-MB-231 cell line with the ASOs in the absence of lipofectamine to determine if they are taken into cells unassisted. Results One ASO variant selectively reduced IR-A mRNA levels with minimal impact on IR-B mRNA and significantly reduced total IR protein. The IR-A ASO successfully induced selective IR-A knockdown in MDA-MB-231 breast cancer cells, which was maintained after a one-week incubation with the ASO. The ASO selectively reduced IR-A mRNA when administered to cells in high doses without the use of a vehicle (i.e. gymnotic delivery). The ASO was also effective at reducing IR-A mRNA in Hs822.T Ewing Sarcoma and 22Rv1 prostate carcinoma cells. Discussion We have developed an ASO that targets IR-A with minimal off-target knockdown of IR-B. We hypothesize that the IR-A ASO will be a useful research tool and may have therapeutic value by inhibiting the oncogenic functions of IR-A in cancer cells.
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Affiliation(s)
- Christopher A. Galifi
- Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
| | - Ryan J. Dikdan
- Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
| | - Divyangi Kantak
- Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
| | - Joseph J. Bulatowicz
- Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
| | - Krystopher Maingrette
- Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
| | - Samuel I. Gunderson
- Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers University, Piscataway, NJ, United States
| | - Teresa L. Wood
- Department of Pharmacology, Physiology, & Neuroscience, Center for Cell Signaling and Cancer Institute of New Jersey, Rutgers Biomedical and Health Sciences, Newark, NJ, United States
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Li Y, Xiao P, Boadu F, Goldkamp AK, Nirgude S, Cheng J, Hagen DE, Kalish JM, Rivera RM. Beckwith-Wiedemann syndrome and large offspring syndrome involve alterations in methylome, transcriptome, and chromatin configuration. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2023.12.14.23299981. [PMID: 38168424 PMCID: PMC10760283 DOI: 10.1101/2023.12.14.23299981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Beckwith-Wiedemann Syndrome (BWS) is the most common epigenetic overgrowth syndrome, caused by epigenetic alterations on chromosome 11p15. In ∼50% of patients with BWS, the imprinted region KvDMR1 (IC2) is hypomethylated. Nearly all children with BWS develop organ overgrowth and up to 28% develop cancer during childhood. The global epigenetic alterations beyond the 11p15 region in BWS are not currently known. Uncovering these alterations at the methylome, transcriptome, and chromatin architecture levels are necessary steps to improve the diagnosis and understanding of patients with BWS. Here we characterized the complete epigenetic profiles of BWS IC2 individuals together with the animal model of BWS, bovine large offspring syndrome (LOS). A novel finding of this research is the identification of two molecular subgroups of BWS IC2 individuals. Genome-wide alternations were detected for DNA methylation, transcript abundance, alternative splicing events of RNA, chromosome compartments, and topologically associating domains (TADs) in BWS and LOS, with shared alterations identified between species. Altered chromosome compartments and TADs were correlated with differentially expressed genes in BWS and LOS. Together, we highlight genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular diagnostic methodologies for BWS.
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Faruqui T, Akhtar A, Showket F, Dar MJ, Akhter Y. Identification and Evaluation of IGF1R and Its Associated Proteins as Targets and Design of Novel Inhibitors for Cancer Therapy. J Cell Biochem 2025; 126:e70008. [PMID: 40023828 DOI: 10.1002/jcb.70008] [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: 09/04/2024] [Revised: 01/29/2025] [Accepted: 02/06/2025] [Indexed: 03/04/2025]
Abstract
The insulin-like growth factor 1 receptor (IGF1R) is a crucial receptor tyrosine kinase involved in cellular growth, survival, and metabolism. Abnormal overexpression and activation are common in various cancers and contribute to tumor development and resistance to treatment. The STRING database was used to analyze the protein-protein interaction network of IGF1R and was visualized using Cytoscape to identify the key associated proteins. We assessed IGF1R and its associated protein expression levels across pan-cancer types and compared them to healthy controls using a TNMplot and cBioPortal. The objective of this study was to identify novel, low-toxicity inhibitors targeting the IGF1R and its associated proteins (e.g., AKT1 and EGFR) with better pharmacokinetic profiles for effective cancer treatment, including brain cancer. We screened 693 million drug-like compounds and selected the top 400 for toxicity analysis using ProTox-II, which identified 83 nontoxic candidates. These were categorized as either blood-brain barrier (BBB) permeant or impermeant. Molecular docking studies with AutoDock Vina 4.1 were performed on 17 target proteins, including IGF1R, with the top three compounds. Subsequently, molecular dynamics simulations using Desmond were conducted on the two most promising candidates: two BBB permeants and two impermeants. Our study identified six nontoxic IGF1R inhibitors and 16 other target protein inhibitors. Docking and MD simulations confirmed the potential of these compounds in targeted therapies. Notably, both BBB-permeant and -impermeant compounds in complex with the target proteins showed stability over 50 and 400 ns molecular simulation experiments, highlighting their potential in cancer therapy and suggesting the need for further in vitro and in vivo validation.
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Affiliation(s)
- Tabrez Faruqui
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Aubaidah Akhtar
- Cancer Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research(AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Farheen Showket
- Cancer Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research(AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Mohd Jamal Dar
- Cancer Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, India
| | - Yusuf Akhter
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
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Tian Q, Tian C, Lu Y, Yan B, Zhang K, Wu C. RETRACTED: Poly (lactic-co-glycolic acid)-encapsulated Endostar-loaded calcium phosphate cement as anti-tumor bone cement for the treatment of bone metastasis in lung cancer. ENVIRONMENTAL TOXICOLOGY 2025; 40:E17-E30. [PMID: 38400521 DOI: 10.1002/tox.24166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/14/2024] [Accepted: 01/20/2024] [Indexed: 02/25/2024]
Abstract
Lung cancer is one of the most common malignant tumors in the world. In approximately 30%-40% of lung cancer patients, bone metastases ensues with osteolytic destruction. Worse still, intractable pain, pathological fracture, and nerve compression caused by bone metastases are currently the bottleneck of research, diagnosis, and treatment of lung cancer. Therefore, the present study aims at investigating the effectiveness of a new composite material made of calcium phosphate cement (CPC) and Endostar on repairing bone defects in vitro and in vivo. As indicated in results, the mechanical properties of CPC+Endostar and CPC+PLGA+Endostar do not differ from those of pure CPC. The PLGA-embedded Endostar slow-release microspheres were designed and prepared, and were combined with CPC. Poly (lactic-co-glycolic acid (PLGA) is a biodegradable polymer material in vivo, so the effect on its mechanical properties is negligible. CPC+Endostar and CPC+PLGA+Endostar have been proved to inhibit cell proliferation, promote apoptosis and block cell cycle in G2 phase; the expression levels of osteoclast-related genes CXCL2, TGF-β1, IGF-1, IL-6, and RANKL were significantly decreased while osteogenic ability and alkaline phosphatase activity observably enhanced. In vivo studies have revealed that the expression levels of TRAP, RANKL, and Caspase3 in CPC+PLGA+ENDO-treated tumor tissues after 3 weeks were higher than those in other groups with the prolongation of animal treatment time, while the expression levels of OPN and BCL2 were lower than those in other groups. In hematoxylin and eosin and TUNEL staining, 3 weeks of CPC+PLGA+ENDO-treatment yielded higher tissue necrosis and apoptosis than other groups; computed tomography and magnetic resonance imaging results showed the posterior edge bone damage reduced as a result of the CPC+PLGA+ENDO grafting in vertebral pedicle. Overall, the feasibility and reliability of CPC-loaded Endostar in the treatment of bone metastasis in lung cancer were investigated in this study, so as to promote the basic research and treatment of bone metastasis in lung cancer and other malignant tumors.
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Affiliation(s)
- QingHua Tian
- Department of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cong Tian
- Department of Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - YingYing Lu
- Department of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - BiCong Yan
- Department of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kaixian Zhang
- Department of Oncology, Tengzhou Central People's Hospital Affiliated to Jining Medical College, Tengzhou, China
| | - ChunGen Wu
- Department of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Bora Yildiz C, Du J, Mohan KN, Zimmer-Bensch G, Abdolahi S. The role of lncRNAs in the interplay of signaling pathways and epigenetic mechanisms in glioma. Epigenomics 2025; 17:125-140. [PMID: 39829063 PMCID: PMC11792803 DOI: 10.1080/17501911.2024.2442297] [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: 05/13/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
Gliomas, highly aggressive tumors of the central nervous system, present overwhelming challenges due to their heterogeneity and therapeutic resistance. Glioblastoma multiforme (GBM), the most malignant form, underscores this clinical urgency due to dismal prognosis despite aggressive treatment regimens. Recent advances in cancer research revealed signaling pathways and epigenetic mechanisms that intricately govern glioma progression, offering multifaceted targets for therapeutic intervention. This review explores the dynamic interplay between signaling events and epigenetic regulation in the context of glioma, with a particular focus on the crucial roles played by non-coding RNAs (ncRNAs). Through direct and indirect epigenetic targeting, ncRNAs emerge as key regulators shaping the molecular landscape of glioblastoma across its various stages. By dissecting these intricate regulatory networks, novel and patient-tailored therapeutic strategies could be devised to improve patient outcomes with this devastating disease.
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Affiliation(s)
- Can Bora Yildiz
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, Aachen, Germany
| | - Jian Du
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
| | - K. Naga Mohan
- Molecular Biology and Genetics Laboratory, Department of Biological Sciences, Hyderabad, India
| | - Geraldine Zimmer-Bensch
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, Aachen, Germany
| | - Sara Abdolahi
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
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Zhang X, Fang F, Zhang J, Zhang S, Li H, Li B, Zhong Y, Zhen P. Circ_0006174 Upregulates IGF1R to Enhance Radioresistance and Tumorigenesis in Colorectal Cancer via miR-940 Suppression. Appl Biochem Biotechnol 2025; 197:497-517. [PMID: 39172343 DOI: 10.1007/s12010-024-05028-9] [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] [Accepted: 07/23/2024] [Indexed: 08/23/2024]
Abstract
Colorectal cancer (CRC) is one of the most common malignancies all over the world. Increasing evidence has revealed that circular RNAs (circRNAs) are involved in the progression of CRC. In this study, we aimed to investigate the role and underlying mechanism of circ_0006174 in the development and radiosensitivity of CRC. Circ_0006174, microRNA-940 (miR-940), and insulin-like growth factor 1 receptor (IGF1R) expression levels were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). The radiosensitivity of cells also was assessed using colony formation assay. Besides, cell proliferation, apoptosis, migration, and invasion were detected by cell counting kit-8 (CCK-8), flow cytometry, and transwell assays. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the relationship between miR-940 and circ_0006174 or IGF1R. IGF1R protein level was examined using western blot. A xenograft tumor model was used to verify the function of circ_0006174 in CRC tumor growth in vivo. Circ_0006174 and IGF1R levels were elevated and miR-940 expression was decreased in CRC tissues and cells. Circ_0006174 knockdown enhanced the radiosensitivity of CRC cells by regulating cell proliferation, apoptosis, migration, and invasion in vitro. In mechanism, circ_0006174 served as a sponge for miR-940 to upregulate IGF1R expression. Moreover, circ_0006174 silencing suppressed CRC growth in vivo. Circ_0006174 boosts radioresistance of CRC cells at least partly through upregulating IGF1R expression by sponging miR-940, providing a novel theoretical basis for CRC therapy.
