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Shah Y, Dahiya DS, Tiwari A, Kumar H, Gangwani MK, Ali H, Hayat U, Alsakarneh S, Singh S, Malik S, Sohail AH, Chandan S, Ali MA, Inamdar S. Advancements in Early Detection and Screening Strategies for Pancreatic Cancer: From Genetic Susceptibility to Novel Biomarkers. J Clin Med 2024; 13:4706. [PMID: 39200847 PMCID: PMC11355237 DOI: 10.3390/jcm13164706] [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: 07/25/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a rare but lethal cancer due to its biologically aggressive nature, advanced stage at the time of diagnosis, and poor response to oncologic therapies. The risk of pancreatic cancer is significantly higher to 5% in certain high-risk individuals with inherited genetic susceptibility. Screening for pancreatic cancer in these individuals from high-risk groups can help with the early detection of pancreatic cancer as well as the detection of precursor lesions leading to early surgical resection and improved overall outcomes. The advancements in radiological imaging as well as advanced endoscopic procedures has made a significant impact on the early diagnosis, surveillance, and staging of pancreatic cancer. There is also a significant advancement in the development of biomarkers for the early detection of pancreatic cancer, which has also led to the development of liquid biopsy, allowing for microRNA detection in serum and circulating tumor cells. Various societies and organizations have provided guidelines for pancreatic cancer screening and surveillance in high-risk individuals. In this review, we aim to discuss the hereditary risk factors for developing pancreatic cancer, summarize the screening recommendations by different societies, and discuss the development of novel biomarkers and areas for future research in pancreatic cancer screening for high-risk individuals.
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Affiliation(s)
- Yash Shah
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, USA
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, USA
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, Uttar Pradesh, India
| | - Harendra Kumar
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Manesh Kumar Gangwani
- Department of Gastroenterology and Hepatology, University of Arkansas For Medical Sciences, Little Rock, AR 72205, USA
| | - Hassam Ali
- Division of Gastroenterology, Hepatology & Nutrition, East Carolina University/Brody School of Medicine, Greenville, NC 27834, USA
| | - Umar Hayat
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes Barre, PA 18711, USA
| | - Saqr Alsakarneh
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA
| | - Sahib Singh
- Department of Internal Medicine, Sinai Hospital, Baltimore, MD 21215, USA
| | - Sheza Malik
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Amir H. Sohail
- Department of Surgery, University of New Mexico, Albuquerque, NM 87131, USA
| | - Saurabh Chandan
- Center for Interventional Endoscopy (CIE), Advent Health, Orlando, FL 32803, USA
| | - Meer A. Ali
- Department of Gastroenterology and Hepatology, University of Arkansas For Medical Sciences, Little Rock, AR 72205, USA
| | - Sumant Inamdar
- Department of Gastroenterology and Hepatology, University of Arkansas For Medical Sciences, Little Rock, AR 72205, USA
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Masum MHU, Wajed S, Hossain MI, Moumi NR, Talukder A, Rahman MM. An mRNA vaccine for pancreatic cancer designed by applying in silico immunoinformatics and reverse vaccinology approaches. PLoS One 2024; 19:e0305413. [PMID: 38976715 PMCID: PMC11230540 DOI: 10.1371/journal.pone.0305413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 05/30/2024] [Indexed: 07/10/2024] Open
Abstract
Pancreatic ductal adenocarcinoma is the most prevalent pancreatic cancer, which is considered a significant global health concern. Chemotherapy and surgery are the mainstays of current pancreatic cancer treatments; however, a few cases are suitable for surgery, and most of the cases will experience recurrent episodes. Compared to DNA or peptide vaccines, mRNA vaccines for pancreatic cancer have more promise because of their delivery, enhanced immune responses, and lower proneness to mutation. We constructed an mRNA vaccine by analyzing S100 family proteins, which are all major activators of receptors for advanced glycation end products. We applied immunoinformatic approaches, including physicochemical properties analysis, structural prediction and validation, molecular docking study, in silico cloning, and immune simulations. The designed mRNA vaccine was estimated to have a molecular weight of 165023.50 Da and was highly soluble (grand average of hydropathicity of -0.440). In the structural assessment, the vaccine seemed to be a well-stable and functioning protein (Z score of -8.94). Also, the docking analysis suggested that the vaccine had a high affinity for TLR-2 and TLR-4 receptors. Additionally, the molecular mechanics with generalized Born and surface area solvation analysis of the "Vaccine-TLR-2" (-141.07 kcal/mol) and "Vaccine-TLR-4" (-271.72 kcal/mol) complexes also suggests a strong binding affinity for the receptors. Codon optimization also provided a high expression level with a GC content of 47.04% and a codon adaptation index score 1.0. The appearance of memory B-cells and T-cells was also observed over a while, with an increased level of helper T-cells and immunoglobulins (IgM and IgG). Moreover, the minimum free energy of the mRNA vaccine was predicted at -1760.00 kcal/mol, indicating the stability of the vaccine following its entry, transcription, and expression. This hypothetical vaccine offers a groundbreaking tool for future research and therapeutic development of pancreatic cancer.
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Affiliation(s)
- Md Habib Ullah Masum
- Department of Microbiology, Noakhali Science and Technology University, Noakhali, Bangladesh
- Microbiology, Cancer and Bioinformatics Research Group, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Shah Wajed
- Department of Microbiology, Noakhali Science and Technology University, Noakhali, Bangladesh
- Microbiology, Cancer and Bioinformatics Research Group, Noakhali Science and Technology University, Noakhali, Bangladesh
- Infectiology: Biology of Infectious Diseases, Universite Paris-Saclay, Gif-sur-Yvette, France
| | - Md Imam Hossain
- Department of Microbiology, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Nusrat Rahman Moumi
- Medical Sciences, University of Central Lancashire, Preston, Lancashire, United Kingdom
| | - Asma Talukder
- Microbiology, Cancer and Bioinformatics Research Group, Noakhali Science and Technology University, Noakhali, Bangladesh
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
- School of Pharmacy and Medical Sciences, and Menzies Health Institute Queensland, Griffith University, Brisbane, Queensland, Australia
| | - Md Mijanur Rahman
- Department of Microbiology, Noakhali Science and Technology University, Noakhali, Bangladesh
- Microbiology, Cancer and Bioinformatics Research Group, Noakhali Science and Technology University, Noakhali, Bangladesh
- School of Pharmacy and Medical Sciences, and Menzies Health Institute Queensland, Griffith University, Brisbane, Queensland, Australia
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Rose M, Burgess JT, Cheong CM, Adams MN, Shahrouzi P, O’Byrne KJ, Richard DJ, Bolderson E. The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth. Front Oncol 2024; 14:1222698. [PMID: 38720803 PMCID: PMC11076778 DOI: 10.3389/fonc.2024.1222698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 02/28/2024] [Indexed: 05/12/2024] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a sub-classification of breast carcinomas, which leads to poor survival outcomes for patients. TNBCs do not possess the hormone receptors that are frequently targeted as a therapeutic in other cancer subtypes and, therefore, chemotherapy remains the standard treatment for TNBC. Nuclear envelope proteins are frequently dysregulated in cancer cells, supporting their potential as novel cancer therapy targets. The Lem-domain (Lem-D) (LAP2, Emerin, MAN1 domain, and Lem-D) proteins are a family of inner nuclear membrane proteins, which share a ~45-residue Lem-D. The Lem-D proteins, including Ankle2, Lemd2, TMPO, and Emerin, have been shown to be associated with many of the hallmarks of cancer. This study aimed to define the association between the Lem-D proteins and TNBC and determine whether these proteins could be promising therapeutic targets. Methods GENT2, TCGA, and KM plotter were utilized to investigate the expression and prognostic implications of several Lem-D proteins: Ankle2, TMPO, Emerin, and Lemd2 in publicly available breast cancer patient data. Immunoblotting and immunofluorescent analysis of immortalized non-cancerous breast cells and a panel of TNBC cells were utilized to establish whether protein expression of the Lem-D proteins was significantly altered in TNBC. SiRNA was used to decrease individual Lem-D protein expression, and functional assays, including proliferation assays and apoptosis assays, were conducted. Results The Lem-D proteins were generally overexpressed in TNBC patient samples at the mRNA level and showed variable expression at the protein level in TNBC cell lysates. Similarly, protein levels were generally negatively correlated with patient survival outcomes. siRNA-mediated depletion of the individual Lem-D proteins in TNBC cells induced aberrant nuclear morphology, decreased proliferation, and induced cell death. However, minimal effects on nuclear morphology or cell viability were observed following Lem-D depletion in non-cancerous MCF10A cells. Conclusion There is evidence to suggest that Ankle2, TMPO, Emerin, and Lemd2 expressions are correlated with breast cancer patient outcomes, but larger patient sample numbers are required to confirm this. siRNA-mediated depletion of these proteins was shown to specifically impair TNBC cell growth, suggesting that the Lem-D proteins may be a specific anti-cancer target.
