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Min S, Jang B, Yun JH, Yang H, Sung JY, Lim GE, Kim YN, Lee W, Oh ES. Anticancer effect of a single-chain variable fragment against pro-matrix metalloproteinase-7 in colon cancer. Matrix Biol 2025; 135:125-134. [PMID: 39805673 DOI: 10.1016/j.matbio.2024.12.009] [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: 09/27/2024] [Revised: 12/03/2024] [Accepted: 12/22/2024] [Indexed: 01/16/2025]
Abstract
Disrupting the interaction between matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) can yield anticancer effects in colon cancer cells. Here, a single-chain variable fragment (scFv) targeting the pro-domain of MMP-7 was generated as a potential candidate anticancer agent. Among the generated scFvs, those designated 1B7 and 1C3 showed the strongest abilities to inhibit the ability of MMP-7 pro-domain to directly interact with SDC-2 in vitro and decrease the cancer activities of human HT29 colon adenocarcinoma cells. Consistently, 1B7 and 1C3 inhibited the cell-surface localization of pro-MMP-7, reduced the gelatinolytic activity of MMP-7, and suppressed the cancer activities of metastatic HCT116 human colon carcinoma cells. Notably, 1B7 inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a mouse model. Compared to 1B7, the 1B7-Fc fusion antibody showed better anti-tumorigenic activity against HCT116 cells in culture and a syngeneic mouse model. Together, these data suggest that 1B7-Fc exerts anticancer effects by interfering with the interaction of MMP-7 and SDC-2 and could be a promising therapeutic antibody for colon cancer.
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Affiliation(s)
- Shinhye Min
- Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Bohee Jang
- Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Ji-Hye Yun
- Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea; Epinogen, Ltd., 604 KBIZ DMC Tower, Seoul 03929, South Korea
| | - Hyeonju Yang
- Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Jee Young Sung
- Cancer Metastasis Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Gyeonggi-do, Goyang-si 10408, South Korea
| | - Ga-Eun Lim
- Cancer Metastasis Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Gyeonggi-do, Goyang-si 10408, South Korea
| | - Yong-Nyun Kim
- Cancer Metastasis Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Gyeonggi-do, Goyang-si 10408, South Korea
| | - Weontae Lee
- Epinogen, Ltd., 604 KBIZ DMC Tower, Seoul 03929, South Korea; Structural Biochemistry & Molecular Biophysics Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea
| | - Eok-Soo Oh
- Department of Life Sciences, Ewha Womans University, Seoul 03760, South Korea.
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Xu Y, Qu H, Liang R, Li M, Li M, Li X, Wang Z. A multi-gene blood-based methylation assay for early diagnosis of colorectal cancer. Transl Cancer Res 2024; 13:6699-6708. [PMID: 39816546 PMCID: PMC11730695 DOI: 10.21037/tcr-24-729] [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: 04/30/2024] [Accepted: 10/31/2024] [Indexed: 01/18/2025]
Abstract
Background Early detection for colorectal cancer (CRC) can enhance the patient prognosis. We aimed to validate the combined multi-gene detection in plasma of Septin9, SDC2, KCNQ5, and IKZF1 for early diagnosing of CRC in this prospective study. Methods Overall, 124 participants including 45 CRC patients, 8 advanced adenoma patients, 34 small polyp patients, and 37 normal controls who underwent colonoscopy were enrolled. The carcinoembryonic antigen (CEA) test and methylation tests for Septin9, SDC2, KCNQ5, and IKZF1 were performed. Sensitivity, specificity, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve were utilized to evaluate the diagnostic value of each biomarker. Additionally, the association between the positive rates of methylated Septin9, SDC2, KCNQ5, and IKZF1 and the clinicopathological characteristics of CRC was also analyzed. Results The positive detection rate of multi-gene methylation in CRC patients was 86.67%, for stage I and stage II patients, the positive rates were 90.91% and 87.50%, both of which were significantly higher than CEA, which had rates of 55.56%, 18.18% and 56.25% for the corresponding stages. In patients with advanced adenomas and small polyps, the positive rates for the four-gene combined test were 62.50% and 52.94%, respectively, which were markedly higher than the CEA rates of 12.50% and 14.71%. AUC of the ROC curve indicated that the diagnostic value of the multi-gene test for CRC was superior to that of any single gene. Correlation analysis revealed that the positive rate of the test was not affected by patients' clinicopathological characteristics. Conclusions A combination of methylated Septin9, SDC2, KCNQ5, and IKZF1 test has the potential for early diagnosis of CRC patients, advanced adenoma patients, and small polyp patients.
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Affiliation(s)
- Yingshuo Xu
- Department of Medicine, Molecular diagnostic Engineering Technology Research Center of Zhengzhou, Zhengzhou, China
| | - Huaidong Qu
- Department of Anorectal Surgery, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Rui Liang
- Department of Pathology, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Menglong Li
- Department of Anorectal Surgery, the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Miao Li
- Department of Gynecology, Baoding First Central Hospital, Baoding, China
| | - Xiankun Li
- Department of Medicine, Molecular diagnostic Engineering Technology Research Center of Zhengzhou, Zhengzhou, China
| | - Zhiqiang Wang
- Department of Anorectal Surgery, the Second Hospital of Tianjin Medical University, Tianjin, China
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Emelyanova MA, Ikonnikova AY. Utilization of molecular genetic approaches for colorectal cancer screening. World J Gastroenterol 2024; 30:4950-4957. [PMID: 39679308 PMCID: PMC11612711 DOI: 10.3748/wjg.v30.i46.4950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/14/2024] [Accepted: 11/01/2024] [Indexed: 11/21/2024] Open
Abstract
The feasibility of population screening for colorectal cancer has been demonstrated in several studies. Most of these studies have considered individual characteristics, diagnostic approaches, epidemiological data, and socioeconomic factors. In this article, we comment on an editorial by Metaxas et al published in the recent issue of the journal. The authors emphasized the need to raise public awareness through health education programs and the possibility of using easily accessible non-invasive screening methods. Here, we focus on non-invasive molecular genetic approaches that can aid in colorectal cancer screening. On the one hand, we highlighted the use of tumor DNA/RNA markers directly for screening and, on the other hand, underline the use of polygenic risk assessment and hereditary predisposition to select individuals for more thorough cancer screening.
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Affiliation(s)
- Marina A Emelyanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Anna Y Ikonnikova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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Xu Y, Tan A, Liang R, Qu H, Li X, Wang Z. Evaluation of Multigene Methylation for Blood-Based Detection of Colorectal Cancer. Genet Test Mol Biomarkers 2024; 28:402-409. [PMID: 39308406 DOI: 10.1089/gtmb.2023.0754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024] Open
Abstract
Background: Early screening for colorectal cancer (CRC) has the potential to improve patient prognosis, but current screening methods are limited. In this prospective study, we aimed to evaluate the multigene (Septin9, SDC2, KCNQ5, and IKZF1) detection in patient plasma for CRC diagnosis. Methods: Overall, 67 participants were enrolled, including 31 patients with CRC, 17 patients with colorectal polyp, and 19 normal controls who underwent colonoscopy. Carcinoembryonic antigen (CEA) and Septin9, SDC2, KCNQ5, and IKZF1 methylation tests were performed. Sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve were used to evaluate the diagnostic value of each biomarker. The association between positive rates of methylated Septin9, SDC2, KCNQ5, and IKZF1 and the clinicopathological characteristics of CRC was also analyzed. Results: The positive rate of multigene methylation detection was 87.1% (27/31) in patients with CRC, which was higher than single indicators: CEA (51.61%, 16/31), Septin9 (41.94%, 13/31), SDC2 (41.94%, 13/31), KCNQ5 (58.06%, 18/31), and IKZF1 (32.26%, 10/31). In the colorectal polyp group, the rate of multigene methylation detection is 88.24% (15/17), which was also higher than single indicator: CEA (17.65%, 3/17), Septin9 (11.76%, 2/17), SDC2 (64.71%, 11/17), KCNQ5 (58.82%, 10/17), and IKZF1 (35.29%, 6/17). The ROC curves further showed better diagnostic value of the multigene test for CRC than any single gene. Correlation analysis found that the positive rate of the test was not affected by patients' clinicopathologic characteristics. Conclusion: The combination of methylated Septin9, SDC2, KCNQ5, and IKZF1 tests is preferable to individual gene tests for patients with CRC and polyp.
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Affiliation(s)
- Yingshuo Xu
- Department of Medicine, Molecular Diagnostic Engineering Technology Research Center of Zhengzhou, Zhengzhou, China
| | - Ailin Tan
- Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Rui Liang
- Department of Pathology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Huaidong Qu
- Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xiankun Li
- Department of Medicine, Molecular Diagnostic Engineering Technology Research Center of Zhengzhou, Zhengzhou, China
| | - Zhiqiang Wang
- Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
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Liu X, Qin H, Liu Y, Ma J, Li Y, He Y, Zhu H, Mao L. The biological functions and pathological mechanisms of CASK in various diseases. Heliyon 2024; 10:e28863. [PMID: 38638974 PMCID: PMC11024568 DOI: 10.1016/j.heliyon.2024.e28863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 04/20/2024] Open
Abstract
Background As a scaffold protein, calcium/calmodulin-dependent serine protein kinase (CASK) has been extensively studied in a variety of tissues throughout the body. The Cask gene is ubiquitous in several tissues, such as the neurons, islets, heart, kidneys and sperm, and is mostly localised in the cytoplasm adjacent to the basement membrane. CASK binds to a variety of proteins through its domains to exerting its biological activity. Scope of review Here, we discuss the role of CASK in multiple tissues throughout the body. The role of different CASK domains in regulating neuronal development, neurotransmitter release and synaptic vesicle secretion was emphasised; the regulatory mechanism of CASK on the function of pancreatic islet β cells was analysed; the role of CASK in cardiac physiology, kidney and sperm development was discussed; and the role of CASK in different tumours was compared. Finally, we clarify the importance of the Cask gene in the body, and how deletion or mutation of the Cask gene can have adverse consequences. Major conclusions CASK is a conserved gene with similar roles in various tissues. The function of the Cask gene in the nervous system is mainly involved in the development of the nervous system and the release of neurotransmitters. In the endocrine system, an involvement of CASK has been reported in the process of insulin vesicle transport. CASK is also involved in cardiomyocyte ion channel regulation, kidney and sperm development, and tumour proliferation. CASK is an indispensable gene for the whole body, and CASK mutations can cause foetal malformations or death at birth. In this review, we summarise the biological functions and pathological mechanisms of CASK in various systems, thereby providing a basis for further in-depth studies of CASK functions.