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Affiliation(s)
- Xuefeng Zhang
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Fang Fang
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Jiarui Zhang
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Sujuan Zhang
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Haonan Li
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Bingyao Li
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Yibo Zhong
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China
| | - Peng Zhen
- Department of Radliation Oncology, Chifeng Tumor Hospital, No.45, Jiefang Street, Hongshan District, Chifeng City, Inner Mongolia, 024000, PR China.
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Wen Y, Yang X, Li Y, Zhao X, Ding A, Song D, Duan L, Cheng S, Zhu X, Peng B, Chang X, Zhang C, Yang F, Cheng T, Wang H, Zhang Y, Zhang T, Zheng S, Ren L, Gao S. DRAIC mediates hnRNPA2B1 stability and m 6A-modified IGF1R instability to inhibit tumor progression. Oncogene 2024; 43:2266-2278. [PMID: 38811846 DOI: 10.1038/s41388-024-03071-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 05/31/2024]
Abstract
Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.
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MESH Headings
- Humans
- Receptor, IGF Type 1/metabolism
- Receptor, IGF Type 1/genetics
- Mice
- Kidney Neoplasms/genetics
- Kidney Neoplasms/pathology
- Kidney Neoplasms/metabolism
- Animals
- Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism
- Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics
- Disease Progression
- RNA Stability/genetics
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Protein Stability
- Adenosine/analogs & derivatives
- Adenosine/metabolism
- Ubiquitination
- Cell Proliferation/genetics
- Mice, Nude
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Affiliation(s)
- Ya Wen
- Medical College, Guizhou University, Guiyang, 550025, China
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan, 030032, China
| | - Xiwang Yang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Yifei Li
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xueqing Zhao
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Ao Ding
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Dalong Song
- The People's Hospital of Guizhou Province, Guiyang, 550002, China
| | - Liqiang Duan
- Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan, 030032, China
| | - Shuwen Cheng
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- Medical School of Nanjing University, Nanjing, 210046, China
| | - Xiaofeng Zhu
- Medical College, Guizhou University, Guiyang, 550025, China
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Bo Peng
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163, Suzhou, China
| | - Xiaoli Chang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- College of Veterinary Medicine, Shanxi Agricultural University, Shanxi, 030801, China
| | - Chang Zhang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- Department of Oncology, The Key Laboratory of Advanced Interdisciplinary Studies, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510530, China
| | - Facai Yang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Tianyou Cheng
- Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan, 030032, China
| | - He Wang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai, 200444, China
| | - Yibi Zhang
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
- CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163, Suzhou, China
| | - Tiantian Zhang
- Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan, 030032, China
| | - Shizhong Zheng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Li Ren
- Department of Clinical Laboratory Diagnostics, Tianjin Medical University, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
| | - Shan Gao
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China.
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Yang K, Hu Y, Feng Y, Li K, Zhu Z, Liu S, Lin Y, Yu B. IGF-1R mediates crosstalk between nasopharyngeal carcinoma cells and osteoclasts and promotes tumor bone metastasis. J Exp Clin Cancer Res 2024; 43:46. [PMID: 38342894 PMCID: PMC10860326 DOI: 10.1186/s13046-024-02970-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 01/29/2024] [Indexed: 02/13/2024] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) poses a significant health burden in specific regions of Asia, and some of NPC patients have bone metastases at the time of initial diagnosis. Bone metastasis can cause pathologic fractures and pain, reducing patients' quality of life, and is associated with worse survival. This study aims to unravel the complex role of insulin-like growth factor 1 receptor (IGF-1R) in NPC bone metastasis, offering insights into potential therapeutic targets. METHODS We assessed IGF-1R expression in NPC cells and explored its correlation with bone metastasis. Experiments investigated the impact of osteoclast-secreted IGF-1 on the IGF-1R/AKT/S6 pathway in promoting NPC cell proliferation within the bone marrow. Additionally, the reciprocal influence of tumor-secreted Granulocyte-macrophage colony-stimulating factor (GM-CSF) on osteoclast differentiation and bone resorption was examined. The effects of IGF-1 neutralizing antibody, IGF-1R specific inhibitor (NVP-AEW541) and mTORC inhibitor (rapamycin) on nasopharyngeal carcinoma bone metastasis were also explored in animal experiments. RESULTS Elevated IGF-1R expression in NPC cells correlated with an increased tendency for bone metastasis. IGF-1, secreted by osteoclasts, activated the IGF-1R/AKT/S6 pathway, promoting NPC cell proliferation in the bone marrow. Tumor-secreted GM-CSF further stimulated osteoclast differentiation, exacerbating bone resorption. The IGF-1 neutralizing antibody, NVP-AEW541 and rapamycin were respectively effective in slowing down the rate of bone metastasis and reducing bone destruction. CONCLUSION The intricate interplay among IGF-1R, IGF-1, and GM-CSF highlights potential therapeutic targets for precise control of NPC bone metastasis, providing valuable insights for developing targeted interventions.
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Affiliation(s)
- Kaifan Yang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yanjun Hu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuanyuan Feng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Kaiqun Li
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ziyan Zhu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shuyi Liu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yanling Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
| | - Bin Yu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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9
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Galal MA, Alouch SS, Alsultan BS, Dahman H, Alyabis NA, Alammar SA, Aljada A. Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance. Int J Mol Sci 2023; 24:15006. [PMID: 37834454 PMCID: PMC10573852 DOI: 10.3390/ijms241915006] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Samhar Samer Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Buthainah Saad Alsultan
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Nouf Abdullah Alyabis
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Sarah Ammar Alammar
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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10
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Piau TB, de Queiroz Rodrigues A, Paulini F. Insulin-like growth factor (IGF) performance in ovarian function and applications in reproductive biotechnologies. Growth Horm IGF Res 2023; 72-73:101561. [PMID: 38070331 DOI: 10.1016/j.ghir.2023.101561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/25/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023]
Abstract
The role of the insulin-like growth factor (IGF) system has attracted close attention. The activity of IGF binding proteins (IGFBPs) within the ovary has not been fully elucidated to date. These proteins bind to IGF with an equal, or greater, affinity than to the IGF1 receptor, thus being in the main position to regulate IGF signalling, in addition to extending the half-life of IGFs within the bloodstream and promoting IGF storage in specific tissue niches. IGF1 has an important part in cell proliferation, differentiation and apoptosis. Considering the importance of IGFs in oocyte maturation, this review sought to elucidate aspects including: IGF production mechanisms; constituent members of their family and their respective functions; the role that these factors play during folliculogenesis, together with their functions during oocyte maturation and apoptosis, and their performance during luteal development. This review also explores the role of IGFs in biotechnological applications, focusing specifically on animal genetic gain.
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Affiliation(s)
- Tathyana Benetis Piau
- University of Brasília, Institute of Biological Sciences, Department of Physiological Sciences, Brasília, DF 70910-900, Brazil
| | - Aline de Queiroz Rodrigues
- University of Brasília, Institute of Biological Sciences, Department of Physiological Sciences, Brasília, DF 70910-900, Brazil
| | - Fernanda Paulini
- University of Brasília, Institute of Biological Sciences, Department of Physiological Sciences, Brasília, DF 70910-900, Brazil.
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11
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Chen D, Guo X, Wang K, Zhao W, Chang Z, Wang Q, Xu C. Multi-Omics Analysis Reveals the Pathogenesis of Growth-Disordered Raccoon Dog. Int J Mol Sci 2023; 24:14237. [PMID: 37762538 PMCID: PMC10531513 DOI: 10.3390/ijms241814237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/08/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Microorganisms of the genus Eperythrozoon are a zoonotic chronic infectious disease with wide distribution. We found that raccoons infected with Eperythrozoon showed obvious stunting, which seriously affected the economic benefits of raccoon dogs. To investigate the pathogenesis of the raccoon dog, we used transcriptome and proteome sequencing to analyze the changes in mRNA, miRNA, and protein expression in raccoon dogs infected with Eperythrozoon and normal raccoons. The results showed that the expression levels of genes related to immunity, metabolism, and enzyme activity were significantly changed. Among these, ERLIN1, IGF1R, CREB3L1, TNS1, TENC1, and mTOR play key roles. Additionally, the miR-1268, miR-125b, miR-10-5p, and miR-10 as central miRNAs regulate the expression of these genes. Integrated transcriptomic and proteomic analyses revealed consistent trends in mRNA and protein changes in MYH9, FKBP1A, PRKCA, and CYP11B2. These results suggest that Eperythrozoon may contribute to the slow development of raccoons by affecting the expression of mRNAs and miRNAs, reducing their immunity and causing metabolic abnormalities.
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Affiliation(s)
- Danyang Chen
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
| | - Xiaolan Guo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
| | - Kaiying Wang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
| | - Weigang Zhao
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
| | - Zhongjuan Chang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
| | - Quankai Wang
- College of Animal Science and Technology, Jilin Agriculture University, Changchun 130118, China;
| | - Chao Xu
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun 130112, China; (D.C.); (X.G.); (K.W.); (W.Z.); (Z.C.)
- Innovation Center for Feeding and Utilization of Special Animals in Jilin Province and Research Center for Microbial Feed Engineering of Special Animals in Jilin Province, 4899 Juye Street, Changchun 130112, China
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12
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Torrez Lamberti MF, Parker LA, Gonzalez CF, Lorca GL. Pasteurization of human milk affects the miRNA cargo of EVs decreasing its immunomodulatory activity. Sci Rep 2023; 13:10057. [PMID: 37344543 DOI: 10.1038/s41598-023-37310-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 06/20/2023] [Indexed: 06/23/2023] Open
Abstract
In this report, we evaluated the effect of the pasteurization (P) process of mother's own milk (MOM) on the miRNA content of extracellular vesicles (EVs) and its impact on innate immune responses. Differences in size or particle number were not observed upon pasteurization of MOM (PMOM). However, significant differences were observed in the EV membrane marker CD63 and miRNA profiles. miRNA sequencing identified 33 differentially enriched miRNAs between MOMEV and PMOMEV. These changes correlated with significant decreases in the ability of PMOMEV to modulate IL-8 secretion in intestinal Caco2 cells where only MOMEV were able to decrease IL-8 secretion in presence of TNFα. While EVs from MOMEV and PMOMEV were both able to induce a tolerogenic M2-like phenotype in THP-1 macrophages, a significant decrease in the transcript levels of IL-10 and RNA sensing genes was observed with PMOMEV. Together, our data indicates that pasteurization of MOM impacts the integrity and functionality of MOMEV, decreasing its EVs-mediated immunomodulatory activity. This data provides biomarkers that may be utilized during the optimization of milk processing to preserve its bioactivity.