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Affiliation(s)
- Maddison Rose
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Joshua T. Burgess
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Chee Man Cheong
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Mark N. Adams
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Parastoo Shahrouzi
- Department of Medical Genetics, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kenneth J. O’Byrne
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
- Cancer Services, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Derek J. Richard
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Emma Bolderson
- Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
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Sun J, Baker JR, Russell CC, Pham HNT, Goldsmith CD, Cossar PJ, Sakoff JA, Scarlett CJ, McCluskey A. Novel piperazine-1,2,3-triazole leads for the potential treatment of pancreatic cancer. RSC Med Chem 2023; 14:2246-2267. [PMID: 37974967 PMCID: PMC10650957 DOI: 10.1039/d2md00289b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 06/26/2023] [Indexed: 11/19/2023] Open
Abstract
From lead 1, (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an in silico modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1's phenylacetamide moiety, gave Library 1 with only modest pancreatic cancer activity. Modification of the 3-OCH3Ph moiety (Library 2) gave 4-CH3 (26), 4-CH2CH3 (27), 4-CF3 (31) and 4-NO2 (32) with sterically bulky groups more active. A 4-CF3 acetamide replacement enhanced cytotoxicity (Library 3). The 4-C(CH3)336 resulted in a predicted steric clash in the S100A2-p53 binding groove, with a potency decrease. Alkyl moieties afforded more potent analogues, 34 (4-CH3) and 35 (CH2CH3), a trend evident against pancreatic cancer: GI50 3.7 (35; BxPC-3) to 18 (40; AsPC-1) μM. Library 4 analogues with a 2-CF3 and 3-CF3 benzenesulfonamide moiety were less active than the corresponding Library 3 analogues. Two additional analogues were designed: 51 (4-CF3; 4-OCH3) and 52 (4-CF3; 2-OCH3) revealed 52 to be 10-20 fold more active than 51, against the pancreatic cancer cell lines examined with sub-micromolar GI50 values 0.43 (HPAC) to 0.61 μM (PANC-1). MOE calculated binding scores for each pose are also consistent with the observed biological activity with 52. The obtained SAR data is consistent with the proposed interaction within the S100A2-p53 bonding groove.
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Affiliation(s)
- Jufeng Sun
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
- Medicinal Chemistry, School of Pharmacy, Binzhou Medical University Yantai 264003 China
| | - Jennifer R Baker
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
| | - Cecilia C Russell
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
| | - Hong N T Pham
- Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street Waratah NSW 2298 Australia
| | - Chloe D Goldsmith
- Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street Waratah NSW 2298 Australia
| | - Peter J Cossar
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
| | - Jennette A Sakoff
- Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street Waratah NSW 2298 Australia
| | - Christopher J Scarlett
- School of Environmental & Life Sciences, The University of Newcastle Ourimbah NSW 2258 Australia
| | - Adam McCluskey
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive Callaghan NSW 2308 Australia
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Hopkins MD, Costello IJ, Brandeburg ZC, Slay EL, Zanders LA, Dunn CE, Derewonko CA, Davitt CL, Reeder MA, Prichard K, Chiew B, McCluskey A, Sheaff RJ, Lamar AA. Expansion of a Synthesized Library of N-Benzyl Sulfonamides Derived from an Indole Core to Target Pancreatic Cancer. ChemMedChem 2023; 18:e202300265. [PMID: 37421174 DOI: 10.1002/cmdc.202300265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 07/09/2023]
Abstract
In an effort to further investigate previously observed activity of indolyl sulfonamides towards pancreatic cancer cell lines, a library of 44 compounds has been synthesized. The biological activity of the compounds has been determined using two different screening assay techniques against 7 pancreatic cancer cell lines and 9 non-pancreatic cancer cell lines. In the first assay, the cytotoxicity of the compounds was evaluated using a traditional (48 hour compound exposure) method. An in silico investigation was conducted to determine if the compounds might be inducing cell death by inhibiting the S100A2-p53 protein-protein interaction. In the second assay, the potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (1-2 hour compound exposure) method. IC50 values of the hit compounds were obtained and four compounds displayed sub-micromolar potency against PANC-1 cells. The investigation has provided several compounds that display selective in vitro activity toward pancreatic cancer that warrant further development.
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Affiliation(s)
- Megan D Hopkins
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Ian J Costello
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Zachary C Brandeburg
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Emily L Slay
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Levi A Zanders
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Caroline E Dunn
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Carina A Derewonko
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Colin L Davitt
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Madison A Reeder
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Kate Prichard
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, 2308, Callaghan, NSW, Australia
| | - Beatrice Chiew
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, 2308, Callaghan, NSW, Australia
| | - Adam McCluskey
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, 2308, Callaghan, NSW, Australia
| | - Robert J Sheaff
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
| | - Angus A Lamar
- Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, 74104, Tulsa, OK, USA
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Wang Y, Kang X, Kang X, Yang F. S100A6: molecular function and biomarker role. Biomark Res 2023; 11:78. [PMID: 37670392 PMCID: PMC10481514 DOI: 10.1186/s40364-023-00515-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/03/2023] [Indexed: 09/07/2023] Open
Abstract
S100A6 (also called calcyclin) is a Ca2+-binding protein that belongs to the S100 protein family. S100A6 has many functions related to the cytoskeleton, cell stress, proliferation, and differentiation. S100A6 also has many interacting proteins that are distributed in the cytoplasm, nucleus, cell membrane, and outside the cell. Almost all these proteins interact with S100A6 in a Ca2+-dependent manner, and some also have specific motifs responsible for binding to S100A6. The expression of S100A6 is regulated by several transcription factors (such as c-Myc, P53, NF-κB, USF, Nrf2, etc.). The expression level depends on the specific cell type and the transcription factors activated in specific physical and chemical environments, and is also related to histone acetylation, DNA methylation, and other epigenetic modifications. The differential expression of S100A6 in various diseases, and at different stages of those diseases, makes it a good biomarker for differential diagnosis and prognosis evaluation, as well as a potential therapeutic target. In this review, we mainly focus on the S100A6 ligand and its transcriptional regulation, molecular function (cytoskeleton, cell stress, cell differentiation), and role as a biomarker in human disease and stem cells.
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Affiliation(s)
- Yidian Wang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Xuewen Kang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Xin Kang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi, China.
| | - Fengguang Yang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China.
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China.
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China.
- The Orthopedics Department of the Second Hospital of Lanzhou University, 82 Cuiying Men, Lanzhou, Gansu Province, 730000, PR China.
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Koltai T. Earlier Diagnosis of Pancreatic Cancer: Is It Possible? Cancers (Basel) 2023; 15:4430. [PMID: 37760400 PMCID: PMC10526520 DOI: 10.3390/cancers15184430] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires C1094, Argentina
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Qi M, Yi X, Yue B, Huang M, Zhou S, Xiong J. S100A6 inhibits MDM2 to suppress breast cancer growth and enhance sensitivity to chemotherapy. Breast Cancer Res 2023; 25:55. [PMID: 37217945 DOI: 10.1186/s13058-023-01657-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/10/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND S100A6 and murine double minute 2 (MDM2) are important cancer-related molecules. A previous study identified an interaction between S100A6 and MDM2 by size exclusion chromatography and surface plasmon resonance experiments. The present study investigated whether S100A6 could bind to MDM2 in vivo and further explored its functional implication. METHODS Co-immunoprecipitation, glutathione-S-transferase pull-down assay, and immunofluorescence were performed to determine the in vivo interaction between S100A6 and MDM2. Cycloheximide pulse-chase assay and ubiquitination assay were performed to clarify the mechanism by which S100A6 downregulated MDM2. In addition, clonogenic assay, WST-1 assay, and flow cytometry of apoptosis and the cell cycle were performed and a xenograft model was established to evaluate the effects of the S100A6/MDM2 interaction on growth and paclitaxel-induced chemosensitivity of breast cancer. The expressions of S100A6 and MDM2 in patients with invasive breast cancer were analyzed by immunohistochemistry. In addition, the correlation between the expression of S100A6 and the response to neoadjuvant chemotherapy was statistically analyzed. RESULTS S100A6 promoted the MDM2 translocation from nucleus to cytoplasm, in which the S100A6 bound to the binding site of the herpesvirus-associated ubiquitin-specific protease (HAUSP) in MDM2, disrupted the MDM2-HAUSP-DAXX interactions, and induced the MDM2 self-ubiquitination and degradation. Furthermore, the S100A6-mediated MDM2 degradation suppressed the growth of breast cancer and enhanced its sensitivity to paclitaxel both in vitro and in vivo. For patients with invasive breast cancer who received epirubicin and cyclophosphamide followed by docetaxel (EC-T), expressions of S100A6 and MDM2 were negatively correlated, and high expression of S100A6 suggested a higher rate of pathologic complete response (pCR). Univariate and multivariate analyses showed that the high expression of S100A6 was an independent predictor of pCR. CONCLUSION These results reveal a novel function for S100A6 in downregulating MDM2, which directly enhances sensitivity to chemotherapy.