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Affiliation(s)
- Xingjing Liu
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Haonan Qin
- Department of Orthopedics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yuanyuan Liu
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Jingjing Ma
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yiming Li
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Yu He
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Huimin Zhu
- Department of Electrophysiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
| | - Li Mao
- Department of Endocrinology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China
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Luo WF, Jiao YT, Lin XL, Zhao Y, Wang SB, Shen J, Deng J, Ye YF, Han ZP, Xie FM, He JH, Wan Y. Effectiveness of fecal DNA syndecan-2 methylation testing for detection of colorectal cancer in a high-risk Chinese population. World J Gastrointest Oncol 2024; 16:1361-1373. [PMID: 38660655 PMCID: PMC11037044 DOI: 10.4251/wjgo.v16.i4.1361] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/12/2024] [Accepted: 02/07/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. Syndecan-2 methylation (mSDC2) testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. Cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. AIM To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China. METHODS A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing. Sensitivity and specificity for CRC, advanced adenoma (AA) and advanced colorectal neoplasia (ACN) were determined. High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test. RESULTS A total of 1035 high-risk individuals were included in this study according to established criteria. Among them, 16 suffered from CRC (1.55%), 65 from AA (6.28%) and 189 from non-AAs (18.26%); 150 patients were diagnosed with polyps (14.49%). Diagnoses were established based upon colonoscopic and pathological examinations. Sensitivities of the mSDC2 test for CRC and AA were 87.50% and 40.00%, respectively; specificities were 95.61% for other groups. Positive predictive values of the mSDC2 test for CRC, AA and ACN were 16.09%, 29.89% and 45.98%, respectively; the negative predictive value for CRC was 99.79%. After adjusting for other high-risk covariates, mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN (P < 0.001). CONCLUSION Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.
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Affiliation(s)
- Wen-Feng Luo
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yu-Ting Jiao
- South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Xiao-Ling Lin
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Ying Zhao
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Sheng-Bo Wang
- Digestive Disease Center, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Jian Shen
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Jie Deng
- Shunde Vocational and Technical College, Foshan 528300, Guangdong Province, China
| | - Yu-Feng Ye
- Medical Imaging Institute of Panyu, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Ze-Ping Han
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Fang-Mei Xie
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Jin-Hua He
- Central Laboratory of Panyu Central Hospital, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yu Wan
- Digestive Disease Center, Guangzhou Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
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Lee S, Jang B, Hwang J, Lee Y, Cho S, Yang H, Yun JH, Shin DH, Lee W, Oh ES. Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells. Am J Physiol Cell Physiol 2024; 326:C1067-C1079. [PMID: 38314724 DOI: 10.1152/ajpcell.00669.2023] [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: 12/05/2023] [Revised: 01/28/2024] [Accepted: 01/28/2024] [Indexed: 02/07/2024]
Abstract
Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer.NEW & NOTEWORTHY The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.
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Affiliation(s)
- Seohyeon Lee
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Bohee Jang
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Jisun Hwang
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Yejin Lee
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Subin Cho
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Hyeonju Yang
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Ji-Hye Yun
- PCG-Biotech, Ltd. Yonsei Engineering Research Park 114A, Yonsei University, Seoul, Republic of Korea
- Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of Korea
| | - Dong Hae Shin
- College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Weontae Lee
- PCG-Biotech, Ltd. Yonsei Engineering Research Park 114A, Yonsei University, Seoul, Republic of Korea
| | - Eok-Soo Oh
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
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Siri G, Alesaeidi S, Dizghandi SE, Alani B, Mosallaei M, Soosanabadi M. Analysis of SDC2 gene promoter methylation in whole blood for noninvasive early detection of colorectal cancer. J Cancer Res Ther 2022; 18:S354-S358. [PMID: 36510988 DOI: 10.4103/jcrt.jcrt_1072_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Objectives Considering the limitations of the current approaches to colorectal cancer (CRC) screening, scientists strived to find noninvasive and more powerful biomarkers for the early diagnosis of CRC. Nowadays, there are different sources of biomarkers for CRC diagnosis. Blood-based samples including circulating cell-free tumor DNA (ctDNA) and DNA extracted from leukocytes in peripheral blood might be promising sources of noninvasive cancer biomarkers such as cancer-specific methylation patterns. In this study, we aimed to evaluate the noninvasive early diagnosis of CRC via quantitative promotor methylation analysis of SDC2 gene in whole blood. Materials and Methods Sixty-five CRC patients and 65 healthy participants were enrolled to assess promoter methylation of SDC2 gene in whole blood using the methylation quantification endonuclease-resistant DNA (MethyQESD) technique. Results Our findings demonstrated drastic hypermethylation of SDC2 in blood samples from CRC subjects (37.91%) compared with non-malignant individuals (17.02%) (P < 0.001). The sensitivity for detection of CRC by methylation of SDC2 was 81.54%, with a specificity of 69.23%. The ROC curve analysis demonstrated that the AUC was 0.847 (P < 0.001), indicating that the status of SDC2 promoter methylation in whole blood is an excellent biomarker of CRC diagnosis. Furthermore, our results showed that methylation level in CRC patients significantly increased in higher tumor stages, demonstrating that an increased percentage of methylation is correlated with tumor progression (P < 0.001). Conclusion SDC2 promoter methylation status in blood samples is a valuable cancer biomarker and holds high power and accuracy in distinguishing CRC patients from healthy subjects in the early stages of the disease.
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Affiliation(s)
- Goli Siri
- Department of Internal Medicine, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Alesaeidi
- Department of Rheumatology and Internal Medicine, Rheumatology Research Center, Amir-Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- School of Medicine, Aja University of Medical Science, Tehran; Department of Medical Genetics, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Soosanabadi
- Department of Medical Genetics, Semnan University of Medical Sciences; Abnormal Uterine Bleeding Research Center, Semnan University of Medical Sciences, Semnan, Iran
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Wang L, Liu Y, Zhang D, Xiong X, Hao T, Zhong L, Zhao Y. Diagnostic accuracy of DNA-based SDC2 methylation test in colorectal cancer screening: a meta-analysis. BMC Gastroenterol 2022; 22:314. [PMID: 35754025 PMCID: PMC9235166 DOI: 10.1186/s12876-022-02395-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background A growing body of research suggests that methylated genes can be used as early diagnostic markers for cancer. Some studies on methylated Syndecan 2 (SDC2) have shown that it has a great diagnostic ability in colorectal cancer. This meta-analysis was aimed to estimate the diagnostic performance of methylated SDC2 as a potential novel biomarker to screen for the colorectal cancer. Methods Two independent researchers conducted a comprehensive literature search to identify all relevant studies on SDC2 methylation for the diagnosis of colorectal cancer from inception to March 1, 2021. By using STATA and Revman software, the data were analyzed using a Bivariate mixed model. The quality of each study was also evaluated. Results A total of 12 studies comprised of 1574 colorectal cancer patients and 1945 healthy people were included in our meta-analysis. Bivariate analysis showed a pooled sensitivity of 0.81 [95% confidence interval (CI) 0.74–0.86], specificity of 0.95 (95% CI 0.93–0.96), positive likelihood ratio of 15.29 (95% CI 10.83–21.60), and negative likelihood ratio of 0.21 (95% CI 0.15–0.27). The diagnostic odds ratio and the area under the summary ROC curve for diagnosing colorectal cancer were 74.42 (95% CI45.44–121.89) and 0.96 (95% CI 0.94–0.97), respectively. For adenomas, the pooled sensitivity and specificity were 0.47 (95% CI 0.34–0.61) and 0.95 (95% CI 0.92–0.97), respectively. Conclusions Our analysis revealed that methylated SDC2 could be considered as a potential novel biomarker to screen for colorectal cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02395-7.
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Affiliation(s)
- Lixing Wang
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Yu Liu
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Duohan Zhang
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Xiaoliang Xiong
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Tingting Hao
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Lili Zhong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, 130041, China.
| | - Yinlong Zhao
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Changchun, 130041, China.
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Substituted Syndecan-2-Derived Mimetic Peptides Show Improved Antitumor Activity over the Parent Syndecan-2-Derived Peptide. Int J Mol Sci 2022; 23:ijms23115888. [PMID: 35682569 PMCID: PMC9180903 DOI: 10.3390/ijms23115888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/11/2022] [Accepted: 05/19/2022] [Indexed: 11/17/2022] Open
Abstract
We previously showed that a synthetic peptide (S2-P) corresponding to a portion of the human syndecan-2 (SDC2) sequence can bind to the pro-domain of matrix metalloproteinase-7 (MMP-7) to inhibit colon cancer activities. Since S2-P had a relatively weak binding affinity for the MMP-7 pro-domain, we herein modified the amino acid sequence of S2-P to improve the anticancer potential. On the basis of the interaction structure of S2-P and MMP-7, four peptides were generated by replacing amino acids near Tyr 51, which is critical for the interaction. The SDC2-mimetic peptides harboring an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-D) or with an Ala-to-Phe substitution at the N-terminal side of Tyr 51 and an Ala-to-Asp substitution at the C-terminal side of Tyr 51 (S2-FE) showed improved interaction affinities for the MMP-7 pro-domain. Compared to S2-P, S2-FE was better able to inhibit the SDC2-MMP-7 interaction, the cell surface localization of MMP-7, the gelatin degradation activity of MMP-7, and the cancer activities (cell migration, invasion, and colony-forming activity) of human HCT116 colon cancer cells in vitro. In vivo, S2-FE inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a xenograft mouse model. Together, these data suggest that S2-FE could be useful therapeutic anticancer peptides for colon cancer.
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Van Doren SR. MMP-7 marks severe pancreatic cancer and alters tumor cell signaling by proteolytic release of ectodomains. Biochem Soc Trans 2022; 50:839-851. [PMID: 35343563 PMCID: PMC10443904 DOI: 10.1042/bst20210640] [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: 01/31/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 11/17/2022]
Abstract
Pancreatic cancer incurs the worst survival rate of the major cancers. High levels of the protease matrix metalloproteinase-7 (MMP-7) in circulation correlate with poor prognosis and limited survival of patients. MMP-7 is required for a key path of pancreatic tumorigenesis in mice and is present throughout tumor progression. Enhancements to chemotherapies are needed for increasing the number of pancreatic tumors that can be removed and for preventing relapses after surgery. With these ends in mind, selective inhibition of MMP-7 may be worth investigation. An anti-MMP-7 monoclonal antibody was recently shown to increase the susceptibility of several pancreatic cancer cell lines to chemotherapeutics, increase their apoptosis, and decrease their migration. MMP-7 activities are most apparent at the surfaces of innate immune, epithelial, and tumor cells. Proteolytic shedding of multiple protein ectodomains by MMP-7 from such cell surfaces influence apoptosis, proliferation, migration, and invasion. These activities warrant targeting of MMP-7 selectively in pancreatic cancer and other tumors of mucosal epithelia. Competitive and non-competitive modes of MMP-7 inhibition are discussed.