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Affiliation(s)
- Monica F Torrez Lamberti
- Department of Microbiology and Cell Science, Genetics Institute, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | | | - Claudio F Gonzalez
- Department of Microbiology and Cell Science, Genetics Institute, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Graciela L Lorca
- Department of Microbiology and Cell Science, Genetics Institute, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, USA.
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13
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Hassan N, Efing J, Kiesel L, Bendas G, Götte M. The Tissue Factor Pathway in Cancer: Overview and Role of Heparan Sulfate Proteoglycans. Cancers (Basel) 2023; 15:1524. [PMID: 36900315 PMCID: PMC10001432 DOI: 10.3390/cancers15051524] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
Historically, the only focus on tissue factor (TF) in clinical pathophysiology has been on its function as the initiation of the extrinsic coagulation cascade. This obsolete vessel-wall TF dogma is now being challenged by the findings that TF circulates throughout the body as a soluble form, a cell-associated protein, and a binding microparticle. Furthermore, it has been observed that TF is expressed by various cell types, including T-lymphocytes and platelets, and that certain pathological situations, such as chronic and acute inflammatory states, and cancer, may increase its expression and activity. Transmembrane G protein-coupled protease-activated receptors can be proteolytically cleaved by the TF:FVIIa complex that develops when TF binds to Factor VII (PARs). The TF:FVIIa complex can activate integrins, receptor tyrosine kinases (RTKs), and PARs in addition to PARs. Cancer cells use these signaling pathways to promote cell division, angiogenesis, metastasis, and the maintenance of cancer stem-like cells. Proteoglycans play a crucial role in the biochemical and mechanical properties of the cellular extracellular matrix, where they control cellular behavior via interacting with transmembrane receptors. For TFPI.fXa complexes, heparan sulfate proteoglycans (HSPGs) may serve as the primary receptor for uptake and degradation. The regulation of TF expression, TF signaling mechanisms, their pathogenic effects, and their therapeutic targeting in cancer are all covered in detail here.
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Affiliation(s)
- Nourhan Hassan
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
- Biotechnology/Biomolecular Chemistry Program, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Janes Efing
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
| | - Gerd Bendas
- Pharmaceutical Department, University Bonn, An der Immenburg 4, 53225 Bonn, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany
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14
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Ramos R, Cabré E, Vinyals A, Lorenzo D, Ferreres JR, Varela M, Gomá M, Paules MJ, Gutierrez C, Piulats JM, Fabra À, Caminal JM. Orthotopic murine xenograft model of uveal melanoma with spontaneous liver metastasis. Melanoma Res 2023; 33:1-11. [PMID: 36302215 DOI: 10.1097/cmr.0000000000000860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Uveal melanoma is the most common intraocular malignancy in adults. Despite the effective primary treatment, up to 50% of patients with uveal melanoma will develop metastatic lesions mainly in the liver, which are resistant to conventional chemotherapy and lead to patient's death. To date, no orthotopic murine models of uveal melanoma which can develop spontaneous metastasis are available for preclinical studies. Here, we describe a spontaneous metastatic model of uveal melanoma based on the orthotopic injection of human uveal melanoma cells into the suprachoroidal space of immunodeficient NSG mice. All mice injected with bioluminescent OMM2.5 ( n = 23) or MP41 ( n = 19) cells developed a primary tumor. After eye enucleation, additional bioluminescence signals were detected in the lungs and in the liver. At necropsy, histopathological studies confirmed the presence of lung metastases in 100% of the mice. Liver metastases were assessed in 87 and in 100% of the mice that received OMM2.5 or MP41 cells, respectively. All tumors and metastatic lesions expressed melanoma markers and the signaling molecules insulin-like growth factor type I receptor and myristoylated alanine-rich C-kinase substrate, commonly activated in uveal melanoma. The novelty of this orthotopic mouse xenograft model is the development of spontaneous metastases in the liver from the primary site, reproducing the organoespecificity of metastasis observed in uveal melanoma patients. The faster growth and the high metastatic incidence may be attributed at least in part, to the severe immunodeficiency of NSG mice. This model may be useful for preclinical testing of targeted therapies with potential uveal melanoma antimetastatic activity and to study the mechanisms involved in liver metastasis.
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Affiliation(s)
- Raquel Ramos
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)
| | - Eduard Cabré
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)
| | - Antònia Vinyals
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)
| | - Daniel Lorenzo
- Ophthalmology Department, Spanish Ocular Oncology National referal center (CSUR) and Ocular Translational Eye Research Unit, Hospital Universitari de Bellvitge (HUB)-IDIBELL
| | | | - Mar Varela
- Pathology Department, Hospital Universitari de Bellvitge
| | - Montse Gomá
- Pathology Department, Hospital Universitari de Bellvitge
| | | | - Cristina Gutierrez
- Radiotherapy Department, Institut Catalá d'Oncologia (ICO), Hospital Duran Reynals
| | - Josep M Piulats
- Medical Oncology, Institut Catalá d'Oncologia (ICO), Hospital Duran Reynals, Barcelona, Spain
| | - Àngels Fabra
- Ophthalmology Department, Spanish Ocular Oncology National referal center (CSUR) and Ocular Translational Eye Research Unit, Hospital Universitari de Bellvitge (HUB)-IDIBELL
| | - José M Caminal
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)
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15
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Convissar S, Bennett-Toomey J, Stocco C. Insulin-like growth factor 1 enhances follicle-stimulating hormone-induced phosphorylation of GATA4 in rat granulosa cells. Mol Cell Endocrinol 2023; 559:111807. [PMID: 36279967 PMCID: PMC10041677 DOI: 10.1016/j.mce.2022.111807] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
Preovulatory granulosa cell (GC) differentiation is essential for the maturation and release of oocytes from the ovary. We have previously demonstrated that follicle-stimulating hormone (FSH) and insulin-like growth factors (IGFs) closely interact to control GC function. Similarly, we showed that GATA4 mediates FSH actions and it is required for preovulatory follicle formation. This report aimed to determine in vivo the effect of FSH on GATA4 phosphorylation and to investigate whether FSH and IGF1 interact to regulate GATA4 activity. In rat ovaries, treatment with equine chorionic gonadotropin (eCG) increased the phosphorylation of GATA4, which was confined to the nucleus of GCs. Using primary rat GCs, we observed that GATA4 phosphorylation at serine 105 increases the transcriptional activity of this transcription factor. Like FSH, IGF1 stimulated GATA4 phosphorylation at serine 105. Interestingly, GATA4 phosphorylation was significantly higher in cells cotreated with FSH and IGF1 when compared to FSH or IGF1 alone, suggesting that IGF1 augments the effects of FSH on GATA4. It was also found that the enhancing effect of IGF1 requires AKT activity and is mimicked by the inhibition of glycogen synthase kinase-3 β (GSK3β), suggesting that AKT inhibition of GSK3β may play a role in the regulation of GATA4 phosphorylation. The data support an important role of the IGF1/AKT/GSK3β signaling pathway in the regulation of GATA4 transcriptional activity and provide new insights into the mechanisms by which FSH and IGF1 regulate GC differentiation. Our findings suggest that GATA4 transcriptional activation may, at least partially, mediate AKT actions in GCs.
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Affiliation(s)
- Scott Convissar
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Jill Bennett-Toomey
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Carlos Stocco
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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16
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Xia Q, Shen J, Wang Q, Ke Y, Yan Q, Li H, Zhang D, Duan S. LINC00324 in cancer: Regulatory and therapeutic implications. Front Oncol 2022; 12:1039366. [PMID: 36620587 PMCID: PMC9815511 DOI: 10.3389/fonc.2022.1039366] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
LINC00324 is a 2082 bp intergenic noncoding RNA. Aberrant expression of LINC00324 was associated with the risk of 11 tumors and was closely associated with clinicopathological features and prognostic levels of 7 tumors. LINC00324 can sponge multiple miRNAs to form complex ceRNA networks, and can also recruit transcription factors and bind RNA-binding protein HuR, thereby regulating the expression of a number of downstream protein-coding genes. LINC00324 is involved in 4 signaling pathways, including the PI3K/AKT signaling pathway, cell cycle regulatory pathway, Notch signaling pathway, and Jak/STAT3 signaling pathway. High expression of LINC00324 was associated with larger tumors, a higher degree of metastasis, a higher TNM stage and clinical stage, and shorter OS. Currently, four downstream genes in the LINC00324 network have targeted drugs. In this review, we summarize the molecular mechanisms and clinical value of LINC00324 in tumors and discuss future directions and challenges for LINC00324 research.
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Affiliation(s)
- Qing Xia
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China,College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang, China,Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China
| | - Jinze Shen
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Qurui Wang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Yufei Ke
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Qibin Yan
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Hanbing Li
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Dayong Zhang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China,*Correspondence: Dayong Zhang, ; Shiwei Duan,
| | - Shiwei Duan
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China,*Correspondence: Dayong Zhang, ; Shiwei Duan,
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17
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Liu J, Liu S, Hao L, Liu F, Mu S, Wang T. Uncovering the mechanism of Radix Paeoniae Alba in the treatment of restless legs syndrome based on network pharmacology and molecular docking. Medicine (Baltimore) 2022; 101:e31791. [PMID: 36401463 PMCID: PMC9678500 DOI: 10.1097/md.0000000000031791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Restless legs syndrome (RLS) is a neurological motor disorder with a high prevalence. The treatment efficacy of RLS is unsatisfactory. Radix Paeoniae Alba (RPA) can effectively treat RLS symptoms such as the discomfort of the legs. RPA has great potential for the development of new medications for RLS. Hence, we explored the mechanism of RPA in the treatment of RLS using network pharmacology and molecular docking. The active components and targets of RPA were obtained from the Traditional Chinese Medicine System Pharmacology database and analysis platform and PharmMapper platform. The RLS-related targets were found in GeneCards, OMIM, DrugBank, and DisGeNET databases. The overlapping targets of RPA and RLS were then collected. The "active components-overlapping targets" network was built, and network topology analysis was performed. Furthermore, Cytoscape 3.9.1 software was used to screen the key components of RPA in the treatment of RLS. Protein-protein interaction was performed using the Search Tool for the Retrieval of Interacting Genes. The gene ontology functions and Kyoto Encyclopedia of Genes and Genomes signaling pathways were analyzed using ClusterProfiler, PathView, and other R packages to reveal the main mechanism of RPA in treating RLS. Component and protein structures were downloaded from the Traditional Chinese Medicine System Pharmacology and Protein Data Bank databases, respectively. The AutoDock 4.2.6 software was used for molecular docking. A total of 12 active components and 109 targets of RPA, as well as 2387 RLS-related targets, were collected. Following that, 47 overlapping targets were obtained. Furthermore, 5 key components and 12 core targets were screened. The results of gene ontology functions were as follows: 2368 biological processes, 264 molecular functions, and 164 cellular components. A total of 207 Kyoto Encyclopedia of Genes and Genomes signaling pathways were obtained, including the lipid and atherosclerosis pathway, the endocrine resistance pathway, the prolactin signaling pathway, and the IL-17 signaling pathway. The components and the core targets completed molecular docking stably. RPA has multi-component, multi-target, and multi-pathway characteristics in treating RLS, which could provide a basis for future research and improve clinical efficacy.
