|
1
|
Zheng Y, Zhong G, He C, Li M. Targeted splicing therapy: new strategies for colorectal cancer. Front Oncol 2023; 13:1222932. [PMID: 37664052 PMCID: PMC10470845 DOI: 10.3389/fonc.2023.1222932] [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: 05/15/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.
Collapse
Affiliation(s)
| | | | - Chengcheng He
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | | |
Collapse
|
|
2
|
Debelenko L, Mansukhani MM, Remotti F. Papillary Intralymphatic Angioendothelioma in a Child With PIK3CA-Related Overgrowth Spectrum: Implication of PI3K Pathway in the Vascular Tumorigenesis. Pediatr Dev Pathol 2023; 26:166-171. [PMID: 36775953 DOI: 10.1177/10935266231152370] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Papillary intralymphatic angioendothelioma (PILA) is an extremely rare vascular tumor and its pathogenesis is unknown. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS) is a heterogeneous group of disorders caused by mosaicism for activating mutations of PIK3CA and characterized by asymmetric overgrowth, skeletal anomalies, skin lesions, and vascular malformations. An association between PILA and PROS has not been known. We report a case of PILA involving the spleen of a young girl with the clinical and molecular diagnosis of PROS. Sequencing of the patient's germ-line DNA detected a pathogenic PIK3CA variant c.1357G>A in 10.6% of alleles. Splenectomy revealed a 4-cm tumor composed of ectatic lymphatics with intraluminal papillary projections, consistent with PILA. The tumor cells showed immunohistochemical expression of CD31, CD34, ERG, FLI-1, PROX1, and caldesmon, while D2-40 was negative. The latter may suggest that the tumor derived from an endothelial precursor arrested in the final steps of lymphothelial differentiation, in keeping with the known role of the PIK3CA-governed molecular pathway in the progression of vascular progenitors to mature endothelial cells. The data implicates PIK3CA in the pathogenesis of PILA and broadens the spectrum of phenotypic expressions of PROS.
Collapse
Affiliation(s)
- Larisa Debelenko
- Department of Pathology and Cell Biology, Columbia University-Irving Medical Center, New York, NY, USA
| | - Mahesh M Mansukhani
- Department of Pathology and Cell Biology, Columbia University-Irving Medical Center, New York, NY, USA
| | - Fabrizio Remotti
- Department of Pathology and Cell Biology, Columbia University-Irving Medical Center, New York, NY, USA
| |
Collapse
|
|
3
|
Alnuaimi AR, Bottner J, Nair VA, Ali N, Alnakhli R, Dreyer E, Talaat IM, Busch H, Perner S, Kirfel J, Hamoudi R, Abdel-Rahman WM. Immunohistochemical Expression Analysis of Caldesmon Isoforms in Colorectal Carcinoma Reveals Interesting Correlations with Tumor Characteristics. Int J Mol Sci 2023; 24:2275. [PMID: 36768598 PMCID: PMC9916900 DOI: 10.3390/ijms24032275] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The CALD1 gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.
Collapse
Affiliation(s)
- Alya R. Alnuaimi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Justus Bottner
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Vidhya A. Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Nival Ali
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Razaz Alnakhli
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Eva Dreyer
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Iman M. Talaat
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hauke Busch
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Luebeck Institute for Experimental Dermatology, University of Luebeck, 23562 Luebeck, Germany
| | - Sven Perner
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Jutta Kirfel
- Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Wael M. Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| |
Collapse
|
|
4
|
Alnuaimi AR, Nair VA, Malhab LJB, Abu-Gharbieh E, Ranade AV, Pintus G, Hamad M, Busch H, Kirfel J, Hamoudi R, Abdel-Rahman WM. Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers. World J Gastrointest Oncol 2022; 14:1637-1653. [PMID: 36187394 PMCID: PMC9516648 DOI: 10.4251/wjgo.v14.i9.1637] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/05/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.