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Affiliation(s)
- Steven R. Van Doren
- Department of Biochemistry, University of Missouri, Columbia, MO 65211 USA
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211 USA
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Jang B, Song HK, Hwang J, Lee S, Park E, Oh A, Hwang ES, Sung JY, Kim YN, Park K, Lee YM, Oh ES. Shed syndecan-2 enhances colon cancer progression by increasing cooperative angiogenesis in the tumor microenvironment. Matrix Biol 2022; 107:40-58. [DOI: 10.1016/j.matbio.2022.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/12/2022] [Accepted: 02/02/2022] [Indexed: 12/24/2022]
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Hua R, Zhang Y, Yan X, Tang D, Li X, Ni Q, Wang D, Zhu J. Syndecan-2, negatively regulated by miR-20b-5p, contributes to 5-fluorouracil resistance of colorectal cancer cells via the JNK/ERK signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1547-1557. [PMID: 34596215 DOI: 10.1093/abbs/gmab124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
5-Fluorouracil (5-FU) resistance has been long considered as an obstacle to the efficacy of chemotherapy in colorectal cancer (CRC). In this study, we demonstrated the role of miR-20b-5p-regulated syndecan-2 (SDC2) in 5-FU resistance of CRC cells. 5-FU-resistant SW480 CRC cells were established by treatment of SW480 cells with stepwise increase of 5-FU concentration. The results showed that SDC2 was expressed significantly higher in SW480/5-FU cells than in SW480/WT cells as revealed by quantitative real-time polymerase chain reaction and western blot analysis. MTT assay and BrdU assay showed that SDC2 overexpression led to increased cell survival rate, while SDC2 knockdown reversed the drug resistance of SW480/5-FU cells. Wound healing and transwell invasion assays revealed that knockdown of SDC2 inhibited the migratory and invasive ability of SW480/5-FU cells. Moreover, animal experiments indicated that si-SDC2 plays a suppressive role in tumor growth in vivo. We also confirmed that miR-20b-5p interacted with SDC2, which reversed the effect of SDC2 in SW480/5-FU cells via the c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinases (ERK) signaling pathway. These findings showed that JNK/ERK signaling pathway is involved in miR-20b-5p/SDC2 axis-mediated 5-FU resistance in SW480/5-FU cells, indicating that the miR-20b-5p/SDC2 axis is a potential target for reversing 5-FU resistance in CRC.
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Affiliation(s)
- Ruheng Hua
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong 226021, China
- Department of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Yan Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong 226021, China
| | - Xiyue Yan
- Department of Hematology, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - Dong Tang
- Department of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Xiaolong Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong 226021, China
| | - Qingfeng Ni
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong 226021, China
| | - Daorong Wang
- Department of General Surgery, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Jianwei Zhu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Nantong 226021, China
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Kim MS, Ha SE, Wu M, Zogg H, Ronkon CF, Lee MY, Ro S. Extracellular Matrix Biomarkers in Colorectal Cancer. Int J Mol Sci 2021; 22:9185. [PMID: 34502094 PMCID: PMC8430714 DOI: 10.3390/ijms22179185] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/12/2021] [Accepted: 08/18/2021] [Indexed: 12/12/2022] Open
Abstract
The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.
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Affiliation(s)
- Min-Seob Kim
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
| | - Se-Eun Ha
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Moxin Wu
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang 332000, China
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Charles F. Ronkon
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Moon-Young Lee
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
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Gachabayov M, Lebovics E, Rojas A, Felsenreich DM, Latifi R, Bergamaschi R. Performance evaluation of stool DNA methylation tests in colorectal cancer screening: a systematic review and meta-analysis. Colorectal Dis 2021; 23:1030-1042. [PMID: 33410272 DOI: 10.1111/codi.15521] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
AIM There is not sufficient evidence about whether stool DNA methylation tests allow prioritizing patients to colonoscopy. Due to the COVID-19 pandemic, there will be a wait-list for rescheduling colonoscopies once the mitigation is lifted. The aim of this meta-analysis was to evaluate the accuracy of stool DNA methylation tests in detecting colorectal cancer. METHODS The PubMed, Cochrane Library and MEDLINE via Ovid were searched. Studies reporting the accuracy (Sackett phase 2 or 3) of stool DNA methylation tests to detect sporadic colorectal cancer were included. The DerSimonian-Laird method with random-effects model was utilized for meta-analysis. RESULTS Forty-six studies totaling 16 149 patients were included in the meta-analysis. The pooled sensitivity and specificity of all single genes and combinations was 62.7% (57.7%, 67.4%) and 91% (89.5%, 92.2%), respectively. Combinations of genes provided higher sensitivity compared to single genes (80.8% [75.1%, 85.4%] vs. 57.8% [52.3%, 63.1%]) with no significant decrease in specificity (87.8% [84.1%, 90.7%] vs. 92.1% [90.4%, 93.5%]). The most accurate single gene was found to be SDC2 with a sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). CONCLUSIONS Stool DNA methylation tests have high specificity (92%) with relatively lower sensitivity (81%). Combining genes increases sensitivity compared to single gene tests. The single most accurate gene is SDC2, which should be considered for further research.
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Affiliation(s)
- Mahir Gachabayov
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Edward Lebovics
- Section of Gastroenterology, Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Aram Rojas
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Daniel M Felsenreich
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Rifat Latifi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Roberto Bergamaschi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
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Zhang W, Yang C, Wang S, Xiang Z, Dou R, Lin Z, Zheng J, Xiong B. SDC2 and TFPI2 Methylation in Stool Samples as an Integrated Biomarker for Early Detection of Colorectal Cancer. Cancer Manag Res 2021; 13:3601-3617. [PMID: 33958894 PMCID: PMC8096344 DOI: 10.2147/cmar.s300861] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Detection of aberrant methylated DNA in the stool is an effective early screening method for colorectal cancer (CRC). Previously, reporters identified that syndecan-2 (SDC2) and tissue factor pathway inhibitor 2 (TFPI2) were aberrantly methylated in most CRC tissues. However, the combined diagnostic role of them remains undefined. Our research aimed at probing the role and efficiency of the methylation status of SDC2 and TFPI2 in CRC early screening by using bioinformatics analysis and clinical stool sample validation. Methods The promoter and CpG site methylation levels of SDC2 and TFPI2 and their correlation with clinicopathological characteristics of CRC were analyzed using UALCAN, Methsurv, and Wanderer. UCSC Xena was used to perform survival analyses. LinkedOmics was used to do functional network analysis. DNA was isolated and purified from stool, and quantitative methylation-specific PCR (qMSP) was applied to detect methylatedSDC2 and TFPI2. Results The results showed that promoter and most CpG site methylation levels of SDC2 and TFPI2 were significantly higher in CRC than in normal tissues. Moreover, SDC2 and TFPI2 methylation showed a positive correlation. Functional network analysis suggested that both methylated SDC2 and TFPI2 were involved in tumor cells’ metabolic programs. Besides, there was a higher positive integrated detection rate in CRC (n=61) with a sensitivity of 93.4% and in adenoma (Ade) (n=16) with a sensitivity of 81.3% than normal with a specificity of 94.3% in stool samples. What is more, integration of methylated SDC2 and TFPI2 showed a higher sensitivity and Youden index than a single gene in detecting Adeor CRC. Conclusion Our data indicate that SDC2 and TFPI2 were hypermethylated in CRC, and integrated detection of methylated SDC2 and TFPI2 in stool has the potential to be an effective and noninvasive tool of CRC early screening.
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Affiliation(s)
- Weisong Zhang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Zhenxian Xiang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Zaihuan Lin
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Jinsen Zheng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
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Jang B, Kim A, Hwang J, Song HK, Kim Y, Oh ES. Emerging Role of Syndecans in Extracellular Matrix Remodeling in Cancer. J Histochem Cytochem 2020; 68:863-870. [PMID: 32623937 PMCID: PMC7711240 DOI: 10.1369/0022155420930112] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/06/2020] [Indexed: 12/20/2022] Open
Abstract
The extracellular matrix (ECM) offers a structural basis for regulating cell functions while also acting as a collection point for bioactive molecules and connective tissue cells. To perform pathological functions under a pathological condition, the involved cells need to regulate the ECM to support their altered functions. This is particularly common in the development of cancer. The ECM has been recognized as a key driver of cancer development and progression, and ECM remodeling occurs at all stages of cancer progression. Thus, cancer cells need to change the ECM to support relevant cell surface adhesion receptor-mediated cell functions. In this context, it is interesting to examine how cancer cells regulate ECM remodeling, which is critical to tumor malignancy and metastatic progression. Here, we review how the cell surface adhesion receptor, syndecan, regulates ECM remodeling as cancer progresses, and explore how this can help us better understand ECM remodeling under these pathological conditions.
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Affiliation(s)
- Bohee Jang
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Ayoung Kim
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Jisun Hwang
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Hyun-Kuk Song
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Yunjeon Kim
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Eok-Soo Oh
- Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea
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Liu Y, Huang H, Fu J, Zhang Y, Xu J, Zhang L, Sun S, Zhao L, Zhang D, Onwuka JU, Sun H, Cui B, Zhao Y. Colorectal cancer patients with CASK promotor heterogeneous and homogeneous methylation display different prognosis. Aging (Albany NY) 2020; 12:20561-20586. [PMID: 33113509 PMCID: PMC7655177 DOI: 10.18632/aging.103928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/30/2020] [Indexed: 06/11/2023]
Abstract
Homogenous DNA methylation clearly affects clinical outcomes. However, less is known about the effects of heterogeneous methylation. We aimed to investigate the different effects between CASK promoter methylation heterogeneity and homogeneity on colorectal cancer (CRC) patients' prognosis. The methylation status of CASK in 296 tumor tissues and 255 adjacent normal tissues were evaluated using Methylation-sensitive high-resolution melting (MS-HRM). Digital MS-HRM (dMS-HRM) visualized heterogeneous methylation and subsequent sequencing provided exact patterns. Log-rank test and Cox regression model were adopted to assess the association between CASK methylation status and CRC prognosis with propensity score (PS) method to control confounding biases. Heterogeneous methylation was detected in both tumor (52.2%) and non-neoplastic tissue surrounding the tumor (62.4%). It occurred more frequently in lower levels of tumor invasion (P = 0.002) and male patients (P < 0.001). Compared with heterogeneous methylation, patients with CASK homogeneous methylation presented poorer overall survival (OS) (HR: 1.919, 95% CI: 1.146-3.212, P = 0.013) and disease-free survival (DFS) (HR: 1.913, 95% CI: 1.146-3.194, P = 0.013). This unfavorable effect still existed among older (≥ 50), Dukes staging C/D, and rectal cancer patients. MS-HRM and dMS-HRM when combined can assess the degree and complexity of heterogeneous methylation with a visible pattern.