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Affiliation(s)
- Mengxin Qi
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xianglan Yi
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Baohui Yue
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Mingxiang Huang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sheng Zhou
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Jing Xiong
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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S100A6 Protein-Expression and Function in Norm and Pathology. Int J Mol Sci 2023; 24:ijms24021341. [PMID: 36674873 PMCID: PMC9866648 DOI: 10.3390/ijms24021341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
S100A6, also known as calcyclin, is a calcium-binding protein belonging to the S100 protein family. It was first identified and purified more than 30 years ago. Initial structural studies, focused mostly on the mode and affinity of Ca2+ binding and resolution of the resultant conformational changes, were soon complemented by research on its expression, localization and identification of binding partners. With time, the use of biophysical methods helped to resolve the structure and versatility of S100A6 complexes with some of its ligands. Meanwhile, it became clear that S100A6 expression was altered in various pathological states and correlated with the stage/progression of many diseases, including cancers, indicative of its important, and possibly causative, role in some of these diseases. This, in turn, prompted researchers to look for the mechanism of S100A6 action and to identify the intermediary signaling pathways and effectors. After all these years, our knowledge on various aspects of S100A6 biology is robust but still incomplete. The list of S100A6 ligands is growing all the time, as is our understanding of the physiological importance of these interactions. The present review summarizes available data concerning S100A6 expression/localization, interaction with intracellular and extracellular targets, involvement in Ca2+-dependent cellular processes and association with various pathologies.
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Wang Y, Song C, Zhao J, Zhang Y, Zhao X, Feng C, Zhang G, Zhu J, Wang F, Qian F, Zhou L, Zhang J, Bai X, Ai B, Liu X, Wang Q, Li C. SEdb 2.0: a comprehensive super-enhancer database of human and mouse. Nucleic Acids Res 2023; 51:D280-D290. [PMID: 36318264 PMCID: PMC9825585 DOI: 10.1093/nar/gkac968] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/09/2022] [Accepted: 10/13/2022] [Indexed: 01/09/2023] Open
Abstract
Super-enhancers (SEs) are cell-specific DNA cis-regulatory elements that can supervise the transcriptional regulation processes of downstream genes. SEdb 2.0 (http://www.licpathway.net/sedb) aims to provide a comprehensive SE resource and annotate their potential roles in gene transcriptions. Compared with SEdb 1.0, we have made the following improvements: (i) Newly added the mouse SEs and expanded the scale of human SEs. SEdb 2.0 contained 1 167 518 SEs from 1739 human H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) samples and 550 226 SEs from 931 mouse H3K27ac ChIP-seq samples, which was five times that of SEdb 1.0. (ii) Newly added transcription factor binding sites (TFBSs) in SEs identified by TF motifs and TF ChIP-seq data. (iii) Added comprehensive (epi)genetic annotations of SEs, including chromatin accessibility regions, methylation sites, chromatin interaction regions and topologically associating domains (TADs). (iv) Newly embedded and updated search and analysis tools, including 'Search SE by TF-based', 'Differential-Overlapping-SE analysis' and 'SE-based TF-Gene analysis'. (v) Newly provided quality control (QC) metrics for ChIP-seq processing. In summary, SEdb 2.0 is a comprehensive update of SEdb 1.0, which curates more SEs and annotation information than SEdb 1.0. SEdb 2.0 provides a friendly platform for researchers to more comprehensively clarify the important role of SEs in the biological process.
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Affiliation(s)
- Yuezhu Wang
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Chao Song
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Jun Zhao
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Yuexin Zhang
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xilong Zhao
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Chenchen Feng
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Guorui Zhang
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
| | - Jiang Zhu
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Fan Wang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Fengcui Qian
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Liwei Zhou
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Jian Zhang
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Xuefeng Bai
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Bo Ai
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Xinyu Liu
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Qiuyu Wang
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China,Hengyang, Hunan 421001, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China,Hengyang, Hunan 421001, China
| | - Chunquan Li
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing 163319, China
- School of Computer, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- Hunan Provincial Base for Scientific and Technological Innovation Cooperation, University of South China, Hengyang, Hunan 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China,Hengyang, Hunan 421001, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China,Hengyang, Hunan 421001, China
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11
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Khedr NF, El-Feky OA, Werida RH. L-Carnitine Mitigates Trazadone Induced Rat Cardiotoxicity Mediated via Modulation of Autophagy and Oxidative Stress. Cardiovasc Toxicol 2022; 22:831-841. [PMID: 35781619 PMCID: PMC9381465 DOI: 10.1007/s12012-022-09759-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/08/2022] [Indexed: 11/28/2022]
Abstract
Trazodone (TRZ) is an antidepressant drug which widely used to treat insomnia, but it has a cardiotoxic effect which considered one of the TRZ limitations. The aim of this study was to investigate the protective role of l-carnitine in rats against TRZ-induced cardiotoxicity, as well as to look into the molecular mechanisms underlying its cardioprotective effects via autophagy-mediated cell death and oxidative stress. Male albino rats were randomized into four experimental groups (n = 8): normal control, TRZ group (TRZ, 20 mg/kg/day), l-carnitine group (LC, 200 mg/kg/day), and Co-treated group (l-carnitine and TRZ). All treatments were administered via oral gavage for 4 weeks. Cardiac enzymes (AST & CK-MB) and serum cardiac troponin T(cTnI) were assessed. Oxidative stress biomarkers in heart tissue (malondialdehyde; MDA, total thiol, and catalase activity) were measured. Autophagy related-genes (ATG-5 and Beclin-1), P62, and TNF-α were quantified. AST and CK-MB and cTnI significantly (p < 0.001) were increased with enhanced autophagy as well as severe histopathological changes which were manifested as scattered chronic inflammatory cells with focal fragmentation of myocardial fibers and loss of nuclei in TRZ-treated group. However, daily administration of l-carnitine (200 mg/kg) for 28 days completely reversed TRZ-induced the increased cardiac enzymes, autophagy, and myocardial inflammatory processes to the normal values. TRZ administration might have the potential to cause cardiotoxic effects that can be treated with l-carnitine administration.
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Affiliation(s)
- Naglaa F Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Al-Baher Street, Medical Campus, Tanta, 31527, Egypt.
| | - Ola A El-Feky
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Al-Baher Street, Medical Campus, Tanta, 31527, Egypt
| | - Rehab H Werida
- Clinical Pharmacy & Pharmacy Practice Department, Faculty of Pharmacy, Damanhur University, El-Bahiara, Egypt.
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12
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Shi X, Li Y, Yuan Q, Tang S, Guo S, Zhang Y, He J, Zhang X, Han M, Liu Z, Zhu Y, Gao S, Wang H, Xu X, Zheng K, Jing W, Chen L, Wang Y, Jin G, Gao D. Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity. Nat Commun 2022; 13:2169. [PMID: 35449156 PMCID: PMC9023604 DOI: 10.1038/s41467-022-29857-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/31/2022] [Indexed: 12/16/2022] Open
Abstract
Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.
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Affiliation(s)
- Xiaohan Shi
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yunguang Li
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qiuyue Yuan
- CEMS, NCMIS, HCMS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China
- School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shijie Tang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shiwei Guo
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yehan Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Juan He
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyu Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ming Han
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhuang Liu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiqin Zhu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Suizhi Gao
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Huan Wang
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xiongfei Xu
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Kailian Zheng
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Wei Jing
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China.
- Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong, 519031, China.
| | - Yong Wang
- CEMS, NCMIS, HCMS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China.
- School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China.
| | - Gang Jin
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.
| | - Dong Gao
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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13
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Hu Y, Zeng N, Ge Y, Wang D, Qin X, Zhang W, Jiang F, Liu Y. Identification of the Shared Gene Signatures and Biological Mechanism in Type 2 Diabetes and Pancreatic Cancer. Front Endocrinol (Lausanne) 2022; 13:847760. [PMID: 35432196 PMCID: PMC9010232 DOI: 10.3389/fendo.2022.847760] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/24/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The relationship between pancreatic cancer (PC) and type 2 diabetes mellitus (T2DM) has long been widely recognized, but the interaction mechanisms are still unknown. This study was aimed to investigate the shared gene signatures and molecular processes between PC and T2DM. METHODS The Gene Expression Omnibus (GEO) database was used to retrieve the RNA sequence and patient information of PC and T2DM. Weighted gene co-expression network analysis (WGCNA) was performed to discover a co-expression network associated with PC and T2DM. Enrichment analysis of shared genes present in PC and T2DM was performed by ClueGO software. These results were validated in the other four cohorts based on differential gene analysis. The predictive significance of S100A6 in PC was evaluated using univariate and multivariate Cox analyses, as well as Kaplan-Meier plots. The biological process of S100A6 enrichment in PC was detected using Gene Set Enrichment Analysis (GSEA). The involvement of S100A6 in the tumor immune microenvironment (TIME) was assessed by CIBERSORT. In vitro assays were used to further confirm the function of S100A6 in PC. RESULTS WGCNA recognized three major modules for T2DM and two major modules for PC. There were 44 shared genes identified for PC and T2DM, and Gene Ontology (GO) analysis showed that regulation of endodermal cell fate specification was primarily enriched. In addition, a key shared gene S100A6 was derived in the validation tests. S100A6 was shown to be highly expressed in PC compared to non-tumor tissues. PC patients with high S100A6 expression had worse overall survival (OS) than those with low expression. GSEA revealed that S100A6 is involved in cancer-related pathways and glycometabolism-related pathways. There is a strong relationship between S100A6 and TIME. In vitro functional assays showed that S100A6 helped to induce the PC cells' proliferation and migration. We also proposed a diagram of common mechanisms of PC and T2DM. CONCLUSIONS This study firstly revealed that the regulation of endodermal cell fate specification may be common pathogenesis of PC and T2DM and identified S100A6 as a possible biomarker and therapeutic target for PC and T2DM patients.