Collapse
Affiliation(s)
- Alya R Alnuaimi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Vidhya A Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Lara J Bou Malhab
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Eman Abu-Gharbieh
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Clinical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anu Vinod Ranade
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Basic Medical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Gianfranco Pintus
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
| | - Mohamad Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hauke Busch
- University Cancer Center Schleswig-Holstein and Luebeck Institute for Experimental Dermatology, University of Luebeck, Luebeck 23560, Germany
| | - Jutta Kirfel
- Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck 23560, Germany
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Clinical Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London WC1E 6BT, United Kingdom
| | - Wael M Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| |
Collapse
|
|
5
|
Wang J, Wang C, Li L, Yang L, Wang S, Ning X, Gao S, Ren L, Chaulagain A, Tang J, Wang T. Alternative splicing: An important regulatory mechanism in colorectal carcinoma. Mol Carcinog 2021; 60:279-293. [PMID: 33629774 DOI: 10.1002/mc.23291] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/01/2021] [Accepted: 02/11/2021] [Indexed: 12/17/2022]
Abstract
Alternative splicing (AS) is a process that produces various mRNA splicing isoforms via different splicing patterns of mRNA precursors (pre-mRNAs). AS is the primary mechanism for increasing the types and quantities of proteins to improve biodiversity and influence multiple biological processes, including chromatin modification, signal transduction, and protein expression. It has been reported that AS is involved in the tumorigenesis and development of colorectal carcinoma (CRC). In this review, we delineate the concept, types, regulatory processes, and technical advances of AS and focus on the role of AS in CRC initiation, progression, treatment, and prognosis. This summary of the current knowledge about AS will contribute to our understanding of CRC initiation and development. This study will help in the discovery of novel biomarkers and therapeutic targets for CRC prognosis and treatment.
Collapse
Affiliation(s)
- Jianyi Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Chuhan Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Lirui Yang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Shuoshuo Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Xuelian Ning
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Shuangshu Gao
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Lili Ren
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Anita Chaulagain
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Jing Tang
- Department of Pathology, Harbin Medical University, Harbin, China.,Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Tianzhen Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| |
Collapse
|
|
6
|
Xu L, Lee JR, Hao S, Ling XB, Brooks JD, Wang SX, Gambhir SS. Improved detection of prostate cancer using a magneto-nanosensor assay for serum circulating autoantibodies. PLoS One 2019; 14:e0221051. [PMID: 31404106 PMCID: PMC6690541 DOI: 10.1371/journal.pone.0221051] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/29/2019] [Indexed: 12/22/2022] Open
Abstract
Purpose To develop a magneto-nanosensor (MNS) based multiplex assay to measure protein and autoantibody biomarkers from human serum for prostate cancer (CaP) diagnosis. Materials and methods A 4-panel MNS autoantibody assay and a MNS protein assay were developed and optimized in our labs. Using these assays, serum concentration of six biomarkers including prostate-specific antigen (PSA) protein, free/total PSA ratio, as well as four autoantibodies against Parkinson disease 7 (PARK7), TAR DNA-binding protein 43 (TARDBP), Talin 1 (TLN1), and Caldesmon 1 (CALD1) and were analyzed. Human serum samples from 99 patients (50 with non-cancer and 49 with clinically localized CaP) were evaluated. Results The MNS assay showed excellent performance characteristics and no cross-reactivity. All autoantibody assays showed a statistically significant difference between CaP and non-cancer samples except for PARK7. The most significant difference was the combination of the four autoantibodies as a panel in addition to the free/total PSA ratio. This combination had the highest area under the curve (AUC)– 0.916 in ROC analysis. Conclusions Our results suggest that this autoantibody panel along with PSA and free PSA have potential to segregate patients without cancer from those with prostate cancer with higher sensitivity and specificity than PSA alone.