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Affiliation(s)
- Ying Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Jinming Fu
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Simin Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Liyuan Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Ding Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Justina Ucheojor Onwuka
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Binbin Cui
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, The People’s Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Nangang District, Harbin 150086, Heilongjiang Province, The People’s Republic of China
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Mathiesen SB, Lunde M, Stensland M, Martinsen M, Nyman TA, Christensen G, Carlson CR. The Cardiac Syndecan-2 Interactome. Front Cell Dev Biol 2020; 8:792. [PMID: 32984315 PMCID: PMC7483480 DOI: 10.3389/fcell.2020.00792] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/28/2020] [Indexed: 12/31/2022] Open
Abstract
The extracellular matrix (ECM) is important in cardiac remodeling and syndecans have gained increased interest in this process due to their ability to convert changes in the ECM to cell signaling. In particular, syndecan-4 has been shown to be important for cardiac remodeling, whereas the role of its close relative syndecan-2 is largely unknown in the heart. To get more insight into the role of syndecan-2, we here sought to identify interaction partners of syndecan-2 in rat left ventricle. By using three different affinity purification methods combined with mass spectrometry (MS) analysis, we identified 30 novel partners and 9 partners previously described in the literature, which together make up the first cardiac syndecan-2 interactome. Eleven of the novel partners were also verified in HEK293 cells (i.e., AP2A2, CAVIN2, DDX19A, EIF4E, JPH2, MYL12A, NSF, PFDN2, PSMC5, PSMD11, and RRAD). The cardiac syndecan-2 interactome partners formed connections to each other and grouped into clusters mainly involved in cytoskeletal remodeling and protein metabolism, but also into a cluster consisting of a family of novel syndecan-2 interaction partners, the CAVINs. MS analyses revealed that although syndecan-2 was significantly enriched in fibroblast fractions, most of its partners were present in both cardiomyocytes and fibroblasts. Finally, a comparison of the cardiac syndecan-2 and -4 interactomes revealed surprisingly few protein partners in common.
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Affiliation(s)
- Sabrina Bech Mathiesen
- Institute for Experimental Medical Research and Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Marianne Lunde
- Institute for Experimental Medical Research and Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Maria Stensland
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marita Martinsen
- Institute for Experimental Medical Research and Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Tuula A Nyman
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Geir Christensen
- Institute for Experimental Medical Research and Oslo University Hospital, University of Oslo, Oslo, Norway.,K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Cathrine Rein Carlson
- Institute for Experimental Medical Research and Oslo University Hospital, University of Oslo, Oslo, Norway
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20
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Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment. Int J Mol Sci 2020; 21:ijms21186588. [PMID: 32916872 PMCID: PMC7554799 DOI: 10.3390/ijms21186588] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.
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21
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Hua R, Yu J, Yan X, Ni Q, Zhi X, Li X, Jiang B, Zhu J. Syndecan-2 in colorectal cancer plays oncogenic role via epithelial-mesenchymal transition and MAPK pathway. Biomed Pharmacother 2019; 121:109630. [PMID: 31707342 DOI: 10.1016/j.biopha.2019.109630] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/01/2019] [Accepted: 11/01/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE In this study, we aimed to elucidate the biological roles of Syndecan-2 (SDC2) in colorectal cancer (CRC), thereby further understanding its clinical role. METHODS The expression of SDC2 was assessed by qRT-PCR and Western blot analysis. To understand the potential biological role of SDC2, we also explored the correlation between its expression level and clinicopathologic parameters. By using MTT, plate colony formation assay, Transwell invasion assays, and flow cytometry in vitro, the biological impact of SDC2 on CRC cell proliferation, migration, invasion, and apoptosis. In addition, the related signaling pathways were investigated. RESULTS SDC2 expression was significantly upregulated in CRC tissues. The expression of SDC2 was highly associated with four parameters, i.e., stage (P < 0.01), vascular invasion (P = 0.0045), lymph node metastasis (P=0.0018), and distant metastasis (P = 0.0019). Knockdown of SDC2 significantly reduced proliferation, migration, and invasion of HCT116 and SW480 cells, and induced cell apoptosis. Moreover, SDC2 promoted epithelial-mesenchymal transition (EMT) in CRC cells, whereas the ratio of p-MEK/MEK and p-ERK/ERK markedly reduced after depleting SDC2. CONCLUSION During CRC development, overexpression of SDC2 plays a carcinogenic role in CRC. Therapeutic solutions targeting SDC2 may provide potential insights into CRC prevention and treatment.
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Affiliation(s)
- Ruheng Hua
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Jiawei Yu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Xiyue Yan
- Department of Hematology, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Qingfeng Ni
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Xiaofei Zhi
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Xiaolong Li
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China
| | - Bin Jiang
- Department of General Surgery, Xinghua First People's Hospital, Taizhou 225300, Jiangsu, PR China
| | - Jianwei Zhu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226021, Jiangsu, PR China.
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Jang B, Yun JH, Choi S, Park J, Shin DH, Lee ST, Lee W, Oh ES. Tyrosine 51 residue of the syndecan-2 extracellular domain is involved in the interaction with and activation of pro-matrix metalloproteinase-7. Sci Rep 2019; 9:10625. [PMID: 31337828 PMCID: PMC6650482 DOI: 10.1038/s41598-019-47140-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/11/2019] [Indexed: 01/16/2023] Open
Abstract
Although syndecan-2 is known to interact with the matrix metalloproteinase-7 (MMP-7), the details of their interaction were unknown. Our experiments with a series of syndecan-2 extracellular domain deletion mutants show that the interaction is mediated through an interaction of the extracellular domain of syndecan-2 (residues 41 to 60) with the α2 helix-loop-α3 helix in the pro-domain of MMP-7. NMR and molecular docking model show that Glu7 of the α1 helix, Glu32 of the α2 helix, and Gly48 and Ser52 of the α2 helix-loop-α3 helix of the MMP-7 pro-domain form the syndecan-2-binding pocket, which is occupied by the side chain of tyrosine residue 51 (Tyr51) of syndecan-2. Consistent with this notion, the expression of a syndecan-2 mutant in which Tyr51 was changed to Ala diminished the interaction between the syndecan-2 extracellular domain and the pro-domain of MMP-7. Furthermore, HT-29 colon adenocarcinoma cells expressing the interaction-defective mutant exhibited reductions in the cell-surface localization of MMP-7, the processing of pro-MMP-7 into active MMP-7, the MMP-7-mediated extracellular domain shedding of both syndecan-2 and E-cadherin, and syndecan-2-mediated anchorage-independent growth. Collectively, these data strongly suggest that Tyr51 of the syndecan-2 extracellular domain mediates its interaction with and activating processing of pro-MMP-7 and regulates MMP-7-dependent syndecan-2 functions.
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Affiliation(s)
- Bohee Jang
- From the Department of Life Sciences, the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Republic of Korea
| | - Ji-Hye Yun
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea
| | - Sojoong Choi
- From the Department of Life Sciences, the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Republic of Korea
| | - Jimin Park
- College of Pharmacy, Ewha Womans University, Seoul, 120-750, Republic of Korea
| | - Dong Hae Shin
- College of Pharmacy, Ewha Womans University, Seoul, 120-750, Republic of Korea
| | - Seung-Taek Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea
| | - Weontae Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea.
| | - Eok-Soo Oh
- From the Department of Life Sciences, the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Republic of Korea.
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23
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Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis. Cell Immunol 2018; 333:46-57. [DOI: 10.1016/j.cellimm.2018.03.007] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 03/13/2018] [Accepted: 03/16/2018] [Indexed: 01/20/2023]
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24
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Oh TJ, Oh HI, Seo YY, Jeong D, Kim C, Kang HW, Han YD, Chung HC, Kim NK, An S. Feasibility of quantifying SDC2 methylation in stool DNA for early detection of colorectal cancer. Clin Epigenetics 2017; 9:126. [PMID: 29225717 PMCID: PMC5715626 DOI: 10.1186/s13148-017-0426-3] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 11/23/2017] [Indexed: 01/04/2023] Open
Abstract
Background Colorectal cancer (CRC) screening is the most efficient strategy to reduce disease-related mortality. Frequent aberrant DNA methylation is known to occur in selected genes and early during CRC development, which has emerged as a new epigenetic biomarker for early detection of CRC. Previously, we reported that we identified that CpG sites of SDC2 were aberrantly methylated in tumor tissues of most CRC patients through comprehensive methylation analysis and demonstrated a high potential of quantification of SDC2 methylation in blood for early detection of colorectal cancer. In this study, we aim to investigate the feasibility of quantifying SDC2 methylation in stool DNA for the early detection of CRC. The objective of this study was to confirm a high frequency of SDC2 methylation in tumor tissues at various stages of CRC and investigate the feasibility of a quantitative test for SDC2 methylation in fecal DNA by highly sensitive and accurate real-time PCR for early detection of CRC. Methods Bisulfite-pyrosequencing assay was performed to measure the SDC2 methylation status in tissue samples. For methylation analysis in stool DNA, a highly sensitive and accurate method was applied which implements consecutive two rounds of PCR consisting of unidirectional linear target enrichment (LTE) of SDC2 and quantitative methylation-specific real time PCR (qMSP) for SDC2, named as meSDC2 LTE-qMSP assay. Its limit of detection was 0.1% methylation (corresponding to ~ 6 copies in total ~ 6200 genome copies). Results Positive SDC2 methylation was observed in 100% of primary tumors, 90.6% of adenomatous polyps, 94.1% of hyperplastic polyps, and 0% of normal tissues. SDC2 methylation level also significantly (P < 0.01) increased according to the severity of lesions. In stool DNA test for SDC2 methylation by LTE-qMSP comparing CRC patients with various stages (I to IV) (n = 50) and precancerous lesions (n = 21) with healthy subjects (n = 22), the overall sensitivity was 90.0% for detecting CRC and 33.3% for detecting small polyps, with a specificity of 90.9%. Conclusions Taken together, our result indicates that stool DNA-based SDC2 methylation test by LTE-qMSP is a potential noninvasive diagnostic tool for early detection of CRC.