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Affiliation(s)
- Yifang Hu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ni Zeng
- Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yaoqi Ge
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dan Wang
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoxuan Qin
- Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wensong Zhang
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yun Liu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Medical Informatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
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14
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3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety. Bioorg Med Chem Lett 2022; 61:128591. [PMID: 35114371 DOI: 10.1016/j.bmcl.2022.128591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/23/2022] [Accepted: 01/26/2022] [Indexed: 11/24/2022]
Abstract
Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total. Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 - 18 μM against cohort-1 and 1.4-18 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) >47 (3-Cl) >46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b]1,4dioxine (51) returned cohort-2 GI50 values of 1.7 - 3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.
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15
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Altered protein profile of plasma extracellular vesicles in oral squamous cell carcinoma development. J Proteomics 2022; 251:104422. [PMID: 34775099 DOI: 10.1016/j.jprot.2021.104422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/16/2021] [Accepted: 11/01/2021] [Indexed: 11/20/2022]
Abstract
Extracellular vesicles (EVs) are involved in a wide range of pathological processes and recognized as potential and novel biomarkers for oral squamous cell carcinoma (OSCC). Here, we describe the plasma EV proteome of rats with 4-nitroquinoline-1-oxide (4NQO)-induced OSCC or moderate dysplasia (MD), which can progress to OSCC, by tandem mass tag (TMT)-labeled mass spectrometry. The proteomic profiles suggest the differential expression of various proteins in MD and OSCC, some well-recognized pathological changes (e.g., translation, ATP metabolism, and mesenchymal transition), and some novel pathological changes (e.g., podosome, focal adhesion, and S100 binding). We re-examined the presence of traditional exosomal markers and the reported novel pan-EV markers. In summary, these results suggest potential EV biomarkers and underlying pathological changes in early OSCC as well as the presence of oral-derived EVs in plasma and the need for pan-EV markers. SIGNIFICANCE: This research suggests potential EV biomarkers and underlying pathological changes in early OSCC as well as the presence of oral-derived EVs in plasma and the need for pan-EV markers.
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16
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Wu Y, Zhou Q, Guo F, Chen M, Tao X, Dong D. S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives. Front Oncol 2021; 11:711180. [PMID: 34527585 PMCID: PMC8435722 DOI: 10.3389/fonc.2021.711180] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.
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Affiliation(s)
- Yu Wu
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.,College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qi Zhou
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Fangyue Guo
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Mingming Chen
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.,College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xufeng Tao
- School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Deshi Dong
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
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17
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Xu L, Liu F, Li H, Li M, Xie Y, Li Z, Guo Y. Comprehensive characterization of pathological stage-related genes of papillary thyroid cancer along with survival prediction. J Cell Mol Med 2021; 25:8390-8404. [PMID: 34342109 PMCID: PMC8419169 DOI: 10.1111/jcmm.16799] [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: 12/29/2020] [Revised: 06/08/2021] [Accepted: 07/09/2021] [Indexed: 02/05/2023] Open
Abstract
It is crucial to understand the differences across papillary thyroid cancer (PTC) stages, so as to provide a basis for individualized treatments. Here, comprehensive function characterization of PTC stage‐related genes was performed and a new prognostic signature was developed for advanced patients. Two gene modules were confirmed to be closely associated with PTC stages and further six hub genes were identified that yield excellent diagnostic efficiency between tumour and normal tissues. Genetic alteration analysis indicates that they are much conservative since mutations in the DNA of them rarely occur, but changes of DNA methylation on these six genes show that 12 DNA methylation sites are significantly associated with their corresponding genes' expression. Validation data set testing also suggests that these six stage‐related hub genes would be probably potential biomarkers for marking four stages. Subsequently, a 21‐mRNA‐based prognostic risk model was constructed for PTC stage III/IV patients and it could effectively predict the survival of patients with strong prognostic ability. Functional analysis shows that differential expression genes between high‐ and low‐risk patients would promote the progress of PTC to some extent. Moreover, tumour microenvironment (TME) of high‐risk patients may be more conducive to tumour growth by ESTIMATE analysis.
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Affiliation(s)
- Lei Xu
- College of Chemistry, Sichuan University, Chengdu, China
| | - Feng Liu
- Department of Thyroid Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Haiyan Li
- College of Chemistry, Sichuan University, Chengdu, China
| | - Menglong Li
- College of Chemistry, Sichuan University, Chengdu, China
| | - Yongmei Xie
- Department of Thyroid Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Zhihui Li
- Department of Thyroid Surgery, West China Hospital of Sichuan University, Chengdu, China.,Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China
| | - Yanzhi Guo
- College of Chemistry, Sichuan University, Chengdu, China
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18
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Sun J, Ambrus JI, Russell CC, Baker JR, Cossar PJ, Pirinen MJ, Sakoff JA, Scarlett CJ, McCluskey A. Targeting the S100A2-p53 Interaction with a Series of 3,5-Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity. ChemMedChem 2021; 16:2851-2863. [PMID: 34047071 DOI: 10.1002/cmdc.202000949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 05/18/2021] [Indexed: 01/02/2023]
Abstract
In silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal; the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N-methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad-spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2-p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.
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Affiliation(s)
- Jufeng Sun
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.,Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai, 264003, China
| | - Joey I Ambrus
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Cecilia C Russell
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Jennifer R Baker
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Peter J Cossar
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Melanie J Pirinen
- School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW, 2258, Australia
| | - Jennette A Sakoff
- Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street, Waratah, NSW, 2298, Australia
| | - Christopher J Scarlett
- School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW, 2258, Australia
| | - Adam McCluskey
- Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
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19
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Wang T, Han S, Du G. S100A6 represses Calu-6 lung cancer cells growth via inhibiting cell proliferation, migration, invasion and enhancing apoptosis. Cell Biochem Funct 2021; 39:771-779. [PMID: 34008212 PMCID: PMC8453982 DOI: 10.1002/cbf.3639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 11/10/2022]
Abstract
S100 calcium binding protein A6 (S100A6) has been reported to involve in many kinds of cancers through regulating intracellular calcium homeostasis. Previous studies found that S100A6 increased in lung cancer patients' plasma and pleural effusion. This study focused on its function in Calu-6 lung cancer cells. S100A6 gene was transferred into Calu-6 lung cancer cell line by lentivirus vector, the empty vector transfected cells and the blank cells were set as control groups. MTT was evaluating cell proliferation. The transwell assay was reflecting cell migration and cell invasion. The flow cytometric analysis was detecting cell apoptosis and cell cycle of three groups (Calu-6, Calu-6/neo, Calu-6/S100A6). Nude mouse tumorigenicity was then applied to evaluate S100A6's effect on cellular tumorigenicity. Compared with control groups, Calu-6/S100A6 cells showed a weakening trend in the cell behaviours of proliferation, migration and invasiveness, while had an enhancement of cell apoptosis, with all P < .05. The cell cycle of Calu-6/S100A6 cells had a reduction of S phase and an increase of G1 phase (P < .05). In animal study, after 5 weeks of cell injection, the tumour bulk of Calu-6/S100A6 group was smaller than controls, with P < .05. Our results demonstrate S100A6 inhibits the growth of Calu-6 lung cancer cells, as well as impairs Calu-6's ability in tumorigenesis. At cellular level, S100A6 is supposed to act as a tumour suppressor gene in lung cancer.