Collapse
Affiliation(s)
- Lingyun Xu
- Department of Radiology, Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States of America
| | - Jung-Rok Lee
- Division of Mechanical and Biomedical Engineering, Ewha Womans University, Seoul, South Korea
| | - Shiying Hao
- Clinical and Translational Research Program, Betty Irene Moore Children's Heart Center, Lucile Packard Children’s Hospital, Palo Alto, California, United States of America
- Departments of Surgery, Stanford University, Stanford, California, United States of America
| | - Xuefeng Bruce Ling
- Clinical and Translational Research Program, Betty Irene Moore Children's Heart Center, Lucile Packard Children’s Hospital, Palo Alto, California, United States of America
- Departments of Surgery, Stanford University, Stanford, California, United States of America
| | - James D. Brooks
- Department of Urology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Shan X. Wang
- Department of Materials Science & Engineering, Stanford University, Stanford, California, United States of America
- Department of Electrical Engineering, Stanford University, Stanford, California, United States of America
- Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Sanjiv Sam Gambhir
- Department of Radiology, Molecular Imaging Program at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States of America
- Department of Electrical Engineering, Stanford University, Stanford, California, United States of America
- Department of Bioengineering, Stanford University, Stanford, California, United States of America
- * E-mail:
| |
Collapse
|
|
7
|
Rivero-Hinojosa S, Lau LS, Stampar M, Staal J, Zhang H, Gordish-Dressman H, Northcott PA, Pfister SM, Taylor MD, Brown KJ, Rood BR. Proteomic analysis of Medulloblastoma reveals functional biology with translational potential. Acta Neuropathol Commun 2018; 6:48. [PMID: 29880060 PMCID: PMC5992829 DOI: 10.1186/s40478-018-0548-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 05/17/2018] [Indexed: 12/14/2022] Open
Abstract
Genomic characterization has begun to redefine diagnostic classifications of cancers. However, it remains a challenge to infer disease phenotypes from genomic alterations alone. To help realize the promise of genomics, we have performed a quantitative proteomics investigation using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and 41 tissue samples spanning the 4 genomically based subgroups of medulloblastoma and control cerebellum. We have identified and quantitated thousands of proteins across these groups and find that we are able to recapitulate the genomic subgroups based upon subgroup restricted and differentially abundant proteins while also identifying subgroup specific protein isoforms. Integrating our proteomic measurements with genomic data, we calculate a poor correlation between mRNA and protein abundance. Using EPIC 850 k methylation array data on the same tissues, we also investigate the influence of copy number alterations and DNA methylation on the proteome in an attempt to characterize the impact of these genetic features on the proteome. Reciprocally, we are able to use the proteome to identify which genomic alterations result in altered protein abundance and thus are most likely to impact biology. Finally, we are able to assemble protein-based pathways yielding potential avenues for clinical intervention. From these, we validate the EIF4F cap-dependent translation pathway as a novel druggable pathway in medulloblastoma. Thus, quantitative proteomics complements genomic platforms to yield a more complete understanding of functional tumor biology and identify novel therapeutic targets for medulloblastoma.
Collapse
|
|
8
|
Zhang LY, Ge XL, Li Z, Tang YJ, Xiong YY, Li XJ, Liu JF, Wanggou SY, Li CT, Yang K, Chen X, Hu ZL, Liu YS, Liu ZX. Fibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas. Sci Rep 2017; 7:17523. [PMID: 29235490 PMCID: PMC5727473 DOI: 10.1038/s41598-017-17679-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 11/23/2017] [Indexed: 12/14/2022] Open
Abstract
Non-functioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. The elucidation of the mechanisms of aggressive NFPAs in bone destruction is required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, we investigated the differential proteomics of fibroblasts isolated from clinical specimens of NFPAs with or without bone destruction. Proteomic analysis revealed a group of molecules associated with cytoskeleton organization, including caldesmon, were differentially expressed between fibroblasts isolated from bone destruction NFPAs (BD-NFPAs) and fibroblasts isolated from non-bone destruction NFPAs (NBD-NFPAs). The secreted proteins analysis found that osteopontin was significantly upregulated in BD-NFPAs fibroblasts. Furthermore, immunohistochemical staining of the NFPAs clinical samples showed that the expression of caldesmon in stromal cells and the expression of osteopontin in both tumor cells and stroma were significantly increased in BD-NFPAs. Taken together, our results indicate a possible way that osteopontin secreted from both NFPA cells and surrounding fibroblasts modify caldesmon expression and polymerization in fibroblasts, which may contribute to bone destruction in NFPA patients.
Collapse
Affiliation(s)
- Li-Yang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China.,Department of Medicine, University of Oklahoma Health Science Center; 975NE, 10th ST, Oklahoma City, Oklahoma, 73104, United States
| | - Xiao-Lu Ge
- High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Zheng Li
- High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, Hunan, 410008, P.R. China
| | - Yong-Jian Tang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Yuan-Yuan Xiong
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Xue-Jun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Jin-Fang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Si-Yi Wanggou
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Chun-Tao Li
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Kui Yang
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Xin Chen
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Zhong-Liang Hu
- Department of Pathology, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Yun-Sheng Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China
| | - Zhi-Xiong Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University; 87 Xiangya Road, Changsha, Hunan, 410078, P.R. China.
| |
Collapse
|
|
9
|
Yu G, Qu G. High molecular weight caldesmon expression in ovarian adult granulosa cell tumour and fibrothecoma. Histopathology 2017; 72:359-361. [PMID: 28833394 DOI: 10.1111/his.13365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Guohua Yu
- Department of Pathology, Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Guimei Qu
- Department of Pathology, Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| |
Collapse
|
|
10
|
Kros JM, Mustafa DM, Dekker LJM, Sillevis Smitt PAE, Luider TM, Zheng PP. Circulating glioma biomarkers. Neuro Oncol 2014; 17:343-60. [PMID: 25253418 DOI: 10.1093/neuonc/nou207] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 07/13/2014] [Indexed: 02/06/2023] Open
Abstract
Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers.