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Affiliation(s)
- Tae Jeong Oh
- Genomictree, Inc, 44-6 Techno 10-ro Yuseong-gu, Daejeon, 34027 South Korea
| | - Hyun Il Oh
- Genomictree, Inc, 44-6 Techno 10-ro Yuseong-gu, Daejeon, 34027 South Korea
| | - Yang Yei Seo
- Genomictree, Inc, 44-6 Techno 10-ro Yuseong-gu, Daejeon, 34027 South Korea
| | - Dongjun Jeong
- Department of Pathology, College of Medicine, Soonchunhyang University, 23-20 Byeongmyeong-dong Dongnam-gu, Cheonan, Chungcheongnam-do 31151 South Korea
| | - Changjin Kim
- Department of Pathology, College of Medicine, Soonchunhyang University, 23-20 Byeongmyeong-dong Dongnam-gu, Cheonan, Chungcheongnam-do 31151 South Korea
| | - Hyoun Woo Kang
- Department of Internal Medicine, Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, 27 Dongguk-ro Ilsandong-gu, Goyang-si, Gyeonggi-do 10326 South Korea
| | - Yoon Dae Han
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul, 03722 South Korea
| | - Hyun Cheol Chung
- Yonsei Cancer Center Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul, 03722 South Korea
| | - Nam Kyu Kim
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul, 03722 South Korea
| | - Sungwhan An
- Genomictree, Inc, 44-6 Techno 10-ro Yuseong-gu, Daejeon, 34027 South Korea
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Oroxyloside inhibits human glioma progression by suppressing proliferation, metastasis and inducing apoptosis related pathways. Biomed Pharmacother 2017; 97:1564-1574. [PMID: 29793319 DOI: 10.1016/j.biopha.2017.09.100] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/02/2017] [Accepted: 09/18/2017] [Indexed: 12/20/2022] Open
Abstract
Malignant glioma are linked to a high mortality rate. Therefore, it is necessary to explore and develop effective therapeutic strategy. Oroxyloside is a metabolite of oroxylin A. However, its inhibitory effects on cancer are little to be known. In the present study, we investigated the effects of oroxyloside on cell proliferation, migration, and apoptosis in vitro and in vivo in human glioma. The results indicated that oroxyloside significantly suppressed the proliferation of human glioma cells through inducing cell cycle arrest at G0/G1 phase through reducing Cyclin D1 and cyclin-dependent kinase 2 (CDK2) while enhancing p53 and p21 expressions. In addition, the migration of glioma cells was dramatically inhibited by oroxyloside in a dose-dependent manner, which was related to its modulation on extracellular matrix (ECM), as evidenced by up-regulated E-cadherin, and metastasis-associated protein 3 (MTA3), whereas down-regulated N-cadherin, Vimentin, Twist, alpha-smooth muscle actin (α-SMA) and Syndecan-2. Furthermore, oroxyloside treatment markedly induced apoptosis in glioma cells through improving Caspase-9, Caspase-3 and PARP cleavage, accompanied with high release of cytochrome c (Cyto-c) into cytoplasm and subsequently increase of apoptotic protease-activating factor 1 (Apaf-1). In vivo, oroxyloside administration significantly inhibited the glioma cell xenograft tumorigenesis through various signaling pathways, including suppression of Cyclin D1/CDK2 and ECM pathways, as well as potentiation of p53/p21 and Caspases pathways. Together, the findings above illustrated that oroxyloside, for the first time, was used as a promising candidate against human glioma.
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Processing of syndecan-2 by matrix metalloproteinase-14 and effect of its cleavage on VEGF-induced tube formation of HUVECs. Biochem J 2017; 474:3719-3732. [PMID: 28972070 DOI: 10.1042/bcj20170340] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 09/15/2017] [Accepted: 09/25/2017] [Indexed: 11/17/2022]
Abstract
Syndecans (SDCs) are transmembrane proteoglycans that are involved in cell adhesion and cell communication. Specifically, SDC2 plays a key role in tumorigenesis, metastasis, and angiogenesis. Previously, we found that rat SDC2 is shed by matrix metalloproteinase-7 (MMP-7) in colon cancer cells. Here, we analyzed the susceptibility of rat SDC2 to various MMPs. We found that the rat SDC2 ectodomain (ECD) fused to the C-terminal Fc region, which was expressed in mammalian cells, was cleaved more efficiently by MMP-14 than MMP-7. Likewise, when anchored on the surface of HeLa cells, rat SDC2 was cleaved more efficiently by the treatment of MMP-14 than MMP-7 and was shed more readily by membrane-anchored MMP-14 than soluble MMP-14. Furthermore, MMP-14 cleaved recombinant SDC2-ECD expressed in Escherichia coli into multiple fragments. Using N-terminal amino acid sequencing and the top-down proteomics approach, we determined that the major cleavage sites were S88↓L89, T98↓M99, T100↓L101, D132↓P133, and N148↓L149 for rat SDC2-ECD and S55↓G56, S65↓P66, P75↓K76, N92↓I93 D122↓P123, and S138↓L139 for human SDC2-ECD. Finally, the rat and human SDC2-ECD lost the ability to suppress vascular endothelial growth factor-induced formation of capillary-like tubes by human umbilical vein endothelial cells following cleavage by MMP-14, but its major cleavage-site mutant of rat SDC2-ECD did not. These results suggest that MMP-14 is a novel enzyme responsible for degrading SDC2 and impairing its physiological roles including angiogenesis.
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27
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Nastase MV, Janicova A, Wygrecka M, Schaefer L. Signaling at the Crossroads: Matrix-Derived Proteoglycan and Reactive Oxygen Species Signaling. Antioxid Redox Signal 2017; 27:855-873. [PMID: 28510506 DOI: 10.1089/ars.2017.7165] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Proteoglycans (PGs), besides their structural contribution, have emerged as dynamic components that mediate a multitude of cellular events. The various roles of PGs are attributed to their structure, spatial localization, and ability to act as ligands and receptors. Reactive oxygen species (ROS) are small mediators that are generated in physiological and pathological conditions. Besides their reactivity and ability to induce oxidative stress, a growing body of data suggests that ROS signaling is more relevant than direct radical damage in development of human pathologies. Recent Advances: Cell surface transmembrane PGs (syndecans, cluster of differentiation 44) represent receptors in diverse and complex transduction networks, which involve redox signaling with implications in cancer, fibrosis, renal dysfunction, or Alzheimer's disease. Through NADPH oxidase (NOX)-dependent ROS, the extracellular PG, hyaluronan is involved in osteoclastogenesis and cancer. The ROS sources, NOX1 and NOX4, increase biglycan-induced inflammation, while NOX2 is a negative regulator. CRITICAL ISSUES The complexity of the mechanisms that bring ROS into the light of PG biology might be the foundation of a new research area with significant promise for understanding health and disease. Important aspects need to be investigated in PG/ROS signaling: the discovery of specific targets of ROS, the precise ROS-induced chemical modifications of these targets, and the study of their pathological relevance. FUTURE DIRECTIONS As we become more and more aware of the interactions between PG and ROS signaling underlying intracellular communication and cell fate decisions, it is quite conceivable that this field will allow to identify new therapeutic targets.-Antioxid. Redox Signal. 27, 855-873.
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Affiliation(s)
- Madalina-Viviana Nastase
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany .,2 National Institute for Chemical-Pharmaceutical Research and Development , Bucharest, Romania
| | - Andrea Janicova
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany
| | - Malgorzata Wygrecka
- 3 Department of Biochemistry, Faculty of Medicine, Justus Liebig University , Giessen, Germany
| | - Liliana Schaefer
- 1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität , Frankfurt am Main, Germany
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Mytilinaiou M, Nikitovic D, Berdiaki A, Kostouras A, Papoutsidakis A, Tsatsakis AM, Tzanakakis GN. Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression. IUBMB Life 2017; 69:824-833. [PMID: 28940845 DOI: 10.1002/iub.1678] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/29/2017] [Indexed: 01/04/2023]
Abstract
Syndecan 2 (SDC2) belongs to a four-member family of evolutionary conserved small type I transmembrane proteoglycans consisting of a protein core to which glycosaminoglycan chains are covalently attached. SDC2 is a cell surface heparan sulfate proteoglycan, which is increasingly drawing attention for its distinct characteristics and its participation in numerous cell functions, including those related to carcinogenesis. Increasing evidence suggests that the role of SDC2 in cancer pathogenesis is dependent on cancer tissue origin rendering its use as a biomarker/therapeutic target feasible. This mini review discusses the mechanisms, through which SDC2, in a distinct manner, modulates complex signalling networks to affect cancer progression. © 2017 IUBMB Life, 69(11):824-833, 2017.
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Affiliation(s)
- Maria Mytilinaiou
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
| | - Dragana Nikitovic
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
| | - Aikaterini Berdiaki
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
| | - Antonis Kostouras
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
| | - Antonis Papoutsidakis
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
| | - Aristidis M Tsatsakis
- Laboratory of Toxicology, School of Medicine, University of Crete, Heraklion, Greece
| | - George N Tzanakakis
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
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Barták BK, Kalmár A, Péterfia B, Patai ÁV, Galamb O, Valcz G, Spisák S, Wichmann B, Nagy ZB, Tóth K, Tulassay Z, Igaz P, Molnár B. Colorectal adenoma and cancer detection based on altered methylation pattern of SFRP1, SFRP2, SDC2, and PRIMA1 in plasma samples. Epigenetics 2017; 12:751-763. [PMID: 28753106 PMCID: PMC5739100 DOI: 10.1080/15592294.2017.1356957] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Aberrant methylation is one of the most frequent epigenetic alterations that can contribute to tumor formation. Cell-free DNA can originate from tumor tissue; therefore, the evaluation of methylation markers in cell-free DNA can be a promising method for cancer screening. Our aim was to develop a panel of biomarkers with altered methylation along the colorectal adenoma-carcinoma sequence in both colonic tissue and plasma. Methylation of selected CpG sites in healthy colonic (n = 15), adenoma (n = 15), and colorectal cancer (n = 15) tissues was analyzed by pyrosequencing. MethyLight PCR was applied to study the DNA methylation of SFRP1, SFRP2, SDC2, and PRIMA1 gene promoters in 121 plasma and 32 biopsy samples. The effect of altered promoter methylation on protein expression was examined by immunohistochemistry. Significantly higher (P < 0.05) DNA methylation levels were detected in the promoter regions of all 4 markers, both in CRC and adenoma tissues compared with healthy controls. Methylation of SFRP1, SFRP2, SDC2, and PRIMA1 promoter sequences was observed in 85.1%, 72.3%, 89.4%, and 80.9% of plasma samples from patients with CRC and 89.2%, 83.8%, 81.1% and 70.3% from adenoma patients, respectively. When applied as a panel, CRC patients could be distinguished from controls with 91.5% sensitivity and 97.3% specificity [area under the curve (AUC) = 0.978], while adenoma samples could be differentiated with 89.2% sensitivity and 86.5% specificity (AUC = 0.937). Immunohistochemical analysis indicated decreasing protein levels of all 4 markers along the colorectal adenoma-carcinoma sequence. Our findings suggest that this methylation biomarker panel allows non-invasive detection of colorectal adenoma and cancer from plasma samples.