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Affiliation(s)
- Ting Wang
- Department of Respiratory Medicine, Xi'an People's Hospital (Xi'an No.4 Hospital), Xi'an, China
| | - Suoli Han
- Department of Oncology, Zibo Mining Coal Hospital, Zibo, China
| | - Ge Du
- Department of Rehabilitation Center for Elderly, Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
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20
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Moehlin J, Mollet B, Colombo BM, Mendoza-Parra MA. Inferring biologically relevant molecular tissue substructures by agglomerative clustering of digitized spatial transcriptomes with multilayer. Cell Syst 2021; 12:694-705.e3. [PMID: 34159899 DOI: 10.1016/j.cels.2021.04.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/08/2021] [Accepted: 04/13/2021] [Indexed: 01/04/2023]
Abstract
Spatially resolved transcriptomics (SrT) can investigate organ or tissue architecture from the angle of gene programs that define their molecular complexity. However, computational methods to analyze SrT data underexploit their spatial signature. Inspired by contextual pixel classification strategies applied to image analysis, we developed MULTILAYER to stratify maps into functionally relevant molecular substructures. MULTILAYER applies agglomerative clustering within contiguous locally defined transcriptomes (gene expression elements or "gexels") combined with community detection methods for graphical partitioning. MULTILAYER resolves molecular tissue substructures within a variety of SrT data with superior performance to commonly used dimensionality reduction strategies and still detects differentially expressed genes on par with existing methods. MULTILAYER can process high-resolution as well as multiple SrT data in a comparative mode, anticipating future needs in the field. MULTILAYER provides a digital image perspective for SrT analysis and opens the door to contextual gexel classification strategies for developing self-supervised molecular diagnosis solutions. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Julien Moehlin
- Génomique métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, 91057, Evry, France
| | - Bastien Mollet
- Génomique métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, 91057, Evry, France; École Normale Supérieure de Lyon, Université Claude Bernard - Lyon 1, Université de Lyon, 69342 Lyon Cedex 07, France
| | - Bruno Maria Colombo
- Génomique métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, 91057, Evry, France
| | - Marco Antonio Mendoza-Parra
- Génomique métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, 91057, Evry, France.
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21
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Tu G, Gao W, Li Y, Dian Y, Xue B, Niu L, Yu X, Zhu H. Expressional and Prognostic Value of S100A16 in Pancreatic Cancer Via Integrated Bioinformatics Analyses. Front Cell Dev Biol 2021; 9:645641. [PMID: 33912559 PMCID: PMC8072221 DOI: 10.3389/fcell.2021.645641] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/10/2021] [Indexed: 12/28/2022] Open
Abstract
Studies have shown that the calcium-binding protein family S100 may play a role in the development of pancreatic cancer (PC), but the role of S100A16 in PC is still unknown. In this study, Oncomine was first used to detect the expression level and prognosis of S100A16 in PC and other tumors. The results showed that S100A16 was highly expressed in PC tissues compared with a normal pancreas, and the increased expression level may be related to poor prognosis in PC patients. The TCGA and ICGC RNA-seq data of PC patients were downloaded, and the S100A16-related differentially expressed genome (DEGs) was defined by taking the intersection of two gene sets. The GO and KEGG pathways were then analyzed. For clinical analysis, boxplots were depicted for the correlation between clinical characteristics and S100A16 expression. Then Cox regression was applied for exploring the prognostic value of S100A16 for PDAC patients. Based on the Cox regression model, we further estabished a S100A16-related risk score system to strengthen the ability to predict patients' prognosis. After integrating the risk score model and multiple clinicopathological factors, we finally established a nomogram that could predict the survival time of patients. Moreover, Gene set enrichment the effect of S100A16 expression differences on downstream biological processes. At last, using TIMER, ImmuneCellAI and GSEA we analyzed the correlation between S100A16 and pancreatic cancer immune infiltration and predicted the response of patients to checkpoint Blocker (ICB). In summary, S100A16 is involved in the occurrence and development of PC, affecting the prognosis of patients, and may have potential reference values for the immunotherapy of PC.
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Affiliation(s)
- Gangping Tu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ying Li
- Medical College of Xiangya, Central South University, Changsha, China
| | - Yating Dian
- Medical College of Xiangya, Central South University, Changsha, China
| | - Bingyang Xue
- Medical College of Xiangya, Central South University, Changsha, China
| | - Li Niu
- Medical College of Xiangya, Central South University, Changsha, China
| | - Xiao Yu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongwei Zhu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
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22
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Zhuang H, Chen X, Dong F, Zhang Z, Zhou Z, Ma Z, Huang S, Chen B, Zhang C, Hou B. Prognostic values and immune suppression of the S100A family in pancreatic cancer. J Cell Mol Med 2021; 25:3006-3018. [PMID: 33580614 PMCID: PMC7957204 DOI: 10.1111/jcmm.16343] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
S100 calcium‐binding protein A (S100A) family members regulate multiple biological functions related to pancreatic cancer (PC) progression and metastasis. However, the prognostic and oncologic values of S100A family have not been systematically investigated in PC. In the present study, the mRNA expression and potential functions of S100A family were investigated by bioinformatic analysis. Our results demonstrated that overexpression of S100A2, S100A6, S100A10, S100A11, S100A14 and S100A16 was significantly associated with higher T stage, advanced histologic grade and worse prognosis in PC. Besides, one CpG of S100A2, three CpG of S100A6, four CpG of S100A10, four CpG of S100A11, two CpG of S100A14 and five CpG of S100A16 were negatively associated with corresponding S100A family members expression and positively associated with overall survival (OS). The signature based on four CpGs showed good prediction ability of OS. Besides, S100A2 overexpression took part in the regulation of mitotic cell cycle, ECM‐receptor interaction and HIF‐1α transcription factor network. Overexpression of S100A6, S100A10, S100A11, S100A14 and S100A16 may impair the infiltration and cytolytic activity of CD8+ T cells through focal adhesion‐Ras‐stimulating signalling pathway in PC. Overall, this study explores the multiple prognostic values and oncologic functions of the S100A family in PC.
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Affiliation(s)
- Hongkai Zhuang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Shantou University of Medical College, Shantou, China
| | - Xinming Chen
- Department of Hepatobiliary Surgery, Shenshan Central Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, China
| | - Fengying Dong
- Forth Department of Geriatrics, General Hospital of Southern Theater Command, Pla, Guangzhou, China
| | - Zedan Zhang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Shantou University of Medical College, Shantou, China
| | - Zixuan Zhou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zuyi Ma
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Shantou University of Medical College, Shantou, China
| | - Shanzhou Huang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Bo Chen
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chuanzhao Zhang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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23
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Lee DS, Lee KL, Jeong JB, Shin S, Kim SH, Kim JW. Expression of Chemokine CCL28 in Ulcerative Colitis Patients. Gut Liver 2021; 15:70-76. [PMID: 32102131 PMCID: PMC7817927 DOI: 10.5009/gnl19273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 12/05/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Ulcerative colitis (UC) is an inflammatory bowel disease for which new serological markers are required. The purpose of this study was to assess the role of the mucosa-associated epithelial chemokine CCL28 in UC. Methods The study included 50 patients; of these, 25 were patients with UC, and 25 were healthy controls. The levels of serum CCL28 were analyzed using enzyme-linked immunosorbent assay. CCL28 expression was analyzed by immunohistochemistry (IHC) in 15 representative colon tissues biopsied based on disease activity (UC patients with severe activity, five samples; UC patients with mild activity, five samples; healthy controls, five samples). Results The serum CCL28 levels were remarkably higher (p<0.05) in patients with UC (median, 235.7 pg/mL; IQR, 63.8 to 117.2 pg/mL) than in healthy controls (median, 48.9, pg/mL; IQR, 35.9 to 42.0 pg/mL). However, there was no significant difference in serum CCL28 according to disease extent or activity. In contrast, IHC analysis revealed a significant difference in CCL28 consistent with disease status, disease extent, and disease activity. Conclusions CCL28 could be useful for diagnosing UC. However, further validations of CCL28 on disease activity and severity are needed.
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Affiliation(s)
- Dong Seok Lee
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Kook Lae Lee
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Ji Bong Jeong
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Sue Shin
- Departments of Laboratory Medicine, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Su Hwan Kim
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Ji Won Kim
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
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24
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Jiang X, Xing L, Chen Y, Qin R, Song S, Lu Y, Xie S, Wang L, Pu H, Gui X, Li T, Xu J, Li J, Jia S, Lu D. CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:310-323. [PMID: 33425489 PMCID: PMC7779543 DOI: 10.1016/j.omtn.2020.11.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/10/2020] [Indexed: 12/13/2022]
Abstract
Circular RNA (CircRNA) is a newly identified special class of non-coding RNA (ncRNA) that plays an important regulatory role in the progression of certain diseases. Herein, our results indicate that CircMEG3 is downregulated expression and negatively correlated with the expression of telomerase-related gene Cbf5 in human liver cancer. Moreover, CircMEG3 inhibits the growth of human liver cancer stem cells in vivo and in vitro. CircMEG3 inhibits the expression of m6A methyltransferase METTL3 dependent on HULC. Moreover, CircMEG3 inhibits the expression of Cbf5, a component of telomere synthetase H/ACA ribonucleoprotein (RNP; catalyst RNA pseudouracil modification) through METTL3 dependent on HULC. Thereby, CircMEG3 inhibits telomerase activity and shortens telomere lifespan dependent on HULC and Cbf5 in human liver cancer stem cell. Strikingly, increased Cbf5 abrogates the ability of CircMEG3 to inhibit malignant differentiation of human liver cancer stem cells. In summary, these observations provide important basic information for finding effective liver cancer therapeutic targets.