Collapse
Affiliation(s)
- Johan M Kros
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Dana M Mustafa
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Lennard J M Dekker
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Peter A E Sillevis Smitt
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Theo M Luider
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| |
Collapse
|
|
11
|
Chang KP, Wang CLA, Kao HK, Liang Y, Liu SC, Huang LL, Hseuh C, Hsieh YJ, Chien KY, Chang YS, Yu JS, Chi LM. Overexpression of caldesmon is associated with lymph node metastasis and poorer prognosis in patients with oral cavity squamous cell carcinoma. Cancer 2013; 119:4003-11. [DOI: 10.1002/cncr.28300] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 06/03/2013] [Accepted: 07/01/2013] [Indexed: 12/15/2022]
Affiliation(s)
- Kai-Ping Chang
- Department of Otolaryngology-Head & Neck Surgery; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
- Molecular Medicine Research Center; Chang Gung University; Tao-Yuan Taiwan
| | - Chih-Lueh Albert Wang
- Muscle and Motility Group; Boston Biomedical Research Institute; Watertown Massachusetts
| | - Huang-Kai Kao
- Department of Plastic and Reconstructive Surgery; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
| | - Ying Liang
- Molecular Medicine Research Center; Chang Gung University; Tao-Yuan Taiwan
| | - Shiau-Chin Liu
- Department of Otolaryngology-Head & Neck Surgery; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
| | - Ling-Ling Huang
- Department of Otolaryngology-Head & Neck Surgery; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
| | - Chuen Hseuh
- Department of Pathology; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
| | - Ya-Ju Hsieh
- Molecular Medicine Research Center; Chang Gung University; Tao-Yuan Taiwan
| | - Kun-Yi Chien
- Department of Biochemistry and Molecular Biology; Chang Gung University; Tao-Yuan Taiwan
| | - Yu-Sun Chang
- Molecular Medicine Research Center; Chang Gung University; Tao-Yuan Taiwan
| | - Jau-Song Yu
- Department of Biochemistry and Molecular Biology; Chang Gung University; Tao-Yuan Taiwan
| | - Lang-Ming Chi
- Molecular Medicine Research Center; Chang Gung University; Tao-Yuan Taiwan
- Department of Medical Research Development; Chang Gung Memorial Hospital; Tao-Yuan Taiwan
| |
Collapse
|
|
12
|
Schwappacher R, Rangaswami H, Su-Yuo J, Hassad A, Spitler R, Casteel DE. cGMP-dependent protein kinase Iβ regulates breast cancer cell migration and invasion via interaction with the actin/myosin-associated protein caldesmon. J Cell Sci 2013; 126:1626-36. [PMID: 23418348 DOI: 10.1242/jcs.118190] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The two isoforms of type I cGMP-dependent protein kinase (PKGIα and PKGIβ) differ in their first ∼100 amino acids, giving each isoform unique dimerization and autoinhibitory domains. The dimerization domains form coiled-coil structures and serve as platforms for isoform-specific protein-protein interactions. Using the PKGIβ dimerization domain as an affinity probe in a proteomic screen, we identified the actin/myosin-associated protein caldesmon (CaD) as a PKGIβ-specific binding protein. PKGIβ phosphorylated human CaD on serine 12 in vitro and in intact cells. Phosphorylation on serine 12 or mutation of serine 12 to glutamic acid (S12E) reduced the interaction between CaD and myosin IIA. Because CaD inhibits myosin ATPase activity and regulates cell motility, we examined the effects of PKGIβ and CaD on cell migration and invasion. Inhibition of the NO/cGMP/PKG pathway reduced migration and invasion of human breast cancer cells, whereas PKG activation enhanced their motility and invasion. siRNA-mediated knockdown of endogenous CaD had pro-migratory and pro-invasive effects in human breast cancer cells. Reconstituting cells with wild-type CaD slowed migration and invasion; however, CaD containing a phospho-mimetic S12E mutation failed to reverse the pro-migratory and pro-invasive activity of CaD depletion. Our data suggest that PKGIβ enhances breast cancer cell motility and invasive capacity, at least in part, by phosphorylating CaD. These findings identify a pro-migratory and pro-invasive function for PKGIβ in human breast cancer cells, suggesting that PKGIβ is a potential target for breast cancer treatment.