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Affiliation(s)
- Barbara Kinga Barták
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Alexandra Kalmár
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Bálint Péterfia
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Árpád V. Patai
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Orsolya Galamb
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
| | - Gábor Valcz
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
| | - Sándor Spisák
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Barnabás Wichmann
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
| | - Zsófia Brigitta Nagy
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Kinga Tóth
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
| | - Zsolt Tulassay
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
| | - Péter Igaz
- 2nd Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
| | - Béla Molnár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, H-1088 Budapest, Hungary
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30
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Jang B, Jung H, Choi S, Lee YH, Lee ST, Oh ES. Syndecan-2 cytoplasmic domain up-regulates matrix metalloproteinase-7 expression via the protein kinase Cγ-mediated FAK/ERK signaling pathway in colon cancer. J Biol Chem 2017; 292:16321-16332. [PMID: 28821612 DOI: 10.1074/jbc.m117.793752] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 08/04/2017] [Indexed: 12/25/2022] Open
Abstract
The syndecan family of heparan sulfate proteoglycans contributes to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that overexpression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and ERK in parallel with up-regulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related non-kinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2-mediated up-regulation of MMP-7. Activation of PKC enhanced syndecan-2-mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKCγ to the membrane. Expression of syndecan-2 harboring a phosphomimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental suppression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2-mediated up-regulation of MMP-7 in the early period after syndecan-2 overexpression. Taken together, these findings suggest that syndecan-2's cytoplasmic domain up-regulates MMP-7 expression in colon cancer cells via PKCγ-mediated activation of FAK/ERK signaling.
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Affiliation(s)
- Bohee Jang
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760 and
| | - Hyejung Jung
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760 and
| | - Sojoong Choi
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760 and
| | - Young Hun Lee
- the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Seung-Taek Lee
- the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Eok-Soo Oh
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 03760 and
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Abstract
Heparan sulfate proteoglycans activate the matrix metalloproteinase-7 zymogen (proMMP-7) and recruit it in order to shed proteins from cell surfaces. This occurs in uterine and mammary epithelia, bacterial killing, lung healing, and tumor cell signaling. Basic tracks on proMMP-7 recognize polyanionic heparin, according to nuclear magnetic resonance and mutations disruptive of maturation. Contacts and proximity measurements guided docking of a heparin octasaccharide to proMMP-7. The reducing end fits into a basic pocket in the pro-domain while the chain continues toward the catalytic domain. Another oligosaccharide traverses a basic swath remote on the catalytic domain and inserts its reducing end into a slot formed with the basic C terminus. This latter association appears to support allosteric acceleration of proteolysis. The modes of binding account for extended, heterogeneous assemblies of proMMP-7 with heparinoids during maturation and for bridging to pro-α-defensins and proteoglycans. These associations support proteolytic release of activities at epithelial cell surfaces.
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Niu F, Wen J, Fu X, Li C, Zhao R, Wu S, Yu H, Liu X, Zhao X, Liu S, Wang X, Wang J, Zou H. Stool DNA Test of Methylated Syndecan-2 for the Early Detection of Colorectal Neoplasia. Cancer Epidemiol Biomarkers Prev 2017; 26:1411-1419. [PMID: 28619831 DOI: 10.1158/1055-9965.epi-17-0153] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/18/2017] [Accepted: 06/06/2017] [Indexed: 12/12/2022] Open
Abstract
Background: Although the incidence of colorectal cancer is steadily increasing, screening for colorectal cancer with conventional approaches is not routinely performed in China. Noninvasive screening methods are attractive options to resolve this issue. Syndecan-2 (SDC2) is frequently methylated in colorectal cancer. However, the value of a stool test of methylated SDC2 for the detection of colorectal cancer is unknown.Methods: Methylation status of SDC2 was tested in cell lines and 398 colorectal tissue samples and further evaluated with 497 stool samples, including 196 from colorectal cancer patients, 122 from adenoma patients, and 179 from normal individuals, using real-time methylation-specific PCR. The impacts of one quantitative partial stool sampling device and 17 potentially interfering substances on the performance of fecal methylated SDC2 were also analyzed. SDC2 expression was also measured.Results:SDC2 methylation level was higher in 96.8% (120/124) of colorectal cancer tissues compared with paired adjacent normal epithelia. Stool test of methylated SDC2 detected 81.1% (159/196) of colorectal cancer and 58.2% (71/122) of adenomas at a specificity of 93.3% (167/179). No significant difference was found between partial and whole stool collection on colorectal cancer detection (P > 0.05, R2 = 0.80). Among 17 interfering substances, only berberine at high concentrations inhibited fecal detection of methylated SDC2SDC2 was overexpressed in colorectal cancer tissues compared with normal epithelia.Conclusions: Fecal methylated SDC2 is a valuable biomarker for the noninvasive detection of colorectal neoplasms.Impact: Stool DNA test of methylated SDC2 would serve as an alternative method for screening colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 26(9); 1411-9. ©2017 AACR.
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Affiliation(s)
- Feng Niu
- Guangdong Institute of Gastroenterology, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jialing Wen
- Guangdong Institute of Gastroenterology, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinhui Fu
- Guangdong Institute of Gastroenterology, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chujun Li
- Division of GI Endoscopy, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rongsong Zhao
- Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, China
| | - Shan Wu
- Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, China
| | - Hao Yu
- Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, China
| | - Xianglin Liu
- Guangdong Institute of Gastroenterology, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xia Zhao
- Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, China
| | - Side Liu
- Division of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinying Wang
- Division of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianping Wang
- Guangdong Institute of Gastroenterology, Guangdong, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Division of GI Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongzhi Zou
- Guangdong Institute of Gastroenterology, Guangdong, China. .,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Creative Biosciences (Guangzhou) CO., Ltd., Guangzhou, China
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Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer 2017; 16:70. [PMID: 28356111 PMCID: PMC5372323 DOI: 10.1186/s12943-017-0629-4] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 03/02/2017] [Indexed: 12/22/2022] Open
Abstract
Background Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood. Methods Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo. Results We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3β/β-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and β-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model. Conclusion In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0629-4) contains supplementary material, which is available to authorized users.
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Proteolysis in the Interstitium. Protein Sci 2016. [DOI: 10.1201/9781315374307-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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35
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Couchman JR, Multhaupt H, Sanderson RD. Recent Insights into Cell Surface Heparan Sulphate Proteoglycans and Cancer. F1000Res 2016; 5. [PMID: 27408707 PMCID: PMC4930033 DOI: 10.12688/f1000research.8543.1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/27/2016] [Indexed: 01/11/2023] Open
Abstract
A small group of cell surface receptors are proteoglycans, possessing a core protein with one or more covalently attached glycosaminoglycan chains. They are virtually ubiquitous and their chains are major sites at which protein ligands of many types interact. These proteoglycans can signal and regulate important cell processes, such as adhesion, migration, proliferation, and differentiation. Since many protein ligands, such as growth factors, morphogens, and cytokines, are also implicated in tumour progression, it is increasingly apparent that cell surface proteoglycans impact tumour cell behaviour. Here, we review some recent advances, emphasising that many tumour-related functions of proteoglycans are revealed only after their modification in processes subsequent to synthesis and export to the cell surface. These include enzymes that modify heparan sulphate structure, recycling of whole or fragmented proteoglycans into exosomes that can be paracrine effectors or biomarkers, and lateral interactions between some proteoglycans and calcium channels that impact the actin cytoskeleton.
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Affiliation(s)
- John R Couchman
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Hinke Multhaupt
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Ralph D Sanderson
- Department of Pathology and University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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36
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Jang B, Jung H, Chung H, Moon BI, Oh ES. Syndecan-2 enhances E-cadherin shedding and fibroblast-like morphological changes by inducing MMP-7 expression in colon cancer cells. Biochem Biophys Res Commun 2016; 477:47-53. [PMID: 27270030 DOI: 10.1016/j.bbrc.2016.06.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 06/03/2016] [Indexed: 11/30/2022]
Abstract
E-cadherin plays a mechanical role in mediating cell-cell interactions and maintaining epithelial tissue integrity, and the loss of E-cadherin function has been implicated in cancer progression and metastasis. Syndecan-2, a cell-surface heparan sulfate proteoglycan, is upregulated during the development of colon cancer. Here, we assessed the functional relationship between E-cadherin and syndecan-2. We found that stable overexpression of syndecan-2 in a human colorectal adenocarcinoma cell line (HT29) enhanced the proteolytic shedding of E-cadherin to conditioned-media. Either knockdown of matrix metalloproteinase 7 (MMP-7) or inhibition of MMP-7 activity using GM6001 significantly reduced the extracellular shedding of E-cadherin, suggesting that syndecan-2 mediates E-cadherin shedding via MMP-7. Consistent with this notion, enhancement of MMP-7 expression by interleukin-1α treatment increased the shedding of E-cadherin. Conversely, the specific reduction of either syndecan-2 or MMP-7 reduced the shedding of E-cadherin. HT29 cells overexpressing syndecan-2 showed significantly lower cell-surface expression of E-cadherin, decreased cell-cell contact, a more fibroblastic cell morphology, and increased expression levels of ZEB-1. Taken together, these data suggest that syndecan-2 induces extracellular shedding of E-cadherin and supports the acquisition of a fibroblast-like morphology by regulating MMP-7 expression in a colon cancer cell line.
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Affiliation(s)
- Bohee Jang
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Hyejung Jung
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Heesung Chung
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Byung-In Moon
- Department of Surgery, College of Medicine, Ewha Womans University, 911-1 Mok-Dong Yangcheon-Ku, Seoul, 158-710, Republic of Korea.
| | - Eok-Soo Oh
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 03760, Republic of Korea.