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Affiliation(s)
- Xiaoxue Jiang
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Libo Xing
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yingjie Chen
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Rushi Qin
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Shuting Song
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yanan Lu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Sijie Xie
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Liyan Wang
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Hu Pu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xin Gui
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Tianming Li
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jie Xu
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Jiao Li
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Song Jia
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Dongdong Lu
- Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
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25
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Allgöwer C, Kretz AL, von Karstedt S, Wittau M, Henne-Bruns D, Lemke J. Friend or Foe: S100 Proteins in Cancer. Cancers (Basel) 2020; 12:cancers12082037. [PMID: 32722137 PMCID: PMC7465620 DOI: 10.3390/cancers12082037] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/24/2022] Open
Abstract
S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment.
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Affiliation(s)
- Chantal Allgöwer
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (C.A.); (A.-L.K.); (M.W.); (D.H.-B.)
| | - Anna-Laura Kretz
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (C.A.); (A.-L.K.); (M.W.); (D.H.-B.)
| | - Silvia von Karstedt
- Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany;
- CECAD Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany
- Center of Molecular Medicine Cologne, Medical Faculty, University Hospital of Cologne, Weyertal 115b, 50931 Cologne, Germany
| | - Mathias Wittau
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (C.A.); (A.-L.K.); (M.W.); (D.H.-B.)
| | - Doris Henne-Bruns
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (C.A.); (A.-L.K.); (M.W.); (D.H.-B.)
| | - Johannes Lemke
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (C.A.); (A.-L.K.); (M.W.); (D.H.-B.)
- Correspondence: ; Tel.: +49-731-500-53691
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26
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Ji X, Zhu H, Dai X, Xi Y, Sheng Y, Gao C, Liu H, Xue Y, Liu J, Shi J, Zhang Y, Chen Y, Dai X, Li M, Wang A, Dong J. Overexpression of GBP1 predicts poor prognosis and promotes tumor growth in human glioblastoma multiforme. Cancer Biomark 2020; 25:275-290. [PMID: 29991124 DOI: 10.3233/cbm-171177] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Guanylate binding protein-1 (GBP1) is highly associated with cell proliferation, and can modulate growth and invasiveness of gliomas. The relationship between GBP1 expression and the prognosis of glioma patients is further evaluated for the purpose of investigating whether GBP1 can serve as an predictor for evaluating prognosis of glioma patients. METHODS GBP1 expression in 528 glioblastoma multiforme (GBM) patients of The Cancer Genome Atlas (TCGA) database were investigated, then 103 surgical specimens from glioma patients in our center were further evaluated. The effect of GBP1 on proliferation, invasion and migration of glioma cells in vitro was analyzed, and the effects of GBP1 on sensitivity of radiotherapy and chemotherapy on glioma cells in vitro were also analyzed. GBP1 associated signaling pathways were identified with Gene Set Enrichment Analysis (GSEA). Besides, the effect of GBP1 expression on proliferation of glioma cells in vivo was analyzed. RESULTS In both TCGA database and our clinical data, GBM tissues exhibited increased mRNA expression of GBP1 gene, its expression level was co-related to PETN deletion and EGFR amplification, and was associated with prognosis of GBM patients. GBP1 overexpression can enhance migration and invasion ability of tumor cells in vitro, and in vivo studies showed that GBP1 can promote tumor proliferation, decrease survival in tumor-bearing mice. GSEA analysis predicted that GBP1 may play its biological roles via toll-like receptor pathway. CONCLUSION This study provides new insights and evidences that high level expression of GBP1 is significantly correlated with progression and prognosis in GBMs. Furthermore, transfection of GBP1 revealed its regulation on migration and invasiveness of glioma cells, decreasing sensitivity of chemotherapeutic agent, shortening survival of tumor-bearing animals. These data demonstrate that GBP1 may serve as a novel prognostic biomarker and a potential therapeutic target for gliomas.
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27
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Ansari D, Torén W, Zhou Q, Hu D, Andersson R. Proteomic and genomic profiling of pancreatic cancer. Cell Biol Toxicol 2019; 35:333-343. [PMID: 30771135 PMCID: PMC6757097 DOI: 10.1007/s10565-019-09465-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 02/05/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer.
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Affiliation(s)
- Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden.
| | - William Torén
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Qimin Zhou
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dingyuan Hu
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
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28
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Liu L, Wang S, Cen C, Peng S, Chen Y, Li X, Diao N, Li Q, Ma L, Han P. Identification of differentially expressed genes in pancreatic ductal adenocarcinoma and normal pancreatic tissues based on microarray datasets. Mol Med Rep 2019; 20:1901-1914. [PMID: 31257501 DOI: 10.3892/mmr.2019.10414] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 05/01/2019] [Indexed: 11/06/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor with rapid progression and poor prognosis. In the present study, 11 high‑quality microarray datasets, comprising 334 tumor samples and 151 non‑tumor samples from the Gene Expression Omnibus, were screened, and integrative meta‑analysis of expression data was used to identify gene signatures that differentiate between PDAC and normal pancreatic tissues. Following the identification of differentially expressed genes (DEGs), two‑way hierarchical clustering analysis was performed for all DEGs using the gplots package in R software. Hub genes were then determined through protein‑protein interaction network analysis using NetworkAnalyst. In addition, functional annotation and pathway enrichment analyses of all DEGs were conducted in the Database for Annotation, Visualization, and Integrated Discovery. The expression levels and Kaplan‑Meier analysis of the top 10 upregulated and downregulated genes were verified in The Cancer Genome Atlas. A total of 1,587 DEGs, including 1,004 upregulated and 583 downregulated genes, were obtained by comparing PDAC with normal tissues. Of these, hematological and neurological expressed 1, integrin subunit α2 (ITGA2) and S100 calcium‑binding protein A6 (S100A6) were the top upregulated genes, and kinesin family member 1A, Dymeclin and β‑secretase 1 were the top downregulated genes. Reverse transcription‑quantitative PCR was performed to examine the expression levels of S100A6, KRT19 and GNG7, and the results suggested that S100A6 was significantly upregulated in PDAC compared with normal pancreatic tissues. ITGA2 overexpression was significantly associated with shorter overall survival times, whereas family with sequence similarity 46 member C overexpression was strongly associated with longer overall survival times. In addition, network‑based meta‑analysis confirmed growth factor receptor‑bound protein 2 and histone deacetylase 5 as pivotal hub genes in PDAC compared with normal tissue. In conclusion, the results of the present meta‑analysis identified PDAC‑related gene signatures, providing new perspectives and potential targets for PDAC diagnosis and treatment.
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Affiliation(s)
- Liying Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Siqi Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Chunyuan Cen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shuyi Peng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yan Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xin Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Nan Diao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qian Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ling Ma
- Advanced Application Team, GE Healthcare, Shanghai 201203, P.R. China
| | - Ping Han
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Al-Ismaeel Q, Neal CP, Al-Mahmoodi H, Almutairi Z, Al-Shamarti I, Straatman K, Jaunbocus N, Irvine A, Issa E, Moreman C, Dennison AR, Emre Sayan A, McDearmid J, Greaves P, Tulchinsky E, Kriajevska M. ZEB1 and IL-6/11-STAT3 signalling cooperate to define invasive potential of pancreatic cancer cells via differential regulation of the expression of S100 proteins. Br J Cancer 2019; 121:65-75. [PMID: 31123345 PMCID: PMC6738112 DOI: 10.1038/s41416-019-0483-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 05/02/2019] [Indexed: 12/12/2022] Open
Abstract
Background S100 proteins have been implicated in various aspects of cancer, including epithelial-mesenchymal transitions (EMT), invasion and metastasis, and also in inflammatory disorders. Here we examined the impact of individual members of this family on the invasion of pancreatic ductal adenocarcinoma (PDAC) cells, and their regulation by EMT and inflammation. Methods Invasion of PDAC cells was analysed in zebrafish embryo xenografts and in transwell invasion assays. Expression and regulation of S100 proteins was studied in vitro by immunoblotting, quantitative PCR and immunofluorescence, and in pancreatic lesions by immunohistochemistry. Results Whereas the expression of most S100 proteins is characteristic for epithelial PDAC cell lines, S100A4 and S100A6 are strongly expressed in mesenchymal cells and upregulated by ZEB1. S100A4/A6 and epithelial protein S100A14 respectively promote and represses cell invasion. IL-6/11-STAT3 pathway stimulates expression of most S100 proteins. ZEB1 synergises with IL-6/11-STAT3 to upregulate S100A4/A6, but nullifies the effect of inflammation on S100A14 expression. Conclusion EMT/ZEB1 and IL-6/11-STAT3 signalling act independently and congregate to establish the expression pattern of S100 proteins, which drives invasion. Although ZEB1 regulates expression of S100 family members, these effects are masked by IL-6/11-STAT3 signalling, and S100 proteins cannot be considered as bona fide EMT markers in PDAC.