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Affiliation(s)
- Jun Liu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Suxian Liu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liansheng Hao
- Department 2 of Bone Trauma, Liaocheng Hospital of Traditional Chinese Medicine, Liaocheng, China
| | - Fangfang Liu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengkai Mu
- Department 2 of Bone Trauma, Liaocheng Hospital of Traditional Chinese Medicine, Liaocheng, China
| | - Tengteng Wang
- Department of Acupuncture, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- * Correspondence: Tengteng Wang, Department of Acupuncture, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China (e-mail: )
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18
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Jones CE, Sharick JT, Sizemore ST, Cukierman E, Strohecker AM, Leight JL. A miniaturized screening platform to identify novel regulators of extracellular matrix alignment. CANCER RESEARCH COMMUNICATIONS 2022; 2:1471-1486. [PMID: 36530465 PMCID: PMC9757767 DOI: 10.1158/2767-9764.crc-22-0157] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/03/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
Extracellular matrix alignment contributes to metastasis in a number of cancers and is a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Cancer-associated fibroblasts (CAF) play a critical role in this process, particularly via matrix production and modulation of key signaling pathways controlling cell adhesion and contractility. Stroma normalization, as opposed to elimination, is a highly sought strategy, and screening for drugs that effectively alter extracellular matrix (ECM) alignment is a practical way to identify novel CAF-normalizing targets that modulate ECM organization. To meet this need, we developed a novel high-throughput screening platform in which fibroblast-derived matrices were produced in 384-well plates, imaged with automated confocal microscopy, and analyzed using a customized MATLAB script. This platform is a technical advance because it miniaturizes the assay, eliminates costly and time-consuming experimental steps, and streamlines data acquisition and analysis to enable high-throughput screening applications. As a proof of concept, this platform was used to screen a kinase inhibitor library to identify modulators of matrix alignment. A number of novel potential regulators were identified, including several receptor tyrosine kinases (c-MET, tropomyosin receptor kinase 1 (NTRK1), HER2/ERBB2) and the serine/threonine kinases protein kinase A, C, and G (PKA, PKC, and PKG). The expression of these regulators was analyzed in publicly available patient datasets to examine the association between stromal gene expression and patient outcomes.
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Affiliation(s)
- Caitlin E. Jones
- Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio
| | - Joe T. Sharick
- Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio
- The James Comprehensive Cancer Center, Program in Cancer Biology, The Ohio State University, Columbus, Ohio
| | - Steven T. Sizemore
- The James Comprehensive Cancer Center, Program in Cancer Biology, The Ohio State University, Columbus, Ohio
- Department of Radiation Oncology, The Ohio State University, Columbus, Ohio
| | - Edna Cukierman
- Cancer Signaling and Epigenetics, The Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania
| | - Anne Marie Strohecker
- The James Comprehensive Cancer Center, Program in Cancer Biology, The Ohio State University, Columbus, Ohio
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio
| | - Jennifer L. Leight
- Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio
- The James Comprehensive Cancer Center, Program in Cancer Biology, The Ohio State University, Columbus, Ohio
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Tang Y, Sun Y, Zeng J, Yuan B, Zhao Y, Geng X, Jia L, Zhou S, Chen X. Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossification of the posterior longitudinal ligament. J Nanobiotechnology 2022; 20:452. [PMID: 36243800 PMCID: PMC9571456 DOI: 10.1186/s12951-022-01655-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background Ossification of the posterior longitudinal ligament (OPLL) is a disabling disease whose pathogenesis is still unclear, and there are no effective cures or prevention methods. Exosomal miRNA plays an important role in the osteogenesis of ectopic bone. Therefore, we focused on the downregulation of miR-140-5p in OPLL cell-derived exosomes to explore the mechanism by which exosomal miR-140-5p inhibits osteogenesis in OPLL. Results Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and exosomal markers. Exosomal RNA was extracted to perform miRNA sequencing and disclose the differentially expressed miRNAs, among which miR-140-5p was significantly downregulated. Confocal microscopy was used to trace the exosomal miR-140-5p delivered from OPLL cells to human mesenchymal stem cells (hMSCs). In vitro, we verified that exosomal miR-140-5p inhibited the osteoblast differentiation of hMSCs by targeting IGF1R and suppressing the phosphorylation of the IRS1/PI3K/Akt/mTOR pathway. In vivo, we verified that exosomal miR-140-5p inhibited ectopic bone formation in mice as assessed by micro-CT and immunohistochemistry. Conclusions We found that exosomal miR-140-5p could inhibit the osteogenic differentiation of hMSCs by targeting IGF1R and regulating the mTOR pathway, prompting a further potential means of drug treatment and a possible target for molecular therapy of OPLL. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01655-8.
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Affiliation(s)
- Yifan Tang
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Yanqing Sun
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Junkai Zeng
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Bo Yuan
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Yin Zhao
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Xiangwu Geng
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Lianshun Jia
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Shengyuan Zhou
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.
| | - Xiongsheng Chen
- Spine Center, Department of Orthopedics, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.
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20
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Abstract
Single-pass transmembrane receptors (SPTMRs) represent a diverse group of integral membrane proteins that are involved in many essential cellular processes, including signal transduction, cell adhesion, and transmembrane transport of materials. Dysregulation of the SPTMRs is linked with many human diseases. Despite extensive efforts in past decades, the mechanisms of action of the SPTMRs remain incompletely understood. One major hurdle is the lack of structures of the full-length SPTMRs in different functional states. Such structural information is difficult to obtain by traditional structural biology methods such as X-ray crystallography and nuclear magnetic resonance (NMR). The recent rapid development of single-particle cryo-electron microscopy (cryo-EM) has led to an exponential surge in the number of high-resolution structures of integral membrane proteins, including SPTMRs. Cryo-EM structures of SPTMRs solved in the past few years have tremendously improved our understanding of how SPTMRs function. In this review, we will highlight these progresses in the structural studies of SPTMRs by single-particle cryo-EM, analyze important structural details of each protein involved, and discuss their implications on the underlying mechanisms. Finally, we also briefly discuss remaining challenges and exciting opportunities in the field.
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Affiliation(s)
- Kai Cai
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
| | - Xuewu Zhang
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Corresponding Author: Xuewu Zhang, Department of pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Xiao-chen Bai
- Departments of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA
- Corresponding Author: Xiao-chen Bai, Department of Biophysics, UT Southwestern Medical Center, Dallas, TX 75390, USA;
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21
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Association of Helicobacter pylori Infection with Papillary Thyroid Carcinoma: A Case-control Study. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2022. [DOI: 10.5812/ijcm-118031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: The thyroid nodules incidence has risen worldwide. Although factors such as increasing the use of imaging techniques and more rapid detection of small thyroid nodules have been implicated in the recent rise in thyroid cancer incidence, some environmental parameters such as infectious agents may be involved. Helicobacter pylori infection is an environmental risk factor, which may mimic the antigenic properties of membranes of thyrocytes. Objectives: This study aimed at evaluating the association of H. pylori infection with benign and malignant thyroid nodules in comparison with the control group. Methods: Patients with benign thyroid nodules, papillary thyroid cancer (PTC), and euthyroid healthy controls without thyroid nodules that had just been diagnosed were included in the study. All participants underwent clinical examination. Various biochemical parameters such as serum H. pylori Ab (IgG) and thyroid function tests were measured. Comparisons were made between groups. Results: Finally, 370 patients with benign thyroid nodules, 364 patients with PTC, and 360 healthy subjects without nodules participated as a control group. In the patients with PTC, the prevalence of H. pylori infection was 89.6%, while in the group of patients with benign thyroid nodules and the control group was 81.1% and 75%, respectively (P < 0.001). Helicobacter pylori antibody (Ab) titer was not significantly associated with any of the anthropometric and biochemical variables. Conclusions: Helicobacter pylori infection was significantly higher in patients with benign thyroid nodules and PTC than in the control group. Also, the rate of infection was significantly higher in the malignant nodule group than in the benign thyroid nodules group.
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22
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Wang X, Zhou P, Lin L, Wu B, Fu Z, Huang X, Zhu D. Effective natural inhibitors targeting IGF-1R by computational study. Aging (Albany NY) 2022; 14:4874-4887. [PMID: 35680570 PMCID: PMC9217697 DOI: 10.18632/aging.204117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/10/2022] [Indexed: 11/25/2022]
Abstract
IGF-1R belongs to a tyrosine kinase family and is currently a newly discovered drug target. IGF-1R inhibitors can bind directly to IGF-1R to achieve the effect of inhibiting the function of IGF-1R. At present, IGF-1R inhibitors have good clinical effects on Ewing sarcoma in the clinic. In this article, we screened compounds capable of inhibiting IGF-1R function through computer-aided virtual technology. First, some molecules with good docking properties for IGF-1R can be screened by LibDock. Then, ADME analysis (adsorption, distribution, metabolism, and excretion) and toxicity indicators were performed. The mechanism of binding and the binding affinity in the middle of IGF-1R and ligand were verified using molecular docking. Ultimately, the stability of ligand-receptor complex was evaluated using molecular dynamics simulations. In line with the results, two natural compounds ZINC000014946303 and ZINC000006003042 were found in the ZINC database, potential effective inhibitors of IGF-1R. ZINC000014946303 and ZINC000006003042 can bind to IGF-1R with high binding affinity as predicted by molecular docking. It was also found that they are not hepatotoxic, with less developmental toxicity potential, rodent carcinogenicity, Ames mutagenicity, and high tolerance to cytochrome P4502D6. Hereby, this study aimed to screen out ideal compounds that have inhibitory effects on IGF-1R from the drug library and, at the same time, provide a direction for the future development of IGF-1R inhibitors.
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Affiliation(s)
- Xinyu Wang
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
| | - Pengcheng Zhou
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
| | - Liangxin Lin
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
| | - Bo Wu
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
| | - Zhaoyu Fu
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
| | - Xing Huang
- Department of Radiology, Jilin Province People's Hospital, Changchun, China
| | - Dong Zhu
- Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
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Wang X, Song Z, Meng Q, Xia S, Wang C, Huang X. Circular RNA circ_0006089 regulates the IGF1R expression by targeting miR-143-3p to promote gastric cancer proliferation, migration and invasion. Cell Cycle 2022:1-14. [PMID: 35545863 DOI: 10.1080/15384101.2022.2075197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 04/13/2022] [Accepted: 05/03/2022] [Indexed: 02/08/2023] Open
Abstract
Circular RNAs (circRNAs) figure prominently in regulating the progression of a variety of human malignancies. This study was performed to probe how circ_0006089 functioned in gastric cancer (GC). CircRNA expression profile GSE83521 was downloaded from Gene Expression Omnibus (GEO) database, and circRNAs and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure circ_0006089, microRNA-143-3p (miR-143-3p) and insulin-like growth factor 1 receptor (IGF1R) mRNA expressions in GC tissues and cell lines. Kaplan-Meier curves were used to detect the relationship between circ_0006089 expression and overall survival time of GC patients. Cell counting kit-8 (CCK-8) and 5-bromo-2-deoxyuridine (BrdU) assays were employed to detect the proliferative ability of GC cells after circ_0006089 was overexpressed or knocked down. Wound healing assay and Transwell assay were executed to examine the migration and invasion ability of GC cells. Western blot was adopted to detect IGF1R protein expressions. Circ_0006089 expression was up-regulated in GC samples and cell lines. And high circ_0006089 expression was associated with shorter survival time in GC patients. Circ_0006089 overexpression in GC cells significantly accelerated GC cell proliferation, migration and invasion, whereas circ_0006089 knockdown resulted in the opposite effects. Additionally, miR-143-3p was validated as a downstream target of circ_0006089, and circ_0006089 could positively regulate IGF1R expression via repressing miR-143-3p. Circ_0006089 is highly expressed in GC, and it promotes the malignancy of GC cells via modulating miR-143-3p/IGF1R axis, suggesting that circ_0006089 may serve as a promising therapeutic target for GC.