Collapse
Affiliation(s)
- Raphaela Schwappacher
- Department of Medicine and Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
| | | | | | | | | | | |
Collapse
|
|
13
|
Hou Q, Tan HT, Lim KH, Lim TK, Khoo A, Tan IBH, Yeoh KG, Chung MCM. Identification and functional validation of caldesmon as a potential gastric cancer metastasis-associated protein. J Proteome Res 2013; 12:980-90. [PMID: 23265641 DOI: 10.1021/pr3010259] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In this study, we aim to identify biomarkers for gastric cancer metastasis using a quantitative proteomics approach. The proteins extracted from a panel of 4 gastric cancer cell lines, two derived from primary cancer (AGS, FU97) and two from lymph node metastasis (AZ521, MKN7), were labeled with iTRAQ (8-plex) reagents and analyzed by 2D-LC-MALDI-TOF/TOF MS. In total, 641 proteins were identified with at least a 95% confidence. Using cutoff values of >1.5 and <0.67, 19 proteins were found to be up-regulated and 34 were down-regulated in the metastatic versus primary gastric cancer cell lines respectively. Several of these dysregulated proteins, including caldesmon, were verified using Western blotting. It was found that caldesmon expression was decreased in the two metastasis-derived cell lines, and this was confirmed by further analysis of 7 gastric cancer cell lines. Furthermore, immunohistochemical staining of 9 pairs of primary gastric cancer and the matched lymph node metastasis tissue also corroborated this observation. Finally, knockdown of caldesmon using siRNA in AGS and FU97 gastric cancer cells resulted in an increase in cell migration and invasion, while the overexpression of caldesmon in AZ521 cells led to a decrease in cell migration and invasion. This study has thus established the potential role of caldesmon in gastric cancer metastasis, and further functional studies are underway to delineate the underlying mechanism of action of this protein.
Collapse
Affiliation(s)
- Qian Hou
- Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Kim KH, Yeo SG, Kim WK, Kim DY, Yeo HY, Hong JP, Chang HJ, Park JW, Kim SY, Kim BC, Yoo BC. Up-regulated expression of l-caldesmon associated with malignancy of colorectal cancer. BMC Cancer 2012; 12:601. [PMID: 23241148 PMCID: PMC3572427 DOI: 10.1186/1471-2407-12-601] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 12/09/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Caldesmon (CaD), a major actin-associated protein, is found in smooth muscle and non-muscle cells. Smooth muscle caldesmon, h-CaD, is a multifunctional protein, and non-muscle cell caldesmon, l-CaD, plays a role in cytoskeletal architecture and dynamics. h-CaD is thought to be an useful marker for smooth muscle tumors, but the role(s) of l-CaD has not been examined in tumors. METHODS Primary colon cancer and liver metastasis tissues were obtained from colon cancer patients. Prior to chemoradiotherapy (CRT), normal and cancerous tissues were obtained from rectal cancer patients. Whole-tissue protein extracts were analyzed by 2-DE-based proteomics. Expression and phosphorylation level of main cellular signaling proteins were determined by western blot analysis. Cell proliferation after CaD siRNA transfection was monitored by MTT assay. RESULTS The expression level of l-CaD was significantly increased in primary colon cancer and liver metastasis tissues compared to the level in the corresponding normal tissues. In cancerous tissues obtained from the patients showing poor response to CRT (Dworak grade 4), the expression of l-CaD was increased compared to that of good response group (Dworak grade 1). In line with, l-CaD positive human colon cancer cell lines were more resistant to 5-fluorouracil (5-FU) and radiation treatment compared to l-CaD negative cell lines. Artificial suppression of l-CaD increased susceptibility of colon cancer cells to 5-FU, and caused an increase of p21 and c-PARP, and a decrease of NF-kB and p-mTOR expression. CONCLUSION Up-regulated expression of l-CaD may have a role for increasing metastatic property and decreasing CRT susceptibility in colorectal cancer cells.