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Cheng B, Montmasson M, Terradot L, Rousselle P. Syndecans as Cell Surface Receptors in Cancer Biology. A Focus on their Interaction with PDZ Domain Proteins. Front Pharmacol 2016; 7:10. [PMID: 26869927 PMCID: PMC4735372 DOI: 10.3389/fphar.2016.00010] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 01/12/2016] [Indexed: 01/23/2023] Open
Abstract
Syndecans are transmembrane receptors with ectodomains that are modified by glycosaminoglycan chains. The ectodomains can interact with a wide variety of molecules, including growth factors, cytokines, proteinases, adhesion receptors, and extracellular matrix (ECM) components. The four syndecans in mammals are expressed in a development-, cell-type-, and tissue-specific manner and can function either as co-receptors with other cell surface receptors or as independent adhesion receptors that mediate cell signaling. They help regulate cell proliferation and migration, angiogenesis, cell/cell and cell/ECM adhesion, and they may participate in several key tumorigenesis processes. In some cancers, syndecan expression regulates tumor cell proliferation, adhesion, motility, and other functions, and may be a prognostic marker for tumor progression and patient survival. The short cytoplasmic tail is likely to be involved in these events through recruitment of signaling partners. In particular, the conserved carboxyl-terminal EFYA tetrapeptide sequence that is present in all syndecans binds to some PDZ domain-containing proteins that may function as scaffold proteins that recruit signaling and cytoskeletal proteins to the plasma membrane. There is growing interest in understanding these interactions at both the structural and biological levels, and recent findings show their high degree of complexity. Parameters that influence the recruitment of PDZ domain proteins by syndecans, such as binding specificity and affinity, are the focus of active investigations and are important for understanding regulatory mechanisms. Recent studies show that binding may be affected by post-translational events that influence regulatory mechanisms, such as phosphorylation within the syndecan cytoplasmic tail.
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Affiliation(s)
- Bill Cheng
- Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, UMR 5305, CNRS, Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, Université Lyon 1 Lyon, France
| | - Marine Montmasson
- Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, UMR 5305, CNRS, Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, Université Lyon 1 Lyon, France
| | - Laurent Terradot
- Bases Moléculaires et Structurales des Systèmes Infectieux UMR 5086, CNRS, Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, Université Lyon 1 Lyon, France
| | - Patricia Rousselle
- Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, UMR 5305, CNRS, Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, Université Lyon 1 Lyon, France
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38
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Gopal S, Couchman J, Pocock R. Redefining the role of syndecans in C. elegans biology. WORM 2016; 5:e1142042. [PMID: 27073736 DOI: 10.1080/21624054.2016.1142042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 01/08/2016] [Indexed: 12/21/2022]
Abstract
Cytosolic calcium is an important factor during fertilization, development and differentiation. Hence, the control of cytosolic calcium levels has been studied extensively for several decades. Numerous calcium channels have been identified and their mechanism of action elucidated. However, the mode of calcium channel regulation remains elusive. Here we discuss our recent findings regarding the role of syndecans in the regulation of cytosolic calcium levels. Syndecans are transmembrane proteoglycans present in both vertebrates and invertebrates that interact with extracellular ligands resulting in the activation of several downstream signaling pathways. We identified a previously unappreciated role of syndecans in cytosolic calcium regulation in mammals that is conserved in C. elegans. We concluded that calcium regulation is the basic, evolutionarily conserved role for syndecans, which enables them to be integral for multiple cellular functions.
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Affiliation(s)
- Sandeep Gopal
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University , Melbourne, Victoria, Australia
| | - John Couchman
- Department of Biomedical Sciences, University of Copenhagen , Copenhagen, Denmark
| | - Roger Pocock
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University , Melbourne, Victoria, Australia
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Choi S, Choi Y, Jun E, Kim IS, Kim SE, Jung SA, Oh ES. Shed syndecan-2 enhances tumorigenic activities of colon cancer cells. Oncotarget 2016; 6:3874-86. [PMID: 25686828 PMCID: PMC4414160 DOI: 10.18632/oncotarget.2885] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 12/09/2014] [Indexed: 12/14/2022] Open
Abstract
Because earlier studies showed the cell surface heparan sulfate proteoglycan, syndecan-2, sheds from colon cancer cells in culture, the functional roles of shed syndecan-2 were assessed. A non-cleavable mutant of syndecan-2 in which the Asn148-Leu149 residues were replaced with Asn148-Ile149, had decreased shedding, less cancer-associated activities of syndecan-2 in vitro, and less syndecan-2-mediated metastasis of mouse melanoma cells in vivo, suggesting the importance of shedding on syndecan-2-mediated pro-tumorigenic functions. Indeed, shed syndecan-2 from cancer-conditioned media and recombinant shed syndecan-2 enhanced cancer-associated activities, and depletion of shed syndecan-2 abolished these effects. Similarly, shed syndecan-2 was detected from sera of patients from advanced carcinoma (625.9 ng/ml) and promoted cancer-associated activities. Furthermore, a series of syndecan-2 deletion mutants showed that the tumorigenic activity of shed syndecan-2 resided in the C-terminus of the extracellular domain and a shed syndecan-2 synthetic peptide (16 residues) was sufficient to establish subcutaneous primary growth of HT29 colon cancer cells, pulmonary metastases (B16F10 cells), and primary intrasplenic tumor growth and liver metastases (4T1 cells). Taken together, these results demonstrate that shed syndecan-2 directly enhances colon cancer progression and may be a promising therapeutic target for controlling colon cancer development.
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Affiliation(s)
- Sojoong Choi
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Republic of Korea.,Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Korea
| | - Youngsil Choi
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Eunsung Jun
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Korea
| | - In-San Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Korea.,Department of Biochemistry and Cell Biology, School of Medicine and Cell & Matrix Research Institute, Kyungpook National University, Daegu 700-422, Republic of Korea
| | - Seong-Eun Kim
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Republic of Korea
| | - Sung-Ae Jung
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Republic of Korea
| | - Eok-Soo Oh
- Department of Life Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Republic of Korea
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40
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Kwon MJ, Park J, Jang S, Eom CY, Oh ES. The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans. J Biol Chem 2015; 291:872-81. [PMID: 26601939 DOI: 10.1074/jbc.m115.685040] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Indexed: 11/06/2022] Open
Abstract
The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo- and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKCα, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.
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Affiliation(s)
- Mi-Jung Kwon
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea and
| | - Jisu Park
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea and
| | - Sinae Jang
- the Seoul Center, Korea Basic Science Institute, Seoul 136-075, Korea
| | - Chi-Yong Eom
- the Seoul Center, Korea Basic Science Institute, Seoul 136-075, Korea
| | - Eok-Soo Oh
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea and
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41
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Prior SH, Fulcher YG, Koppisetti RK, Jurkevich A, Van Doren SR. Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors. Structure 2015; 23:2099-110. [PMID: 26439767 PMCID: PMC4635031 DOI: 10.1016/j.str.2015.08.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 08/13/2015] [Accepted: 08/24/2015] [Indexed: 02/08/2023]
Abstract
Matrix metalloproteinase-7 (MMP-7) sheds signaling proteins from cell surfaces to activate bacterial killing, wound healing, and tumorigenesis. The mechanism targeting soluble MMP-7 to membranes has been investigated. Nuclear magnetic resonance structures of the zymogen, free and bound to membrane mimics without and with anionic lipid, reveal peripheral binding to bilayers through paramagnetic relaxation enhancements. Addition of cholesterol sulfate partially embeds the protease in the bilayer, restricts its diffusion, and tips the active site away from the bilayer. Its insertion of hydrophobic residues organizes the lipids, pushing the head groups and sterol sulfate outward toward the enzyme's positive charge on the periphery of the enlarged interface. Fluorescence probing demonstrates a similar mode of binding to plasma membranes and internalized vesicles of colon cancer cells. Binding of bilayered micelles induces allosteric activation and conformational change in the auto-inhibitory peptide and the adjacent scissile site, illustrating a potential intermediate in the activation of the zymogen.
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Affiliation(s)
- Stephen H Prior
- Biochemistry Department, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA
| | - Yan G Fulcher
- Biochemistry Department, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA
| | - Rama K Koppisetti
- Biochemistry Department, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA
| | - Alexander Jurkevich
- Molecular Cytology Core, 120 Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Steven R Van Doren
- Biochemistry Department, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA.
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Ortmann C, Pickhinke U, Exner S, Ohlig S, Lawrence R, Jboor H, Dreier R, Grobe K. Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans. J Cell Sci 2015; 128:2374-85. [PMID: 25967551 DOI: 10.1242/jcs.170670] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 05/05/2015] [Indexed: 12/21/2022] Open
Abstract
All Hedgehog morphogens are released from producing cells, despite being synthesized as N- and C-terminally lipidated molecules, a modification that firmly tethers them to the cell membrane. We have previously shown that proteolytic removal of both lipidated peptides, called shedding, releases bioactive Sonic hedgehog (Shh) morphogens from the surface of transfected Bosc23 cells. Using in vivo knockdown together with in vitro cell culture studies, we now show that glypican heparan sulfate proteoglycans regulate this process, through their heparan sulfate chains, in a cell autonomous manner. Heparan sulfate specifically modifies Shh processing at the cell surface, and purified glycosaminoglycans enhance the proteolytic removal of N- and C-terminal Shh peptides under cell-free conditions. The most likely explanation for these observations is direct Shh processing in the extracellular compartment, suggesting that heparan sulfate acts as a scaffold or activator for Shh ligands and the factors required for their turnover. We also show that purified heparan sulfate isolated from specific cell types and tissues mediates the release of bioactive Shh from pancreatic cancer cells, revealing a previously unknown regulatory role for these versatile molecules in a pathological context.
