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He Z, Xie L, Liu J, Wei X, Zhang W, Mei Z. Novel insight into the role of A-kinase anchoring proteins (AKAPs) in ischemic stroke and therapeutic potentials. Biomed Pharmacother 2024; 175:116715. [PMID: 38739993 DOI: 10.1016/j.biopha.2024.116715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/16/2024] Open
Abstract
Ischemic stroke, a devastating disease associated with high mortality and disability worldwide, has emerged as an urgent public health issue. A-kinase anchoring proteins (AKAPs) are a group of signal-organizing molecules that compartmentalize and anchor a wide range of receptors and effector proteins and have a major role in stabilizing mitochondrial function and promoting neurodevelopmental development in the central nervous system (CNS). Growing evidence suggests that dysregulation of AKAPs expression and activity is closely associated with oxidative stress, ion disorder, mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in ischemic stroke. However, the underlying mechanisms remain inadequately understood. This review provides a comprehensive overview of the composition and structure of A-kinase anchoring protein (AKAP) family members, emphasizing their physiological functions in the CNS. We explored in depth the molecular and cellular mechanisms of AKAP complexes in the pathological progression and risk factors of ischemic stroke, including hypertension, hyperglycemia, lipid metabolism disorders, and atrial fibrillation. Herein, we highlight the potential of AKAP complexes as a pharmacological target against ischemic stroke in the hope of inspiring translational research and innovative clinical approaches.
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Affiliation(s)
- Ziyu He
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Letian Xie
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jiyong Liu
- Hunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Xuan Wei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Wenli Zhang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
| | - Zhigang Mei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Third-Grade Pharmacological Laboratory on Chinese Medicine Approved by State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, Hubei 443002, China.
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FSIP1 Is Associated with Poor Prognosis and Can Be Used to Construct a Prognostic Model in Gastric Cancer. DISEASE MARKERS 2022; 2022:2478551. [PMID: 35692888 PMCID: PMC9187450 DOI: 10.1155/2022/2478551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 12/03/2022]
Abstract
Gastric cancer (GC) is one of the most common upper gastrointestinal malignant tumors, and the incidence of the GC shows an increasing trend in the past years. Finding more sensitive markers will help to reveal the mechanism of GC progression and clinic diagnoses. This study first analyzed the mRNA expression level of FSIP1 in TCGA GC samples and the significance in predicting the prognosis. KEGG and GO analyses were used to explore the molecular mechanism of FSIP1 in GC progression. This study further retrospectively analyzed 166 clinical samples of GC from Harbin Medical University Cancer Hospital and evaluated the expression level of FSIP1 by immunohistochemistry. Kaplan-Meier and Cox multivariate analysis was used to investigate the prognostic value of FSIP1 expression in GC patients. We also identified correlations between FSIP1 and clinicopathological characteristics. This study found that the mRNA level of FSIP1 was significantly upregulated in GC compared with nontumor specimens and correlated with poor prognosis. Immunohistochemistry confirmed the results of bioinformatics analysis of the TCGA GC database. FSIP1 was associated with pTNM pathological stage, tumor location, and neural invasion. In addition, multivariate Cox regression analysis showed that FSIP1, T classification, and N classification were independent posterior factors of patients and could be combined with pathological features to construct a nomogram prognostic model. Overall, our results suggest that FSIP1 is expected to be an independent prognostic indicator of GC.
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Lastraioli E, Fraser SP, Guzel RM, Iorio J, Bencini L, Scarpi E, Messerini L, Villanacci V, Cerino G, Ghezzi N, Perrone G, Djamgoz MBA, Arcangeli A. Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation. Cancers (Basel) 2021; 13:3832. [PMID: 34359733 PMCID: PMC8345135 DOI: 10.3390/cancers13153832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/30/2022] Open
Abstract
Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker ('companion diagnostic') useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.
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Affiliation(s)
- Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy; (E.L.); (J.I.); (L.M.); (A.A.)
| | - Scott P. Fraser
- Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK; (S.P.F.); (R.M.G.)
| | - R. Mine Guzel
- Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK; (S.P.F.); (R.M.G.)
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy; (E.L.); (J.I.); (L.M.); (A.A.)
| | - Lapo Bencini
- Department of Oncology, Division of Oncologic Surgery and Robotics, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy; (L.B.); (G.C.); (N.G.)
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Via P Maroncelli 40, 47014 Meldola, Italy;
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy; (E.L.); (J.I.); (L.M.); (A.A.)
| | - Vincenzo Villanacci
- Institute of Pathology, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy;
| | - Giulia Cerino
- Department of Oncology, Division of Oncologic Surgery and Robotics, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy; (L.B.); (G.C.); (N.G.)
| | - Niccolo’ Ghezzi
- Department of Oncology, Division of Oncologic Surgery and Robotics, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134 Florence, Italy; (L.B.); (G.C.); (N.G.)
| | - Giuseppe Perrone
- Pathology Unit, Campus Bio-Medico University, via A del Portillo 200, 00128 Rome, Italy;
| | - Mustafa B. A. Djamgoz
- Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK; (S.P.F.); (R.M.G.)