Collapse
Affiliation(s)
- Kyung-Hee Kim
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
- Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-744, Republic of Korea
| | - Seung-Gu Yeo
- Department of Radiation Oncology, Soonchunhyang University College of Medicine, Cheonan, 330-721, Republic of Korea
| | - Won Ki Kim
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Dae Yong Kim
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
- Center for Colorectal Cancer, Hospital, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Hyun Yang Yeo
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Jun Pyu Hong
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Hee Jin Chang
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
- Center for Colorectal Cancer, Hospital, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Ji Won Park
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
- Center for Colorectal Cancer, Hospital, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Sun Young Kim
- Center for Colorectal Cancer, Hospital, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Byung Chang Kim
- Center for Colorectal Cancer, Hospital, National Cancer Center, Goyang, 410-769, Republic of Korea
| | - Byong Chul Yoo
- Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Goyang, 410-769, Republic of Korea
| |
Collapse
|
|
15
|
O'Rourke DJ, DiJohnson DA, Caiazzo RJ, Nelson JC, Ure D, O'Leary MP, Richie JP, Liu BCS. Autoantibody signatures as biomarkers to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate specific antigen. Clin Chim Acta 2011; 413:561-7. [PMID: 22146597 DOI: 10.1016/j.cca.2011.11.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 11/07/2011] [Accepted: 11/23/2011] [Indexed: 01/26/2023]
Abstract
BACKGROUND Serum prostate specific antigen (PSA) concentrations lack the specificity to differentiate prostate cancer from benign prostate hyperplasia (BPH), resulting in unnecessary biopsies. We identified 5 autoantibody signatures to specific cancer targets which might be able to differentiate prostate cancer from BPH in patients with increased serum PSA. METHODS To identify autoantibody signatures as biomarkers, a native antigen reverse capture microarray platform was used. Briefly, well-characterized monoclonal antibodies were arrayed onto nanoparticle slides to capture native antigens from prostate cancer cells. Prostate cancer patient serum samples (n=41) and BPH patient samples (collected starting at the time of initial diagnosis) with a mean follow-up of 6.56 y without the diagnosis of cancer (n=39) were obtained. One hundred micrograms of IgGs were purified and labeled with a Cy3 dye and incubated on the arrays. The arrays were scanned for fluorescence and the intensity was quantified. Receiver operating characteristic curves were produced and the area under the curve (AUC) was determined. RESULTS Using our microarray platform, we identified autoantibody signatures capable of distinguishing between prostate cancer and BPH. The top 5 autoantibody signatures were TARDBP, TLN1, PARK7, LEDGF/PSIP1, and CALD1. Combining these signatures resulted in an AUC of 0.95 (sensitivity of 95% at 80% specificity) compared to AUC of 0.5 for serum concentration PSA (sensitivity of 12.2% at 80% specificity). CONCLUSION Our preliminary results showed that we were able to identify specific autoantibody signatures that can differentiate prostate cancer from BPH, and may result in the reduction of unnecessary biopsies in patients with increased serum PSA.
Collapse
Affiliation(s)
- Dennis J O'Rourke
- Molecular Urology Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Köhler C. Histochemical localization of caldesmon isoforms in colon adenocarcinoma and lymph node metastases. Virchows Arch 2011; 459:81-9. [DOI: 10.1007/s00428-011-1091-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 04/15/2011] [Accepted: 05/10/2011] [Indexed: 12/21/2022]
|
|
17
|
Zheng PP, Romme E, van der Spek PJ, Dirven CMF, Willemsen R, Kros JM. Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol 2011; 68:835-44. [PMID: 21194153 DOI: 10.1002/ana.22318] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The overall permeability of the blood-brain barrier (BBB) is regulated by specialized cerebral endothelial cells and their junctional complexes, consisting of adherens junctions (AJs) and tight junctions (TJs). Among the members of the glucose transporters (Glut), Glut1 is a unique molecule expressed in the cerebral endothelial cells. Glut1 and the junctional proteins are concomitantly downregulated in situations in which breakdown of the BBB has taken place. We hypothesized that the expression of Glut1 may play a significant role in the development of the cerebral microvasculature with BBB properties. To date, there is no information on the role of Glut1 during the development of BBB. In the present study, the in vivo effects of Glut1 knockdown on the cerebral vascular development were investigated. METHODS Zebrafish was used as a model organism. We confirmed that the structure of the zebrafish homologue of Glut1 is highly similar to the human Glut1 and that the function of the Glut1-mediated cerebral uptake of glucose is evolutionally conserved. RESULTS In the Glut1 knockdown model, we observed loss of the cerebral endothelial cells, with concomitant downregulation of the junctional proteins important for intactness of the AJs/TJs and impaired cerebral circulation. The resulting leaky BBB caused vasogenic brain edema. INTERPRETATION The data suggest a crucial role of Glut1 in the development of the cerebral endothelial cells with BBB properties in vivo. The findings suggest that modulation of Glut1 expression and function may open new directions of research for therapeutic strategies to prevent vasogenic brain edema.