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Affiliation(s)
- Corinna Ortmann
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany
| | - Ute Pickhinke
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany
| | - Sebastian Exner
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany
| | - Stefanie Ohlig
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany
| | - Roger Lawrence
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Hamodah Jboor
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany
| | - Rita Dreier
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, 48149 Münster, Germany
| | - Kay Grobe
- Institute for Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, 48149 Münster, Germany
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Role of syndecan-2 in osteoblast biology and pathology. BONEKEY REPORTS 2015; 4:666. [PMID: 25848534 DOI: 10.1038/bonekey.2015.33] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 02/04/2015] [Indexed: 12/20/2022]
Abstract
Syndecans 1-4 are a family of transmembrane proteins composed of a core protein and glycosaminoglycan chains. Although the four syndecans have common functions, they appear to be connected to different signaling pathways, and their expression occurs in a cell- and development-specific pattern. In contrast to other syndecans, syndecan-2 expression increases during osteoblast differentiation. Mechanistically, syndecan-2 exerts multiple functions in cells of the osteoblast lineage as it serves as a co-receptor for fibroblast growth factors and Wnt proteins and controls cell adhesion, proliferation, differentiation and apoptosis. Recent studies indicate that syndecan-2 also contributes to osteosarcoma cell response to cytotoxic agents through interactions with Wnt/β-catenin signaling. Here we summarize our current understanding of the role of syndecan-2 in the control of osteoblast biology and pathology and discuss how syndecan-2 acts as a modulator of the bone cell microenvironment.
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Suhovskih AV, Aidagulova SV, Kashuba VI, Grigorieva EV. Proteoglycans as potential microenvironmental biomarkers for colon cancer. Cell Tissue Res 2015; 361:833-44. [PMID: 25715761 DOI: 10.1007/s00441-015-2141-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 01/28/2015] [Indexed: 12/18/2022]
Abstract
Glycosylation changes occur widely in colon tumours, suggesting glycosylated molecules as potential biomarkers for colon cancer diagnostics. In this study, proteoglycans (PGs) expression levels and their transcriptional patterns are investigated in human colon tumours in vivo and carcinoma cells in vitro. According to RT-PCR analysis, normal and cancer colon tissues expressed a specific set of PGs (syndecan-1, perlecan, decorin, biglycan, versican, NG2/CSPG4, serglycin, lumican, CD44), while the expression of glypican-1, brevican and aggrecan was almost undetectable. Overall transcriptional activity of the PGs in normal and cancer tissues was similar, although expression patterns were different. Expression of decorin and perlecan was down-regulated 2-fold in colon tumours, while biglycan and versican expression was significantly up-regulated (6-fold and 3-fold, respectively). Expression of collagen1A1 was also increased 6-fold in colon tumours. However, conventional HCT-116 colon carcinoma and AG2 colon cancer-initiating cells did not express biglycan and decorin and were versican-positive and -negative, respectively, demonstrating an extracellular origin of the PGs in cancer tissue. Selective expression of heparan sulfate (HS) proteoglycans syndecan-1 and perlecan in the AG2 colon cancer-initiating cell line suggests these PGs as potential biomarkers for cancer stem cells. Overall transcriptional activity of the HS biosynthetic system was similar in normal and cancer tissues, although significant up-regulation of extracellular sulfatases SULF1/2 argues for a possible distortion of HS sulfation patterns in colon tumours. Taken together, the obtained results suggest versican, biglycan, collagen1A1 and SULF1/2 expression as potential microenvironmental biomarkers and/or targets for colon cancer diagnostics and treatment.
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Affiliation(s)
- Anastasia V Suhovskih
- Institute of Molecular Biology and Biophysics SB RAMS, Timakova str 2, Novosibirsk, 630117, Russia
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Lim HC, Multhaupt HAB, Couchman JR. Cell surface heparan sulfate proteoglycans control adhesion and invasion of breast carcinoma cells. Mol Cancer 2015; 14:15. [PMID: 25623282 PMCID: PMC4326193 DOI: 10.1186/s12943-014-0279-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 12/22/2014] [Indexed: 12/31/2022] Open
Abstract
Background Cell surface proteoglycans interact with numerous regulators of cell behavior through their glycosaminoglycan chains. The syndecan family of transmembrane proteoglycans are virtually ubiquitous cell surface receptors that are implicated in the progression of some tumors, including breast carcinoma. This may derive from their regulation of cell adhesion, but roles for specific syndecans are unresolved. Methods The MDA-MB231 human breast carcinoma cell line was exposed to exogenous glycosaminoglycans and changes in cell behavior monitored by western blotting, immunocytochemistry, invasion and collagen degradation assays. Selected receptors including PAR-1 and syndecans were depleted by siRNA treatments to assess cell morphology and behavior. Immunohistochemistry for syndecan-2 and its interacting partner, caveolin-2 was performed on human breast tumor tissue arrays. Two-tailed paired t-test and one-way ANOVA with Tukey’s post-hoc test were used in the analysis of data. Results MDA-MB231 cells were shown to be highly sensitive to exogenous heparan sulfate or heparin, promoting increased spreading, focal adhesion and adherens junction formation with concomitantly reduced invasion and matrix degradation. The molecular basis for this effect was revealed to have two components. First, thrombin inhibition contributed to enhanced cell adhesion and reduced invasion. Second, a specific loss of cell surface syndecan-2 was noted. The ensuing junction formation was dependent on syndecan-4, whose role in promoting actin cytoskeletal organization is known. Syndecan-2 interacts with, and may regulate, caveolin-2. Depletion of either molecule had the same adhesion-promoting influence, along with reduced invasion, confirming a role for this complex in maintaining the invasive phenotype of mammary carcinoma cells. Finally, both syndecan-2 and caveolin-2 were upregulated in tissue arrays from breast cancer patients compared to normal mammary tissue. Moreover their expression levels were correlated in triple negative breast cancers. Conclusion Cell surface proteoglycans, notably syndecan-2, may be important regulators of breast carcinoma progression through regulation of cytoskeleton, cell adhesion and invasion.
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Affiliation(s)
- Hooi Ching Lim
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark. .,Current address: Stem Cell Center, Lund University, Lund, Sweden.
| | - Hinke A B Multhaupt
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
| | - John R Couchman
- Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
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Kwon MJ, Choi Y, Yun JH, Lee W, Han IO, Oh ES. A unique phenylalanine in the transmembrane domain strengthens homodimerization of the syndecan-2 transmembrane domain and functionally regulates syndecan-2. J Biol Chem 2015; 290:5772-82. [PMID: 25572401 DOI: 10.1074/jbc.m114.599845] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The syndecans are a type of cell surface adhesion receptor that initiates intracellular signaling events through receptor clustering mediated by their highly conserved transmembrane domains (TMDs). However, the exact function of the syndecan TMD is not yet fully understood. Here, we investigated the specific regulatory role of the syndecan-2 TMD. We found that syndecan-2 mutants in which the TMD had been replaced with that of syndecan-4 were defective in syndecan-2-mediated functions, suggesting that the TMD of syndecan-2 plays one or more specific roles. Interestingly, syndecan-2 has a stronger tendency to form sodium dodecyl sulfate (SDS)-resistant homodimers than syndecan-4. Our structural studies showed that a unique phenylalanine residue (Phe(167)) enables an additional molecular interaction between the TMDs of the syndecan-2 homodimer. The presence of Phe(167) was correlated with a higher tendency toward oligomerization, and its replacement with isoleucine significantly reduced the SDS-resistant dimer formation and cellular functions of syndecan-2 (e.g. cell migration). Conversely, replacement of isoleucine with phenylalanine at this position in the syndecan-4 TMD rescued the defects observed in a mutant syndecan-2 harboring the syndecan-4 TMD. Taken together, these data suggest that Phe(167) in the TMD of syndecan-2 endows the protein with specific functions. Our work offers new insights into the signaling mediated by the TMD of syndecan family members.
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Affiliation(s)
- Mi-Jung Kwon
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Youngsil Choi
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea
| | - Ji-Hye Yun
- the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea, and
| | - Weontae Lee
- the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea, and
| | - Inn-Oc Han
- the College of Medicine, Department of Physiology and Biophysics, Inha University, Incheon 402-751 Korea
| | - Eok-Soo Oh
- From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea,
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Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, Iozzo RV, Karamanos NK. Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer. FEBS J 2014; 281:5023-42. [PMID: 25333340 PMCID: PMC5036392 DOI: 10.1111/febs.12927] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/04/2014] [Accepted: 07/09/2014] [Indexed: 01/10/2023]
Abstract
Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer.
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Affiliation(s)
- Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Chrisostomi Gialeli
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Panagiotis Bouris
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Efstathia Giannopoulou
- Clinical Oncology Laboratory, Division of Oncology, University Hospital of Patras, Patras Medical School, Patras 26110, Greece
| | - Spyros S. Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Alexios J. Aletras
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
| | - Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
| | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece
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High expression of CASK correlates with progression and poor prognosis of colorectal cancer. Tumour Biol 2014; 35:9185-94. [DOI: 10.1007/s13277-014-2179-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 06/02/2014] [Indexed: 10/25/2022] Open
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Interleukin-1α promotes extracellular shedding of syndecan-2 via induction of matrix metalloproteinase-7 expression. Biochem Biophys Res Commun 2014; 446:487-92. [PMID: 24613844 DOI: 10.1016/j.bbrc.2014.02.142] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 02/28/2014] [Indexed: 12/11/2022]
Abstract
The cell surface heparan sulfate proteoglycan, syndecan-2, is known to play an important role in the tumorigenic activity of colon cancer cells. In addition, the extracellular domain of syndecan-2 is cleaved by matrix metalloproteinase-7 (MMP-7) in various colon cancer cells, but factors involved in regulating this process remain unknown. Here, we demonstrate a role for interleukin-1α (IL-1α) in syndecan-2 shedding in colon cancer cells. Treatment of low metastatic (HT-29) and highly metastatic (HCT-116) colon cancer cells with various soluble growth factors and cytokines revealed that IL-1α specifically increased extracellular shedding of syndecan-2 in a concentration- and time-dependent manner. IL-1α did not affect the expression of syndecan-2, but did significantly reduce its cell surface levels. Notably, IL-1α increased the mRNA expression and subsequent secreted levels of MMP-7 protein and enhanced the phosphorylation of p38 and ERK mitogen-activated protein kinases. Furthermore, increased syndecan-2 shedding was dependent on the mitogen-activated protein kinase-mediated MMP-7 expression. Taken together, these data suggest that IL-1α regulates extracellular domain shedding of syndecan-2 through regulation of the MAP kinase-mediated MMP-7 expression in colon cancer cells.
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Barbouri D, Afratis N, Gialeli C, Vynios DH, Theocharis AD, Karamanos NK. Syndecans as modulators and potential pharmacological targets in cancer progression. Front Oncol 2014; 4:4. [PMID: 24551591 PMCID: PMC3910246 DOI: 10.3389/fonc.2014.00004] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 01/09/2014] [Indexed: 12/17/2022] Open
Abstract
Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs "shed SDCs" in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.
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Affiliation(s)
- Despoina Barbouri
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Nikolaos Afratis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Chrisostomi Gialeli
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Demitrios H. Vynios
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
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