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Affiliation(s)
- Xian Wang
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Chinese PLA Medical School, Beijing, China
| | - Zhou Song
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qingyu Meng
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Shaoyou Xia
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Chunxi Wang
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaohui Huang
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
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Lesire L, Leroux F, Deprez-Poulain R, Deprez B. Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer? Cells 2022; 11:1228. [PMID: 35406791 PMCID: PMC8998118 DOI: 10.3390/cells11071228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE's functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics.
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Affiliation(s)
| | | | - Rebecca Deprez-Poulain
- INSERM U1177 Drugs and Molecules for Living Systems, Institut Pasteur de Lille, European Genomic Institute for Diabetes, University of Lille, F-59000 Lille, France; (L.L.); (F.L.); (B.D.)
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25
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Song X, Wei C, Li X. The Signaling Pathways Associated With Breast Cancer Bone Metastasis. Front Oncol 2022; 12:855609. [PMID: 35372035 PMCID: PMC8965611 DOI: 10.3389/fonc.2022.855609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/16/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Breast cancer (BC) is now the leading cause of cancer in women, and bone is the primary site of distant BC metastasis. BC bone metastasis seriously affects the quality of life of patients and increases the mortality rate. However, the mechanism of BC bone metastasis is not fully understood. MAIN BODY Paget's "seed and soil" hypothesis led experts to explore the relationship between surface markers and receptors in breast tumors and various growth factors in bone. The relevant breast tumor markers serve as "seeds", and the bone microenvironment that is suitable for the survival of the tumor serves as the "soil". These factors interact to make up an entire system and form feedback pathways that accelerate the production of various cytokines, attracting BC cells to migrate to bone tissue, which worsens the development of BC and seriously affects the prognosis of patients. This process is a vicious cycle. At present, there are seven major signaling pathways involved in BC bone metastasis: the OPG/RANK/RANKL signaling pathway, TGF-β signaling pathway, IGF system, PI3K-AKT-mTOR signaling pathway, Wnt signaling pathway and Hippo signaling pathway. In addition, FGF-FGFR signaling pathway, androgen-AR/LSD1-target gene pathway, Notch signaling pathway, JAK-STAT signaling pathway and CaN/NFATC1 signaling pathway also seem to be associated with BC bone metastasis. CONCLUSION This review focuses on the signaling pathways related to BC bone metastasis and explores the interactions among these pathways, which will lay a solid theoretical foundation for further understanding the mechanism of BC bone metastasis and developing effective targeted therapeutic drugs.
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Affiliation(s)
- Xuelian Song
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, China
| | - Changran Wei
- Department of The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiangqi Li
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, China
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miRNA-Profiling in Ejaculated and Epididymal Pig Spermatozoa and Their Relation to Fertility after Artificial Insemination. BIOLOGY 2022; 11:biology11020236. [PMID: 35205102 PMCID: PMC8869492 DOI: 10.3390/biology11020236] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 02/01/2023]
Abstract
Simple Summary The present study searched for the presence and abundance of porcine spermatozoa small RNA sequences (microRNAs) that have the potential to alter gene expression patterns. Four different sperm sources were compared: spermatozoa from three different sections of the ejaculate and from the caudal epididymis, also classed as spermatozoa from higher (HF) or lower (LF) fertility boars. Sperm miRNAs were compared using high-output small RNA sequencing. We identified five sperm miRNAs not previously reported in pigs. Differences in abundance of four miRNAs known to affect the expression of genes with key roles in fertility were related to boar fertility. These miRNAs could be used as fertility markers in artificial insemination programs. Abstract MicroRNAs (miRNAs) are short non-coding RNAs (20–25 nucleotides in length) capable of regulating gene expression by binding -fully or partially- to the 3’-UTR of target messenger RNA (mRNA). To date, several studies have investigated the role of sperm miRNAs in spermatogenesis and their remaining presence toward fertilization and early embryo development. However, little is known about the miRNA cargo in the different sperm sources and their possible implications in boar fertility. Here, we characterized the differential abundance of miRNAs in spermatozoa from the terminal segment of the epididymis and three different fractions of the pig ejaculate (sperm-peak, sperm-rich, and post-sperm rich) comparing breeding boars with higher (HF) and lower (LF) fertility after artificial insemination (AI) using high-output small RNA sequencing. We identified five sperm miRNAs that, to our knowledge, have not been previously reported in pigs (mir-10386, mir-10390, mir-6516, mir-9788-1, and mir-9788-2). Additionally, four miRNAs (mir-1285, mir-92a, mir-34c, mir-30), were differentially expressed among spermatozoa sourced from ejaculate fractions and the cauda epididymis, and also different abundance was found between HF and LF groups in mir-182, mir-1285, mir-191, and mir-96. These miRNAs target genes with key roles in fertility, sperm survival, immune tolerance, or cell cycle regulation, among others. Linking the current findings with the expression of specific sperm proteins would help predict fertility in future AI-sires.
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Yang L, Li K, Li W, Wang C, Liu Y, Zhang H, Pan J, Qi S, Peng J. Expression of Insulin-Like Growth Factor Type 1 Receptor Is Linked to Inflammation in Adamantinomatous Craniopharyngioma. Neuroendocrinology 2022; 112:917-926. [PMID: 34915523 DOI: 10.1159/000521458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/08/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. METHODS We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. RESULTS Patients in the IGF1R high-expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate, and lower progression-free survival. β-Catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell-like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein and decreased the transcription level of interleukin-6. CONCLUSIONS High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor stem cell-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. IGF1R plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.
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Affiliation(s)
- Lang Yang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Neurosurgery, People's Hospital of Deyang City, Deyang, China
| | - Kai Li
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weizhao Li
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chaohu Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Liu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huarong Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Pan
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Songtao Qi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junxiang Peng
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Wen X, Xi Y, Zhang Y, Jiao L, Shi S, Bai S, Sun F, Chang G, Wu R, Hao J, Li H. DR1 activation promotes vascular smooth muscle cell apoptosis via up-regulation of CSE/H 2 S pathway in diabetic mice. FASEB J 2021; 36:e22070. [PMID: 34859931 DOI: 10.1096/fj.202101455r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/07/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022]
Abstract
The important role of hydrogen sulfide (H2 S) as a novel gasotransmitter in inhibiting proliferation and promoting apoptosis of vascular smooth muscle cells (VSMCs) has been widely recognized. The dopamine D1 receptor (DR1), a G protein coupled receptor, inhibits atherosclerosis by suppressing VSMC proliferation. However, whether DR1 contributes to VSMC apoptosis via the induction of endogenous H2 S in diabetic mice is unclear. Here, we found that hyperglycemia decreased the expressions of DR1 and cystathionine-γ-lyase (CSE, a key enzyme for endogenous H2 S production) and reduced endogenous H2 S generation in mouse arteries and cultured VSMCs. DR1 agonist SKF38393 increased DR1 and CSE expressions and stimulated endogenous H2 S generation. Sodium hydrosulfide (NaHS, a H2 S donor) increased CSE expressions and H2 S generation but had no effect on DR1 expression. In addition, high glucose (HG) increased VSMC apoptosis, up-regulated IGF-1-IGF-1R and HB-EGF-EGFR, and stimulated ERK1/2 and PI3K-Akt pathways. Overexpression of DR1, the addition of SKF38393 or supply of NaHS further promoted VSMC apoptosis and down-regulated the above pathways. Knock out of CSE or the addition of the CSE inhibitor poly propylene glycol diminished the effect of SKF38393. Moreover, calmodulin (CaM) interacted with CSE in VSMCs; HG increased intracellular Ca2+ concentration and induced CaM expression, further strengthened the interaction of CaM with CSE in VSMCs, which were further enhanced by SKF38393. CaM inhibitor W-7, inositol 1,4,5-trisphosphate (IP3 ) inhibitor 2-APB, or ryanodine receptor inhibitor tetracaine abolished the stimulatory effect of SKF38393 on CaM expression and intracellular Ca2+ concentration. Taken together, these results suggest that DR1 up-regulates CSE/H2 S signaling by inducing the Ca2+ -CaM pathway followed by down-regulations of IGF-1-IGF-1R and HB-EGF-EGFR and their downstream ERK1/2 and PI3K-Akt, finally promoting the apoptosis of VSMCs in diabetic mice.
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Affiliation(s)
- Xin Wen
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yuxin Xi
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yuanzhou Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lijie Jiao
- School of Medicine, Xiamen University, Xiamen, China
| | - Sa Shi
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Shuzhi Bai
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Fengqi Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Guiquan Chang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Ren Wu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Jinghui Hao
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Hongzhu Li
- Department of Pathophysiology, Harbin Medical University, Harbin, China.,School of Medicine, Xiamen University, Xiamen, China
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Rhyu J, Yu R. Newly discovered endocrine functions of the liver. World J Hepatol 2021; 13:1611-1628. [PMID: 34904032 PMCID: PMC8637678 DOI: 10.4254/wjh.v13.i11.1611] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
The liver, the largest solid visceral organ of the body, has numerous endocrine functions, such as direct hormone and hepatokine production, hormone metabolism, synthesis of binding proteins, and processing and redistribution of metabolic fuels. In the last 10 years, many new endocrine functions of the liver have been discovered. Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones [including 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF-1), and angiotensinogen], hepatic metabolism of hormones (including thyroid hormones, glucagon-like peptide-1, and steroid hormones), and actions of specific binding proteins to glucocorticoids, sex steroids, and thyroid hormones. These studies have furthered insight into cirrhosis-associated endocrinopathies, such as hypogonadism, osteoporosis, IGF-1 deficiency, vitamin D deficiency, alterations in glucose and lipid homeostasis, and controversially relative adrenal insufficiency. Several novel endocrine functions of the liver have also been unraveled, elucidating the liver’s key negative feedback regulatory role in the pancreatic α cell-liver axis, which regulates pancreatic α cell mass, glucagon secretion, and circulating amino acid levels. Betatrophin and other hepatokines, such as fetuin-A and fibroblast growth factor 21, have also been discovered to play important endocrine roles in modulating insulin sensitivity, lipid metabolism, and body weight. It is expected that more endocrine functions of the liver will be revealed in the near future.