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Affiliation(s)
- Qais Al-Ismaeel
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK.,College of Medicine, University of Duhokl, Kurdistan region, Duhok, Iraq
| | - Christopher P Neal
- University Hospitals of Leicester NHS Trust Hepato-Pancreato-Biliary Unit, Leicester, UK
| | - Hanaa Al-Mahmoodi
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Zamzam Almutairi
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | | | - Kees Straatman
- Centre for Core Biotechnology Services, University of Leicester, Leicester, UK
| | - Nabil Jaunbocus
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Andrew Irvine
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Eyad Issa
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Catherine Moreman
- Department of Cellular Pathology, Leicester Royal Infirmary, Leicester, UK
| | - Ashley R Dennison
- University Hospitals of Leicester NHS Trust Hepato-Pancreato-Biliary Unit, Leicester, UK
| | - A Emre Sayan
- Cancer Sciences Division, University of Southampton, Southampton, UK
| | - Jonathan McDearmid
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
| | - Peter Greaves
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Eugene Tulchinsky
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK. .,Moscow Institute of Physics and Technology, Dolgoprudny, Moscow region, Russia. .,Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan.
| | - Marina Kriajevska
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
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Yun D, Wang H, Wang Y, Chen Y, Zhao Z, Ma J, Ji Y, Huang Q, Chen J, Chen H, Lu D. Shuttling SLC2A4RG is regulated by 14-3-3θ to modulate cell survival via caspase-3 and caspase-6 in human glioma. EBioMedicine 2019; 40:163-175. [PMID: 30686753 PMCID: PMC6413354 DOI: 10.1016/j.ebiom.2019.01.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 01/10/2019] [Accepted: 01/11/2019] [Indexed: 12/27/2022] Open
Abstract
Background Glioma is the most common and aggressive primary brain tumor with polygenic susceptibility. The cytoplasmic/nuclear shuttling protein, SLC2A4RG (SLC2A4 regulator), has been identified in the 20q13.33 region influencing glioma susceptibility by genome-wide association studies (GWAS) and fine mapping analyses. Methods To discover the expression of SLC2A4RG and its relationship with patient prognosis, tissue microarray containing glioma samples and normal brains was constructed followed by immunohistochemical staining. The role of SLC2A4RG on cell proliferation, cell cycle, and apoptosis was evaluated by gain- and loss-of-function assays in vivo, and subcutaneous and intracranial xenografts were performed to assess its functional effects. The mechanism underlying SLC2A4RG was further investigated via luciferase reporter analyses, ChIP, mass spectrometry, Co-IP, immunofluorescence, etc. Findings The potential tumor suppressor role of SLC2A4RG was further validated by in vitro and in vivo experiments that SLC2A4RG could attenuate cell proliferation via G2/M phase arrest and induce glioma cell apoptosis by direct transactivation of caspase-3 and caspase-6. Moreover, its function displaying showed to depend on the nuclear transportation of SLC2A4RG, however, bound with 14-3-3θ, it would be sequestered in the cytoplasm followed by reversal effect. Interpretation We identify a new pro-oncogenic mechanism whereby 14-3-3θ negatively regulates the nuclear function of the tumor suppressor SLC2A4RG, with significant therapeutic implications for the intervention of human glioma. Fund This work was supported by the National Natural Science Foundation of China (81372706, 81572501, and 81372235).
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Affiliation(s)
- Dapeng Yun
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Hongxiang Wang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Yuqi Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Yuanyuan Chen
- Department of Critical Care Medicine, Wuxi No'2 People's Hospital, Wuxi, Jiangsu Province, China
| | - Zhipeng Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Jiawei Ma
- Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yuanyuan Ji
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China
| | - Qilin Huang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Juxiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
| | - Hongyan Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China.
| | - Daru Lu
- State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, 2005 Songhu Road, Shanghai 200438, China.
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Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer. PLoS One 2018; 13:e0207405. [PMID: 30440021 PMCID: PMC6237386 DOI: 10.1371/journal.pone.0207405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/30/2018] [Indexed: 12/17/2022] Open
Abstract
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.
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Yun DP, Wang YQ, Meng DL, Ji YY, Chen JX, Chen HY, Lu DR. Actin-capping protein CapG is associated with prognosis, proliferation and metastasis in human glioma. Oncol Rep 2018; 39:1011-1022. [PMID: 29399702 PMCID: PMC5802022 DOI: 10.3892/or.2018.6225] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 01/02/2018] [Indexed: 12/20/2022] Open
Abstract
Glioma is the most aggressive and malignant primary brain tumor in adults. In the present study, we identified a vital oncoprotein, capping actin protein, gelsolin-like (CapG), and investigated its roles in the prognosis, proliferation and metastasis in glioma. The mRNA and protein levels of CapG were significantly increased in human glioma, and higher CapG expression was an independent prognostic factor for predicting unfavorable prognosis. The expression level of CapG was found to be associated with several common molecular features of glioblastoma (GBM; WHO grade IV glioma) in The Cancer Genome Atlas (TCGA) cohort. When analyzing the prognosis of GBM patients according to these molecular features, we observed that the prognostic value of CapG was affected by amplification of CDK6 or EGFR. However, overexpression of CapG markedly promoted cell growth in vitro, while depletion of CapG significantly inhibited cell proliferation by blocking the cell cycle in G1/S transition. Moreover, CapG manipulation in glioma cell lines U87 and U251 showed CapG-dependent cellular migration and invasiveness. These data suggest that CapG may serve as a prognostic biomarker with potentially important therapeutic implications for glioma.
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Affiliation(s)
- Da-Peng Yun
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Yu-Qi Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - De-Long Meng
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuan-Yuan Ji
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Ju-Xiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hong-Yan Chen
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
| | - Da-Ru Lu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
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A review of S100 protein family in lung cancer. Clin Chim Acta 2017; 476:54-59. [PMID: 29146477 DOI: 10.1016/j.cca.2017.11.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/10/2017] [Accepted: 11/12/2017] [Indexed: 02/08/2023]
Abstract
S100 protein family, representing 25 relatively small calcium binding proteins, has been reported to be involved in multiple stages of tumorigenesis and progression. These proteins are considered having potential value to be adopted as novel biomarkers in the detection and accurate prediction of many kinds of tumors, including lung cancer. As the one having the highest morbidity and mortality among all cancers, lung carcinoma is still occult for detection, especially at early stage. S100 proteins take participation in the lung neoplasia through playing intracellular and/or extracellular functions, therefore getting involved in a variety of biological processes such as differentiation, proliferation, and migration. A few members have also been testified to modulate TGF-β/Smad-3 mediated transcriptional activity of target genes involved in tumor promotion. In addition to that, a number of proteins in this family have already been reported to experience an abnormal trend in lung cancer at cell, serum and tissue levels. Thus, S100 proteins may serve as effective biomarkers for suspected or already diagnosed lung cancer patients. In future, S100 protein family might be applied as therapeutic targets in clinical treatment of lung cancer. In this review, we firstly summed up the biological and clinical evidence connecting S100 proteins and lung cancer, which has not been summarized before.
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Park J, Han D, Do M, Woo J, Wang JI, Han Y, Kwon W, Kim SW, Jang JY, Kim Y. Proteome characterization of human pancreatic cyst fluid from intraductal papillary mucinous neoplasm by liquid chromatography/tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2017; 31:1761-1772. [PMID: 28815810 DOI: 10.1002/rcm.7959] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/12/2017] [Accepted: 08/11/2017] [Indexed: 06/07/2023]
Abstract
RATIONALE In recent years, the molecular components of pancreatic cyst fluid have been used for diagnosis and prognosis. Because the protein markers that are currently used in clinical tests are unreliable, proteomic studies to find new protein markers are being conducted. However, such researches have been limited due to the complexity of pancreatic cyst fluid and the immaturity of proteomic techniques. METHODS To overcome these limitations and provide a pancreatic cyst proteome dataset, we examined cyst fluid proteome with tandem mass spectrometry. The proteomic analysis was performed using a Orbitrap-based mass spectrometer (Q-Exactive) coupled with a 50-cm-long nano-liquid chromatography column. Protein mutations were identified using mutation sequence database search. RESULTS A total of 5850 protein groups were identified from microliters of cyst fluid. Among those, 3934 protein groups were reported for the first time in pancreatic cyst fluid. Although high-abundance proteins were not depleted in the experiment, our dataset detected almost all pancreatic tumor markers such as mucin family members, S100 proteins, and CEA-related proteins. In addition, 590 protein mutation marker candidates were discovered. CONCLUSIONS We provide a comprehensive cyst proteome dataset that includes cystic cellular proteins and mutated proteins. Our findings would serve as a rich resource for further IPMN studies and clinical applications. The MS data have been deposited in the ProteomeXchange with identifier PXD005671 (http://proteomecentral.proteomexchange.org/dataset/PXD005671).