- Cyprus International University, Biotechnology Research Centre, Haspolat, Mersin 10, Cyprus
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy; (E.L.); (J.I.); (L.M.); (A.A.)
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Zhang H, Kong Q, Wang J, Jiang Y, Hua H. Complex roles of cAMP-PKA-CREB signaling in cancer. Exp Hematol Oncol 2020; 9:32. [PMID: 33292604 PMCID: PMC7684908 DOI: 10.1186/s40164-020-00191-1] [Citation(s) in RCA: 276] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023] Open
Abstract
Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP-PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP-PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP-PKA-CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.
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Affiliation(s)
- Hongying Zhang
- Laboratory of Oncogene, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qingbin Kong
- Laboratory of Oncogene, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiao Wang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yangfu Jiang
- Laboratory of Oncogene, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Hua
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Wu HY, Yang B, Geng DH. Clinical significance of expression of fibrous sheath interacting protein 1 in colon cancer. World J Gastrointest Oncol 2020; 12:677-686. [PMID: 32699582 PMCID: PMC7340994 DOI: 10.4251/wjgo.v12.i6.677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/11/2020] [Accepted: 05/05/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The occurrence and development of colon cancer are complex, involving a variety of genetic changes, such as mutation and activation of oncogenes, inactivation of tumour suppressor genes, and aberrant proliferation and apoptosis regulation mechanisms. Fibrous sheath interacting protein 1 (FSIP1) is a newly discovered oncogene that is frequently activated in a variety of tumours such as breast cancer and bladder cancer. However, the clinical significance of FSIP1 in colon cancer is unclear. In this study, we analysed the clinical significance of expression of FSIP1 in human colon cancer, aimed to clarify the biological role of FSIP1 in the development and progression of colon cancer.
AIM To investigate the clinical significance of expression of FSIP1 in colon cancer.
METHODS From March 2011 to March 2014, 302 specimens of tumour tissues and paracancerous tissues were obtained from patients pathologically diagnosed with colon cancer at Shengjing Hospital of China Medical University. Immunohistochemistry was used to detect FSIP1 expression in colon cancer tissues and adjacent normal tissues. Spearman correlation coefficient and Cox regression analyses were used to determine the relationship between FSIP1 expression and clinicopathological factors and prognosis, as well as the impact on survival.
RESULTS Compared with its expression in adjacent normal tissues, FSIP1 was expressed at higher levels in colon cancer tissues. Spearman correlation analysis showed that high expression of FSIP1 was positively correlated with clinicopathological stage, lymph node metastasis, and poor prognosis in colon cancer; it was negatively correlated with the degree of tumour differentiation. Cox regression analysis showed that high FSIP1 expression was an independent risk factor for the prognosis of colon cancer patients.
CONCLUSION High expression of FSIP1 may be one of the important factors affecting the clinical outcome of colon cancer patients and leading to poor prognosis.
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Affiliation(s)
- Hui-Ying Wu
- Department of Nursing, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Bin Yang
- Department of Nursing, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dong-Hua Geng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Del Gobbo A, Peverelli E, Treppiedi D, Lania A, Mantovani G, Ferrero S. Expression of protein kinase A regulatory subunits in benign and malignant human thyroid tissues: A systematic review. Exp Cell Res 2016; 346:85-90. [PMID: 27321957 DOI: 10.1016/j.yexcr.2016.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/17/2016] [Accepted: 06/08/2016] [Indexed: 11/30/2022]
Abstract
In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on the malignant thyroid. The PKA signaling pathway is differentially activated by the expression of regulatory subunits 1 (R1) and 2 (R2), whose levels change during development, differentiation, and neoplastic transformation. Following the identification of gene mutations within the PKA regulatory subunit R1A (PRKAR1A) that cause Carney complex-associated neoplasms, several investigators have studied PRKAR1A expression in sporadic thyroid tumors. The PKA regulatory subunit R2B (PRKAR2B) is highly expressed in benign, as well as in malignant differentiated and undifferentiated lesions. PRKAR1A is highly expressed in follicular adenomas and malignant lesions with a statistically significant gradient between benign and malignant tumors; however, it is not expressed in hyperplastic nodules. Although the importance of PKA in human malignancy outcomes is not completely understood, PRKAR1A expression correlates with tumor dimension in malignant lesions. Additional studies are needed to determine whether a relationship exists between PKA subunit expression and clinical outcomes, particularly in undifferentiated tumors. In conclusion, the R1A subunit might be a good molecular candidate for the targeted treatment of malignant thyroid tumors.
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Affiliation(s)
- Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Erika Peverelli
- Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Donatella Treppiedi
- Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Andrea Lania
- Endocrine Unit, IRCCS Humanitas Research Hospital, University of Milan, Milan, Italy
| | - Giovanna Mantovani
- Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan Medical School, Milan, Italy.
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El-Gayar D, El-Abd N, Hassan N, Ali R. Increased Free Circulating DNA Integrity Index as a Serum Biomarker in Patients with Colorectal Carcinoma. Asian Pac J Cancer Prev 2016; 17:939-944. [DOI: 10.7314/apjcp.2016.17.3.939] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
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