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Affiliation(s)
- Jane Rhyu
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Run Yu
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, United States
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Exosomes Derived from lncRNA TCTN2-Modified Mesenchymal Stem Cells Improve Spinal Cord Injury by miR-329-3p/IGF1R Axis. J Mol Neurosci 2021; 72:482-495. [PMID: 34623606 DOI: 10.1007/s12031-021-01914-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/04/2021] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs)-derived exosomes play significant roles in alleviating spinal cord injury (SCI). Previous study showed that long non-coding RNA tectonic family member 2 (TCTN2) was able to relieve SCI. Herein, whether TCTN2 exerted its roles in functional recovery after SCI via exosomes derived from MSCs was explored. The SCI model was established in rats, and the neurological function was evaluated using the Basso, Beattie, and Bresnahan (BBB) scoring. Lipopolysaccharide (LPS)-induced differentiated PC12 cells were used as an in vitro model for neurotoxicity research. The expression of genes and proteins was detected by qRT-PCR and Western blot. Exosomes were isolated by ultracentrifugation and qualified by TEM and Western blot. In vitro assays were performed using CCK-8 assay, EdU assay, and flow cytometry, respectively. Dual-luciferase reporter assay and RIP assay were used to confirm the target relationship between miR-329-3p and TCTN2 or insulin-like growth factor1 receptor (IGF1R). TCTN2 expression was down-regulated in SCI model rat and lipopolysaccharide (LPS)-stimulated PC12 cells. MSCs produced exosomes and could package TCTN2 into secreted exosomes. Tail vein injection of TCTN2 exosomes into rats significantly improved functional recovery of SCI. Meanwhile, TCTN2 exosomes treatment alleviated LPS-induced neuronal apoptosis, inflammation, and oxidative stress in vitro. Additionally, TCTN2 targeted miR-329-3p and subsequently regulated the expression of its target IGF1R. Rescue assays suggested that miR-329-3p/IGF1R axis mediated the beneficial effects of TCTN2 exosomes on LPS-treated PC12 cells. In all, exosomes derived from TCTN2-modified MSCs could improve functional recovery of SCI in vivo and attenuate LPS-induced neuronal apoptosis, inflammation, and oxidative stress in vitro via miR-329-3p/IGF1R axis, suggesting a novel insight into the development of MSC-exosomes-based therapy for SCI.
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Weidle UH, Nopora A. MicroRNAs Involved in Small-cell Lung Cancer as Possible Agents for Treatment and Identification of New Targets. Cancer Genomics Proteomics 2021; 18:591-603. [PMID: 34479913 DOI: 10.21873/cgp.20283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 11/10/2022] Open
Abstract
Small-cell lung cancer, a neuro-endocrine type of lung cancers, responds very well to chemotherapy-based agents. However, a high frequency of relapse due to adaptive resistance is observed. Immunotherapy-based treatments with checkpoint inhibitors has resulted in improvement of treatment but the responses are not as impressive as in other types of tumor. Therefore, identification of new targets and treatment modalities is an important issue. After searching the literature, we identified eight down-regulated microRNAs involved in radiation- and chemotherapy-induced resistance, as well as three up-regulated and four down-regulated miRNAs with impacts on proliferation, invasion and apoptosis of small-cell lung cancer cells in vitro. Furthermore, one up-regulated and four down-regulated microRNAs with in vivo activity in SCLC cell xenografts were identified. The identified microRNAs are candidates for inhibition or reconstitution therapy. The corresponding targets are candidates for inhibition or functional reconstitution with antibody-based moieties or small molecules.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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A phase II study of the insulin-like growth factor type I receptor inhibitor IMC-A12 in patients with metastatic uveal melanoma. Melanoma Res 2021; 30:574-579. [PMID: 32976223 PMCID: PMC7643799 DOI: 10.1097/cmr.0000000000000694] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Uveal melanoma is a rare and aggressive malignancy and up to half of all patients will develop metastatic disease despite the effective treatment of the primary tumor. Insulin-like growth factors I/II play a fundamental role in the cell migration, proliferation, and apoptosis. IMC-A12, a mAb specifically targets insulin-like growth factor type I receptor, has shown promise in preclinical studies. We performed a multicenter phase II study for patients with metastatic uveal melanoma administered IMC-A12 10 mg/kg IV every two weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response (proportion of patients with complete or partial response), and secondary endpoints were disease control rate, progression-free survival, and overall survival. A total of 18 patients enrolled in this study (10 males and eight females) with a median age. Ten patients (55%) had stable disease, seven patients (38%) had progression as best overall response. No partial response or complete response was observed; however, the disease control rate, defined as complete response + partial response + stable disease ≥3 months, was 50%. Median progression-free survival was 3.1 months, and median overall survival was 13.8 months. Adverse events of any grade occurred in 13 patients (72.2%). Treatment-related grade 3 adverse events were rare, and there were no grade 4 or 5 related adverse events. IMC-A12 was very well tolerated, however, showed limited clinical activity in uveal melanoma as a single agent. Due to its low toxicity profile it could be studied in combination with other pathway-specific agents.
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Yang C, Zhang Y, Segar N, Huang C, Zeng P, Tan X, Mao L, Chen Z, Haglund F, Larsson O, Chen Z, Lin Y. Nuclear IGF1R interacts with NuMA and regulates 53BP1‑dependent DNA double‑strand break repair in colorectal cancer. Oncol Rep 2021; 46:168. [PMID: 34165167 PMCID: PMC8250583 DOI: 10.3892/or.2021.8119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Nuclear insulin-like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation-coupled mass spectrometry was performed in an IGF1R-overexpressing SW480-OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double-strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53-binding protein 1 (53BP1)-NuMA colocalization between IGF1R-positive (R+) and IGF1R-negative (R−) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R− cells during IR-induced DNA damage. By contrast, the level of NuMA-53BP1 was markedly lower in R+ cells compared with R− cells. The present data suggested a regulatory role of nIGF1R in 53BP1-dependent DSB repair through its interaction with NuMA. Bright-field PLA analysis on a paraffin-embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA-53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1-dependent DDR by regulating the NuMA-53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.
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Affiliation(s)
- Chen Yang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Yifan Zhang
- Department of Clinical Pathology and Cytology, Karolinska University Hospital Solna, 171 64 Solna, Stockholm, Sweden
| | - Nelly Segar
- Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Changhao Huang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Pengwei Zeng
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Xiangzhou Tan
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Linfeng Mao
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Zhikang Chen
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Felix Haglund
- Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Olle Larsson
- Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China
| | - Yingbo Lin
- Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden
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Tzanakakis GN, Giatagana EM, Berdiaki A, Spyridaki I, Hida K, Neagu M, Tsatsakis AM, Nikitovic D. The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis. Cancers (Basel) 2021; 13:cancers13102478. [PMID: 34069554 PMCID: PMC8160938 DOI: 10.3390/cancers13102478] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Bone sarcomas are mesenchymal origin tumors. Bone sarcoma patients show a variable response or do not respond to chemotherapy. Notably, improving efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges in sarcoma therapy. Insulin-like growth factors 1 and 2 (IGF-1 and -2) and their respective receptors are a multifactorial system that significantly contributes to bone sarcoma pathogenesis. Most clinical trials aiming at the IGF pathway have had limited success. Developing combinatorial strategies to enhance antitumor responses and better classify the patients that could best benefit from IGF-axis targeting therapies is in order. A plausible approach for developing a combinatorial strategy is to focus on the tumor microenvironment (TME) and processes executed therein. Herewith, we will discuss how the interplay between IGF-signaling and the TME constituents affects bone sarcomas’ basal functions and their response to therapy. Potential direct and adjunct therapeutical implications of the extracellular matrix (ECM) effectors will also be summarized. Abstract Bone sarcomas, mesenchymal origin tumors, represent a substantial group of varying neoplasms of a distinct entity. Bone sarcoma patients show a limited response or do not respond to chemotherapy. Notably, developing efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges in sarcoma therapy. Insulin-like growth factors 1 and 2 (IGF-1 and -2) and their respective receptors are a multifactorial system that significantly contributes to bone sarcoma pathogenesis. Whereas failures have been registered in creating novel targeted therapeutics aiming at the IGF pathway, new agent development should continue, evaluating combinatorial strategies for enhancing antitumor responses and better classifying the patients that could best benefit from these therapies. A plausible approach for developing a combinatorial strategy is to focus on the tumor microenvironment (TME) and processes executed therein. Herewith, we will discuss how the interplay between IGF-signaling and the TME constituents affects sarcomas’ basal functions and their response to therapy. This review highlights key studies focusing on IGF signaling in bone sarcomas, specifically studies underscoring novel properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. Potential direct and adjunct therapeutical implications of the extracellular matrix (ECM) effectors will also be summarized.
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Affiliation(s)
- George N. Tzanakakis
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
- Laboratory of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Eirini-Maria Giatagana
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Aikaterini Berdiaki
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Ioanna Spyridaki
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Kyoko Hida
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan;
| | - Monica Neagu
- Department of Immunology, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
| | - Aristidis M. Tsatsakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - Dragana Nikitovic
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
- Correspondence:
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Covell DG. Bioinformatic analysis linking genomic defects to chemosensitivity and mechanism of action. PLoS One 2021; 16:e0243336. [PMID: 33909629 PMCID: PMC8081165 DOI: 10.1371/journal.pone.0243336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/16/2021] [Indexed: 11/18/2022] Open
Abstract
A joint analysis of the NCI60 small molecule screening data, their genetically defective genes, and mechanisms of action (MOA) of FDA approved cancer drugs screened in the NCI60 is proposed for identifying links between chemosensitivity, genomic defects and MOA. Self-Organizing-Maps (SOMs) are used to organize the chemosensitivity data. Student's t-tests are used to identify SOM clusters with enhanced chemosensitivity for tumor cell lines with versus without genetically defective genes. Fisher's exact and chi-square tests are used to reveal instances where defective gene to chemosensitivity associations have enriched MOAs. The results of this analysis find a relatively small set of defective genes, inclusive of ABL1, AXL, BRAF, CDC25A, CDKN2A, IGF1R, KRAS, MECOM, MMP1, MYC, NOTCH1, NRAS, PIK3CG, PTK2, RPTOR, SPTBN1, STAT2, TNKS and ZHX2, as possible candidates for roles in chemosensitivity for compound MOAs that target primarily, but not exclusively, kinases, nucleic acid synthesis, protein synthesis, apoptosis and tubulin. These results find exploitable instances of enhanced chemosensitivity of compound MOA's for selected defective genes. Collectively these findings will advance the interpretation of pre-clinical screening data as well as contribute towards the goals of cancer drug discovery, development decision making, and explanation of drug mechanisms.