Collapse
Affiliation(s)
- Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
| | | | | | | | | | | |
Collapse
|
|
18
|
Lin JJ, Li Y, Eppinga RD, Wang Q, Jin J. Chapter 1 Roles of Caldesmon in Cell Motility and Actin Cytoskeleton Remodeling. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2009; 274:1-68. [DOI: 10.1016/s1937-6448(08)02001-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
19
|
Zheng PP, Severijnen LA, van der Weiden M, Willemsen R, Kros JM. A crucial role of caldesmon in vascular development in vivo. Cardiovasc Res 2008; 81:362-9. [DOI: 10.1093/cvr/cvn294] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
20
|
Zheng PP, Severijnen LA, Willemsen R, Kros JM. Caldesmon is essential for cardiac morphogenesis and function: in vivo study using a zebrafish model. Biochem Biophys Res Commun 2008; 378:37-40. [PMID: 19000902 DOI: 10.1016/j.bbrc.2008.10.165] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2008] [Accepted: 10/28/2008] [Indexed: 01/26/2023]
Abstract
The zebrafish homologue of caldesmon is similar to the mammalian low molecular weight caldesmon (l-CaD). In this study, we explored the effects of caldesmon knockdown on vertebrate heart development in vivo. In a zebrafish model caldesmon was knocked down resulting in defective cardiac morphogenesis, muscularization and function. The data provide the first functional assessment of the role of caldesmon in cardiac development in vivo, and indicate that caldesmon is essential for proper cardiac organogenesis and function. Because caldesmon expression remarkably influences cardiac muscularization, the findings are relevant for designing future therapeutic strategies in the regeneration of cardiac damage.
Collapse
Affiliation(s)
- Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, JNI Room 230-c, Dr. Molewaterplein 50, PO Box 1738, 3000 DR Rotterdam, The Netherlands
| | | | | | | |
Collapse
|
|
21
|
|
|
22
|
Wang CLA. Caldesmon and the regulation of cytoskeletal functions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 644:250-72. [PMID: 19209827 DOI: 10.1007/978-0-387-85766-4_19] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Caldesmon (CaD) is an extraordinary actin-binding protein, because in addition to actin, it also bindsmyosin, calmodulin and tropomyosin. As a component of the smoothmuscle and nonmuscle contractile apparatus CaD inhibits the actomyosin ATPase activity and its inhibitory action is modulated by both Ca2+ and phosphorylation. The multiplicity of binding partners and diverse biochemical properties suggest CaD is a potent and versatile regulatory protein both in contractility and cell motility. However, after decades ofinvestigation in numerous laboratories, hard evidence is still lacking to unequivocally identify its in vivo functions, although indirect evidence is mounting to support an important role in connection with the actin cytoskeleton. This chapter reviews the highlights of the past findings and summarizes the current views on this protein, with emphasis of its interaction with tropomyosin.
Collapse
Affiliation(s)
- C L Albert Wang
- Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472, USA.