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Affiliation(s)
- David G. Covell
- Information Technologies Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick, MD, United States of America
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Candelotti E, De Luca R, Megna R, Maiolo M, De Vito P, Gionfra F, Percario ZA, Borgatti M, Gambari R, Davis PJ, Lin HY, Polticelli F, Persichini T, Colasanti M, Affabris E, Pedersen JZ, Incerpi S. Inhibition by Thyroid Hormones of Cell Migration Activated by IGF-1 and MCP-1 in THP-1 Monocytes: Focus on Signal Transduction Events Proximal to Integrin αvβ3. Front Cell Dev Biol 2021; 9:651492. [PMID: 33898447 PMCID: PMC8060509 DOI: 10.3389/fcell.2021.651492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023] Open
Abstract
Interaction between thyroid hormones and the immune system is reported in the literature. Thyroid hormones, thyroxine, T4, but also T3, act non-genomically through mechanisms that involve a plasma membrane receptor αvβ3 integrin, a co-receptor for insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a crosstalk between thyroid hormones and IGF-1 because thyroid hormones inhibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts, and the effects are mediated by integrin αvβ3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing αvβ3 integrin in their cell membrane, we focused on the crosstalk between thyroid hormones and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1), studying cell migration and proliferation stimulated by the two chemokines, and the role of αvβ3 integrin, using inhibitors of αvβ3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes, stimulating cell migration, and thyroid hormone inhibits the effect through αvβ3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through αvβ3 integrin, an example of a crosstalk between genomic and non-genomic effects. We also studied the effects of thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signaling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of thyroid hormones, integrin αvβ3.
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Affiliation(s)
| | - Roberto De Luca
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Roberto Megna
- Department of Science, Roma Tre University, Rome, Italy
| | | | - Paolo De Vito
- Department of Biology, Tor Vergata University, Rome, Italy
| | - Fabio Gionfra
- Department of Science, Roma Tre University, Rome, Italy
| | | | - Monica Borgatti
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Paul J Davis
- Department of Medicine, Albany Medical College, Albany, NY, United States.,Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, United States
| | - Hung-Yun Lin
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, United States.,Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
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Breast Cancer and the Other Non-Coding RNAs. Int J Mol Sci 2021; 22:ijms22063280. [PMID: 33807045 PMCID: PMC8005115 DOI: 10.3390/ijms22063280] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is very heterogenous and the most common gynaecological cancer, with various factors affecting its development. While its impact on human lives and national health budgets is still rising in almost all global areas, many molecular mechanisms affecting its onset and development remain unclear. Conventional treatments still prove inadequate in some aspects, and appropriate molecular therapeutic targets are required for improved outcomes. Recent scientific interest has therefore focused on the non-coding RNAs roles in tumour development and their potential as therapeutic targets. These RNAs comprise the majority of the human transcript and their broad action mechanisms range from gene silencing to chromatin remodelling. Many non-coding RNAs also have altered expression in breast cancer cell lines and tissues, and this is often connected with increased proliferation, a degraded extracellular environment, and higher endothelial to mesenchymal transition. Herein, we summarise the known abnormalities in the function and expression of long non-coding RNAs, Piwi interacting RNAs, small nucleolar RNAs and small nuclear RNAs in breast cancer, and how these abnormalities affect the development of this deadly disease. Finally, the use of RNA interference to suppress breast cancer growth is summarised.
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Garay-Sevilla ME, Gomez-Ojeda A, González I, Luévano-Contreras C, Rojas A. Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Mol Cell Biochem 2021; 476:1555-1573. [PMID: 33398664 DOI: 10.1007/s11010-020-04022-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023]
Abstract
Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.
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Affiliation(s)
- Ma Eugenia Garay-Sevilla
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Gomez-Ojeda
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Ileana González
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Claudia Luévano-Contreras
- Department of Medical Science, Division of Health Science, University of Guanajuato, Campus León, Guanajuato, Mexico
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, Chile.
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Ngo MHT, Jeng HY, Kuo YC, Nanda JD, Brahmadhi A, Ling TY, Chang TS, Huang YH. The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance. Int J Mol Sci 2021; 22:ijms22041931. [PMID: 33669204 PMCID: PMC7919800 DOI: 10.3390/ijms22041931] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.
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Affiliation(s)
- Mai-Huong Thi Ngo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Han-Yin Jeng
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Yung-Che Kuo
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Josephine Diony Nanda
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Ageng Brahmadhi
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Yen-Hua Huang
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
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Favaro RR, Morales-Prieto DM, Herrmann J, Sonnemann J, Schleussner E, Markert UR, Zorn TMT. Influence of high glucose in the expression of miRNAs and IGF1R signaling pathway in human myometrial explants. Arch Gynecol Obstet 2021; 303:1513-1522. [PMID: 33575847 PMCID: PMC8087607 DOI: 10.1007/s00404-020-05940-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 12/15/2020] [Indexed: 12/26/2022]
Abstract
PURPOSE Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. METHODS Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. RESULTS Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. CONCLUSIONS The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.
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Affiliation(s)
- Rodolfo R Favaro
- Placenta Lab, Department of Obstetrics, Jena University Hospital, Jena, Germany.
- Laboratory of Reproductive and Extracellular Matrix Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
| | | | - Jörg Herrmann
- Department of Gynecology and Obstetrics, Hufeland Klinikum, Weimar, Germany
| | - Jürgen Sonnemann
- Department of Pediatric Hematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany
| | | | - Udo R Markert
- Placenta Lab, Department of Obstetrics, Jena University Hospital, Jena, Germany
| | - Telma M T Zorn
- Laboratory of Reproductive and Extracellular Matrix Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Gaus S, Li H, Li S, Wang Q, Kottek T, Hahnel S, Liu X, Deng Y, Ziebolz D, Haak R, Schmalz G, Liu L, Savkovic V, Lethaus B. Shared Genetic and Epigenetic Mechanisms between the Osteogenic Differentiation of Dental Pulp Stem Cells and Bone Marrow Stem Cells. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6697810. [PMID: 33628811 PMCID: PMC7884974 DOI: 10.1155/2021/6697810] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/04/2021] [Accepted: 01/20/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To identify the shared genetic and epigenetic mechanisms between the osteogenic differentiation of dental pulp stem cells (DPSC) and bone marrow stem cells (BMSC). MATERIALS AND METHODS The profiling datasets of miRNA expression in the osteogenic differentiation of mesenchymal stem cells from the dental pulp (DPSC) and bone marrow (BMSC) were searched in the Gene Expression Omnibus (GEO) database. The differential expression analysis was performed to identify differentially expressed miRNAs (DEmiRNAs) dysregulated in DPSC and BMSC osteodifferentiation. The target genes of the DEmiRNAs that were dysregulated in DPSC and BMSC osteodifferentiation were identified, followed by the identification of the signaling pathways and biological processes (BPs) of these target genes. Accordingly, the DEmiRNA-transcription factor (TFs) network and the DEmiRNAs-small molecular drug network involved in the DPSC and BMSC osteodifferentiation were constructed. RESULTS 16 dysregulated DEmiRNAs were found to be overlapped in the DPSC and BMSC osteodifferentiation, including 8 DEmiRNAs with a common expression pattern (8 upregulated DEmiRNAs (miR-101-3p, miR-143-3p, miR-145-3p/5p, miR-19a-3p, miR-34c-5p, miR-3607-3p, miR-378e, miR-671-3p, and miR-671-5p) and 1 downregulated DEmiRNA (miR-671-3p/5p)), as well as 8 DEmiRNAs with a different expression pattern (i.e., miR-1273g-3p, miR-146a-5p, miR-146b-5p, miR-337-3p, miR-382-3p, miR-4508, miR-4516, and miR-6087). Several signaling pathways (TNF, mTOR, Hippo, neutrophin, and pathways regulating pluripotency of stem cells), transcription factors (RUNX1, FOXA1, HIF1A, and MYC), and small molecule drugs (curcumin, docosahexaenoic acid (DHA), vitamin D3, arsenic trioxide, 5-fluorouracil (5-FU), and naringin) were identified as common regulators of both the DPSC and BMSC osteodifferentiation. CONCLUSION Common genetic and epigenetic mechanisms are involved in the osteodifferentiation of DPSCs and BMSCs.
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Affiliation(s)
- Sebastian Gaus
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Hanluo Li
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Simin Li
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Qian Wang
- Department of Central Laboratory, Taian Central Hospital, Longtan Road No. 29, Taian, 271000 Shandong Province, China
| | - Tina Kottek
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Sebastian Hahnel
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Xiangqiong Liu
- Department of Molecular Cell Biology, Beijing Tibetan Hospital, China Tibetology Research Center, 218 Anwaixiaoguanbeili Street, Chaoyang, Beijing 100029, China
| | - Yupei Deng
- Department of Molecular Cell Biology, Beijing Tibetan Hospital, China Tibetology Research Center, 218 Anwaixiaoguanbeili Street, Chaoyang, Beijing 100029, China
| | - Dirk Ziebolz
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Rainer Haak
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Gerhard Schmalz
- Department of Cariology, Endodontology and Periodontology, University Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Lei Liu
- Department of Neurology, Shandong Provincial Third Hospital, Cheeloo Chollege of Medicine, Shandong University, Jinan, 100191 Shandong Province, China
| | - Vuk Savkovic
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
| | - Bernd Lethaus
- Department of Cranio Maxillofacial Surgery, University Clinic Leipzig, Liebigstr. 12, Leipzig 04103, Germany
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Boughanem H, Yubero-Serrano EM, López-Miranda J, Tinahones FJ, Macias-Gonzalez M. Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance. Int J Mol Sci 2021; 22:ijms22031133. [PMID: 33498859 PMCID: PMC7865532 DOI: 10.3390/ijms22031133] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/13/2021] [Accepted: 01/21/2021] [Indexed: 12/26/2022] Open
Abstract
Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2. We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2.
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Affiliation(s)
- Hatim Boughanem
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
| | - Elena M. Yubero-Serrano
- Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004 Córdoba, Spain; (E.M.Y.-S.); (J.L.-M.)
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José López-Miranda
- Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004 Córdoba, Spain; (E.M.Y.-S.); (J.L.-M.)
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francisco J. Tinahones
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.J.T.); (M.M.-G.); Tel.: +34-951-036-2647 (F.J.T. & M.M.-G.); Fax: +34-951-924-651 (F.J.T. & M.M.-G.)
| | - Manuel Macias-Gonzalez
- Department of Endocrinology and Nutrition, Institute of Biomedical Research Institute in Malaga (IBIMA), Virgen de la Victoria University Hospital, 29010 Málaga, Spain;
- CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (F.J.T.); (M.M.-G.); Tel.: +34-951-036-2647 (F.J.T. & M.M.-G.); Fax: +34-951-924-651 (F.J.T. & M.M.-G.)