| |
Collapse
|
|
23
|
Zheng PP, Hop WC, Luider TM, Sillevis Smitt PAE, Kros JM. Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann Neurol 2007; 62:40-8. [PMID: 17503506 DOI: 10.1002/ana.21151] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Gliomas are among the highest vascularized tumors. We hypothesized that patients with gliomas have increased levels of circulating endothelial progenitor cells (EPCs) and circulating endothelial nitric oxide synthase (eNOS). METHODS The fraction of EPCs was quantified by fluorescence-activated cell sorter analysis using anti-CD34, -CD133 and -KDR (kinase insert domain receptor) monoclonal antibodies in unselected peripheral blood samples of 32 patients with gliomas. Control groups included 47 patients with other central nervous system tumors or diseases, 10 patients with recent ischemic strokes, and 19 healthy blood donors. The circulating eNOS concentration of plasma was measured by a colorimetric assay in the same samples. In addition, CD34(+)CD105(+) KDR(+) and CD34(+)CD146(+)KDR(-) cell fractions were measured. RESULTS The percentage of CD34(+)CD133(+)KDR(+) EPCs in the blood of glioma patients is significantly greater than that in the blood of patients with other central nervous system tumors or diseases (p = 0.003), stroke patients (p = 0.005), or healthy donors (p = 0.013). The plasma eNOS concentration is also significantly greater in glioma patients compared with each of the control groups (p < 0.001 for all groupwise comparisons). No significant differences in the levels of the EPCs or eNOS between any of the control groups were demonstrated. In the glioma patients, the level of eNOS correlated with the fraction of CD34(+)CD105(+)KDR(+) cells (r = 0.748; p = 0.008). INTERPRETATION The data are suggestive of increased mobilization of EPCs contributing to neoplastic vasculogenesis in glioma. The increased levels of EPCs and eNOS in the peripheral blood of glioma patients trigger further investigations as to their value as independent parameters for use in clinical practice.
Collapse
Affiliation(s)
- Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Dr. Molewaterplein 50, 3000 DR Rotterdam, the Netherlands
| | | | | | | | | |
Collapse
|
|
24
|
Zheng PP, van der Weiden M, Kros JM. Hela l-CaD is implicated in the migration of endothelial cells/endothelial progenitor cells in human neoplasms. Cell Adh Migr 2007; 1:84-91. [PMID: 19329885 DOI: 10.4161/cam.1.2.4332] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Caldesmon (CaD) is a major actin-binding protein distributed in a variety of cell types. No functional differences among the isoforms in in vitro studies were found so far. In a previous study we found that the low molecular caldesmon isoform (Hela l-CaD) is expressed in endothelial cells (ECs)/endothelial progenitor cells (EPCs) in tumor vasculature of various human tumors. Activation of cell motility is necessary for the navigation of the tip ECs during angiogenesis, and migration of EPCs from the bone marrow during vasculogenesis. In the present study we searched for features of motility and the intracellular expression sites of Hela l-CaD in ECs/EPCs of various human tumors under histologically preserved microenviroment. We discovered a variety of motility-related cell protrusions like filopodia, microspikes, lamellipodia, podosomes, membrane blebs and membrane ruffles in the activated ECs/EPCs. Hela l-CaD appeared to be invariably expressed in the subregions of these cell protrusions. The findings suggest that Hela l-CaD is implicated in the migration of ECs/EPC in human neoplasms where they contribute to tumor vasculogenesis and angiogenesis.
Collapse
Affiliation(s)
- Ping-Pin Zheng
- Department of Pathology of Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | |
Collapse
|
|
25
|
Zheng PP, Hop WC, Sillevis Smitt PAE, van den Bent MJ, Avezaat CJJ, Luider TM, Kros JM. Low-molecular weight caldesmon as a potential serum marker for glioma. Clin Cancer Res 2005; 11:4388-92. [PMID: 15958622 DOI: 10.1158/1078-0432.ccr-04-2512] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Testing the feasibility of using the serum low-molecular weight caldesmon (l-CaD) level as a serum marker for the presence of glioma. EXPERIMENTAL DESIGN Within a total of 230 serum samples, the l-CaD level was measured in healthy volunteers (30), patients with gliomas (57), nonglial intracranial tumors (107), and nontumor neurologic diseases (36) by ELISA. The specificity of the assay was monitored by combination of immunoprecipitation and immunoblotting. RESULTS The serum level of l-CaD is significantly higher in the group of glioma patients as compared with any of the other groups (P < 0.001). The cutoff value of 45 yields optimal sensitivity and specificity of the assay (91% and 84%, respectively; area under the curve score = 0.91). The specificity of ELISA was confirmed by the immunoprecipitation/immunoblotting control experiments. There were no significant differences in serum l-CaD levels between patients with low- or high-grade gliomas. CONCLUSIONS The serum l-CaD level as determined by ELISA is a good discriminator between glioma patients versus patients with other intracranial tumors, other neurologic diseases, and healthy people. Prospective studies are required to test the contribution of the assay in making the diagnosis of glioma, or its feasibility for monitoring the tumor during treatment.
Collapse
Affiliation(s)
- Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | | | | | | | | | | | | |
Collapse
|