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Rahnama S, Vathsangam N, Spence R, Anderson ST, de Laat MA, Bailey S, Sillence MN. Identification of monoclonal antibodies suitable for blocking IGF-1 receptors in the horse. Domest Anim Endocrinol 2021; 74:106510. [PMID: 32652390 DOI: 10.1016/j.domaniend.2020.106510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 06/11/2020] [Accepted: 06/11/2020] [Indexed: 01/19/2023]
Abstract
Prolonged hyperinsulinemia is thought to be the cause of equine endocrinopathic laminitis, a common and crippling disease of the foot, for which there are no pharmacologic treatments other than pain relief. It has been suggested that insulin causes its effects on the lamellae by activating IGF-1 receptors (IGF-1R), as insulin receptors (InsR) are scarce in this tissue, whereas IGF-1R are abundant and become downregulated after prolonged insulin infusion. As a first step toward confirming this mechanism and beginning to develop a therapeutic anti-IGF-1R monoclonal antibody (mAb) for horses, it was necessary to identify available human IGF-1R mAbs that would recognize equine receptors. Four IGF-1R mAbs were tested using soluble equine IGF-1R, with ELISA and flow cytometry. Frozen equine lamellar and liver tissue was also used in radioligand binding assays. The results demonstrated that only one of the mAbs tested (mAb1) was able to compete effectively with IGF-1 for binding to its receptors in equine lamellar tissue, with an IC50 of 5 to 159 ng/mL. None of the 4 mAbs were able to bind to equine hepatic InsR. This study has generated valuable structure-activity information and has identified a prototype anti-IGF-1R mAb suitable for further development.
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Affiliation(s)
- S Rahnama
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - N Vathsangam
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - R Spence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - S T Anderson
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
| | - M A de Laat
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - S Bailey
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
| | - M N Sillence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia.
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Hermawan A, Putri H, Ikawati M. Bioinformatic analysis reveals the molecular targets of tangeretin in overcoming the resistance of breast cancer to tamoxifen. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Zhang M, Lin B, Liu Y, Huang T, Chen M, Lian D, Deng S, Zhuang C. LINC00324 affects non-small cell lung cancer cell proliferation and invasion through regulation of the miR-139-5p/IGF1R axis. Mol Cell Biochem 2020; 473:193-202. [PMID: 32734536 DOI: 10.1007/s11010-020-03819-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/27/2020] [Indexed: 01/02/2023]
Abstract
Long non-coding RNAs (lncRNAs) are proved to perform critical function in regulating cancer cell behavior. It is reported that LINC00324 promotes lung adenocarcinoma development by regulating miR-615-5p/AKT1 axis. This study aimed to demonstrate whether LINC00324 participates in non-small cell lung cancer (NSCLC) pathogenesis through other molecular mechanism. Relative mRNA, lncRNA, and microRNA levels were analyzed using quantitative real-time-polymerase chain reaction (qRT-PCR). Western blot was used to detect protein level. MTT assay shown proliferation ability and transwell assay shown invasive ability. Luciferase reporter assay illustrated the interaction between RNA molecules. In NSCLC, the high expression of LINC00324 had correlation with the poor prognosis. LINC00324 promoted the proliferation and invasion of NSCLC cells while miR-139-5p inhibited these behaviors. LINC00324 overexpression promoted insulin-like growth factor 1 receptor (IGF1R) expression via absorbing miR-139-5p. The tumor-promoting effects of LINC00324 were attenuated through miR-139-5p overexpression. Highly expressed LINC00324 in NSCLC through sponged miR-139-5p to elevate IGF1R expression and promoted cell proliferation and invasion. This research demonstrated that LINC00324 is a potential NSCLC diagnosis and therapy target.
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Affiliation(s)
- Meiqing Zhang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Baoquan Lin
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Yaming Liu
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Tengfei Huang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Mengmeng Chen
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Duohuang Lian
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Shilong Deng
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China
| | - Congwen Zhuang
- Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, No.156 West Second-beltway Road, Fuzhou, 350025, Fujian, China.
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Xu Y, Kirk NS, Venugopal H, Margetts MB, Croll TI, Sandow JJ, Webb AI, Delaine CA, Forbes BE, Lawrence MC. How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor. Structure 2020; 28:786-798.e6. [PMID: 32459985 PMCID: PMC7343240 DOI: 10.1016/j.str.2020.05.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/23/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023]
Abstract
Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.
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Affiliation(s)
- Yibin Xu
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia
| | - Nicholas S Kirk
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia
| | - Hariprasad Venugopal
- Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC 3800, Australia
| | - Mai B Margetts
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Tristan I Croll
- Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK
| | - Jarrod J Sandow
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia
| | - Andrew I Webb
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia
| | - Carlie A Delaine
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, SA 5042, Australia
| | - Briony E Forbes
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, SA 5042, Australia
| | - Michael C Lawrence
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3050, Australia.
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Guo F, Zhu X, Zhao Q, Huang Q. miR‑589‑3p sponged by the lncRNA TINCR inhibits the proliferation, migration and invasion and promotes the apoptosis of breast cancer cells by suppressing the Akt pathway via IGF1R. Int J Mol Med 2020; 46:989-1002. [PMID: 32705168 PMCID: PMC7388824 DOI: 10.3892/ijmm.2020.4666] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/17/2020] [Indexed: 12/24/2022] Open
Abstract
The long non-coding (lnc)RNA named tissue differentiation inducing non-protein coding RNA (TINCR) is a tumor marker that has not been studied in breast cancer. The present study aimed to investigate the TINCR-targeting micro (mi)RNAs and the regulatory mechanisms of TINCR in breast cancer. Following prediction by TargetScan and confirmation by dual-luciferase reporter assay, TINCR was demonstrated to be a target gene for miR-589-3p. The expression of TINCR and miR-589-3p in breast cancer and adjacent tissues was detected by reverse transcription-quantitative (RT-q)PCR, and the correlation between TINCR and miR-589-3p expression was determined by using Spearman correlation analysis. The 5-years survival was analyzed in patients with breast cancer according to TINCR expression (high or low). The effects of TINCR and miR-589-3p on the proliferation, apoptosis, migratory and invasive abilities of some breast cancer cell lines were detected by MTT assay, flow cytometry, wound healing assay and Transwell assay. The target gene of miR-589-3p was predicted and verified by TargetScan and dual-luciferase reporter assay, and the mechanism of miR-589-3p involvement in breast cancer cells was explored by overexpression or downregulation of miR-589-3p in breast cancer cells. RT-qPCR and western blotting were used to determine the expression of the insulin-like growth factor 1 receptor (IGF1R)/AKT pathway-related genes. The results demonstrated that TINCR expression level was negatively correlated with miR-589-3p expression level in breast cancer tissues and that patients with high expression of TINCR presented with lower survival rates. In addition, TINCR overexpression in cancer cells inhibited miR-589-3p expression, and cell transfection with miR-589-3p mimic partially reversed the effect of TINCR overexpression on the promotion of cancer cell proliferation, migration and invasion, and on the inhibition of cancer cell apoptosis. Furthermore, IGF1R, which is a target gene of miR-589-3p, increased cancer cell proliferation, migration and invasion and inhibited cancer cell apoptosis; however, these effects were partially reversed by miR-589-3p mimic. Furthermore, the results demonstrated that miR-589-3p mimic could downregulate the protein expression of IGF1R and p-AKT. In addition, TINCR overexpression downregulated miR-589-3p expression level. miR-589-3p partially reversed the effects of TINCR overexpression on cancer cell proliferation, migration and invasion, and inhibited cancer cell apoptosis by inhibiting the IGF1R-Akt pathway. The results from the present study demonstrated that TINCR may sponge miR-589-3p in order to inhibit IGF1R-Akt pathway activation in breast cancer cells, promoting therefore cancer cell proliferation, migration and invasion.
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Affiliation(s)
- Fangdong Guo
- Department of Breast and Thyroid Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Xiaoyu Zhu
- Department of Breast and Thyroid Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Qingquan Zhao
- Department of Breast and Thyroid Surgery, The 2nd Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Qirong Huang
- Department of Breast and Thyroid Surgery, Chengdu Dongli Hospital, Chengdu, Sichuan 610000, P.R. China
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van Doorn J. Insulin-like growth factor-II and bioactive proteins containing a part of the E-domain of pro-insulin-like growth factor-II. Biofactors 2020; 46:563-578. [PMID: 32026557 PMCID: PMC7497164 DOI: 10.1002/biof.1623] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022]
Abstract
Insulin-like growth factor (IGF)-II is considered to function as an important fetal growth factor, which is structurally and functionally related to IGF-I and proinsulin. At least in vitro, IGF-II actions are mediated through the IGF-I receptor and to a lesser extent the insulin receptor. After birth, the function of IGF-II is less clear although in adults the serum level of IGF-II exceeds that of IGF-I several fold. The IGF-II gene is maternally imprinted, with exception of the liver and several parts of the brain, where it is expressed from both alleles. The regulation, organization, and translation of the IGF-II gene is complex, with five different putative promotors leading to a range of noncoding and coding mRNAs. The 180-amino acid pre-pro-IGF-II translation product can be divided into five domains and include a N-terminal signal peptide of 24 amino acid residues, the 67 amino acid long mature protein, and an 89 residues extension at the COOH terminus, designated as the E-domain. After removal of the signal peptide, the processing of pro-IGF-II into mature IGF-II requires various steps including glycosylation of the E-domain followed by the action of endo-proteases. Several of these processing intermediates can be found in the human circulation. There is increasing evidence that, besides IGF-II, several incompletely processed precursor forms of the protein, and even a 34-amino acid peptide (preptin) derived from the E-domain of pro-IGF-II, exhibit distinct biological activities. This review will focus on the current insights regarding the specific roles of the latter proteins in cancer, glucose homeostasis, and bone physiology. To address this topic clearly in the right context, a concise overview of the biological and biochemical properties of IGF-II and several relevant aspects of the IGF system will be provided.
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Affiliation(s)
- Jaap van Doorn
- Department of Genetics, Section Metabolic DiagnosticsUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
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Böckers M, Paul NW, Efferth T. Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor α. Toxicol Appl Pharmacol 2020; 399:115030. [DOI: 10.1016/j.taap.2020.115030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/21/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
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50
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Du C, da Silva A, Morales-Oyarvide V, Dias Costa A, Kozak MM, Dunne RF, Rubinson DA, Perez K, Masugi Y, Hamada T, Brais LK, Yuan C, Babic A, Ducar MD, Thorner AR, Aguirre A, Kulke MH, Ng K, Clancy TE, Findeis-Hosey JJ, Chang DT, Hornick JL, Fuchs CS, Ogino S, Koong AC, Hezel AF, Wolpin BM, Nowak JA. Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2020; 29:1586-1595. [PMID: 32467349 DOI: 10.1158/1055-9965.epi-19-1315] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/17/2020] [Accepted: 05/19/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. RESULTS Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). CONCLUSIONS Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IMPACT IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
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Affiliation(s)
- Chunxia Du
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Annacarolina da Silva
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Vicente Morales-Oyarvide
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Andressa Dias Costa
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Margaret M Kozak
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
| | - Richard F Dunne
- Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Lauren K Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Matthew D Ducar
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Aaron R Thorner
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Andrew Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Matthew H Kulke
- Section of Hematology/Oncology, Boston University and Boston Medical Center, Boston, Massachusetts
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Thomas E Clancy
- Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Daniel T Chang
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
| | - Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Charles S Fuchs
- Yale Cancer Center, Smilow Cancer Hospital and Yale School of Medicine, New Haven, Connecticut
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Program in MPE Molecular Pathological Epidemiology, Brigham and Women's Hospital, Boston, Massachusetts.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Albert C Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aram F Hezel
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jonathan A Nowak
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. .,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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