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MESH Headings
- Amino Acid Sequence
- Biomarkers, Tumor/analysis
- Carcinoma, Pancreatic Ductal/chemistry
- Carcinoma, Pancreatic Ductal/pathology
- Chromatography, Liquid/methods
- Cyst Fluid/chemistry
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/chemistry
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreas/chemistry
- Pancreas/pathology
- Pancreatic Cyst/chemistry
- Pancreatic Cyst/pathology
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/pathology
- Proteome/analysis
- Proteomics/methods
- Tandem Mass Spectrometry/methods
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Affiliation(s)
- Joonho Park
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Dohyun Han
- Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Seoul, Korea
| | - Misol Do
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jongmin Woo
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Joseph I Wang
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngmin Han
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Wooil Kwon
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
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Zheng S, Shen H, Jia Q, Jing C, Lin J, Zhang M, Zhang X, Zhang B, Liu Y. S100A6 promotes proliferation of intrahepatic cholangiocarcinoma cells via the activation of the p38/MAPK pathway. Future Oncol 2017; 13:2053-2063. [PMID: 28984474 DOI: 10.2217/fon-2017-0199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aim: We explored the expression of S100A6 and its role in intrahepatic cholangiocarcinoma (ICC). Methods: The expression of S100A6 in ICC samples was detected by immunohistochemistry. In vitro experiments, we silenced and overexpressed S100A6 to investigate its role in cell functions. Results: The expression of S100A6 was markedly increased in ICC tissues and cell lines. S100A6 overexpression was an independent risk factor for patients’ survival. Silencing S100A6 resulted in a suppression of proliferation and p38/MAPK activity, while overexpressing S100A6 caused a promotion of proliferation and p38/MAPK. Discussion: S100A6 participated in the proliferation of ICC cells and correlated with a more aggressive behavior of ICC. Conclusion: S100A6 may serve as a novel prognostic marker and a potential therapeutic target for ICC patients.
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Affiliation(s)
- Susu Zheng
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Hujia Shen
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Qingan Jia
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Chuyu Jing
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Jiajia Lin
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Meixia Zhang
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Xiaolei Zhang
- Department of Pathology, Zhongshan hospital, Fudan University, Shanghai 20032, PR China
| | - Boheng Zhang
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
| | - Yinkun Liu
- Department of Hepatic Oncology, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai 20032, PR China
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Donato R, Sorci G, Giambanco I. S100A6 protein: functional roles. Cell Mol Life Sci 2017; 74:2749-2760. [PMID: 28417162 PMCID: PMC11107720 DOI: 10.1007/s00018-017-2526-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 02/24/2017] [Accepted: 02/27/2017] [Indexed: 12/20/2022]
Abstract
S100A6 protein belongs to the A group of the S100 protein family of Ca2+-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6's effects. Dosage of serum S100A6 might aid in diagnosis in oncology.
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Affiliation(s)
- Rosario Donato
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
- Department of Experimental Medicine, Istituto Interuniversitario di Miologia (Interuniversity Institute for Myology), Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
| | - Guglielmo Sorci
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Department of Experimental Medicine, Istituto Interuniversitario di Miologia (Interuniversity Institute for Myology), Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine, Centro Universitario per la Ricerca sulla Genomica Funzionale, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
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Agrawal S. Potential prognostic biomarkers in pancreatic juice of resectable pancreatic ductal adenocarcinoma. World J Clin Oncol 2017; 8:255-260. [PMID: 28638795 PMCID: PMC5465015 DOI: 10.5306/wjco.v8.i3.255] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/01/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
Despite potentially curative surgery pancreatic cancer has a dismal prognosis. Serum cancer antigen 19-9 (CA 19-9) correlates with tumor burden, resectability and survival in patients with pancreatic ductal adenocarcinoma. Identification of novel biomarkers may facilitate early diagnosis of pancreatic cancer and improve survival. Pancreatic juice is a rich source of cancer-specific proteins rendering it a promising tool for identifying biomarkers. Recent proteomic and microRNA expression analyses have identified several biomarkers of potential diagnostic and prognostic value. Tumor markers CA 19-9 and carcinoembryonic antigen (CEA) are widely used in the characterization of premalignant and malignant lesions of the pancreas. Elevated level of CEA in bile is a marker for malignancy and a predictor of hepatic recurrence. The potential value of CA 19-9, CEA and lactate dehydrogenase as prognostic biomarkers in pancreatic juice and bile is unknown. Specimens of pancreatic juice and bile can be readily collected during surgical resection of the tumor. Profiling of pancreatic juice and bile to identify novel prognostic biomarkers may improve selection of patients for adjuvant therapy with a favorable impact on overall survival in patients diagnosed with pancreatic cancer.
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38
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Lu Z, Lai ZQ, Leung AWN, Leung PS, Li ZS, Lin ZX. Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies. Oncotarget 2017; 8:84974-84985. [PMID: 29156697 PMCID: PMC5689587 DOI: 10.18632/oncotarget.17761] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 04/17/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile. In addition, brusatol showed a synergistic anti-proliferative effect toward PANC-1 and Capan-2 cell lines when combined with gemcitabine or 5-fluorouracil. The results of flow cytometry suggested that brusatol combination treatment with gemcitabine or 5-fluorouracil was able to cause cell cycle arrest at G2/M phase, and accentuate apoptosis in PANC-1 cells. Moreover, brusatol deactivated gemcitabine/5-fluorouracil-induced NF-κB activation. Western blot analysis and qRT-PCR results showed that brusatol significantly down-regulated the expression of vimentin and Twist, and markedly stimulated the expression of E-cadherin, the key regulatory factors of the epithelial-mesenchymal transition process. Furthermore, treatment with combination of brusatol and gemcitabine or 5-fluorouracil significantly reduced in vivo tumor growth when compared with treatment of either brusatol or gemcitabine/5-fluorouracil alone. Taken together, these results have amply demonstrated that brusatol is a potent anti-pancreatic cancer natural compound, and the synergistic anti-pancreatic cancer effects of brusatol and gemcitabine/5-fluorouracil observed both in vitro and in vivo are associated with the suppression of epithelial-mesenchymal transition process, indicating that brusatol is a promising adjunct to the current chemotherapeutic regimen.
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Affiliation(s)
- Zheng Lu
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China.,Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.,Liver Cirrhosis Diagnosis and Treatment Center, Beijing 302 Hospital, Beijing, China
| | - Zheng-Quan Lai
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Albert W N Leung
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Po Sing Leung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Zhi-Xiu Lin
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
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Rezaei M, Hosseini A, Nikeghbalian S, Ghaderi A. Establishment and characterization of a new human acinar cell carcinoma cell line, Faraz-ICR, from pancreas. Pancreatology 2017; 17:303-309. [PMID: 28215484 DOI: 10.1016/j.pan.2017.02.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 01/25/2017] [Accepted: 02/06/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Basic research in the field of acinar cell carcinoma (ACC) as a rare neoplasm of the pancreas is dependent on the availability of pragmatic model such as new pancreatic cancer cell lines. Thus, establishment and characterization of new pancreatic cancer cell lines from ACC origin are deemed important. METHODS Faraz-ICR cell line was derived from a 58-years old woman with pancreatic acinar cell carcinoma by the collagenase digestion protocol. We characterized the cell line by examining its morphology and cytostructural and functional profile. RESULTS Faraz-ICR has a doubling time of 35 hours and grows in soft agar with a colony-forming efficiency of 25%. The cell had nearly normal pattern of chromosomes in karyotype analysis and Comparative Genomic Hybridization (CGH) array analysis. Evaluation of cells by flowcytometry showed that Faraz-ICR is negative for EpCAM and mesenchymal markers in different passages, and has epithelial nature. Immunofluorescence staining revealed that cells were strongly positive for vimentin, desmin, ezrin, S100, nestin and they were negative for pan-cytokeratins, chromogranin and alpha smooth muscle actin. CONCLUSIONS We were able to establish a new pancreatic carcinoma cell line with partial aspects of Epithelial-mesenchymal transition and aggressiveness. This cell line might be suitable for studying various anticancer drugs and protein profile aiming to see any possible tumor associated marker for ACC.
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Affiliation(s)
- Marzieh Rezaei
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Hosseini
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Department of Surgery, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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40
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Zhang X, Liu Z, Chen M, Cao Q, Huang D. Effects of S100A6 gene silencing on the biological features of eutopic endometrial stromal cells and β‑catenin expression. Mol Med Rep 2017; 15:1279-1285. [PMID: 28075439 PMCID: PMC5367373 DOI: 10.3892/mmr.2017.6105] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 11/25/2016] [Indexed: 11/12/2022] Open
Abstract
Protein expression levels of S100 calcium binding protein A6 (S100A6) are increased in various malignancies and are associated with tumor behavior; however, the association between S100A6 and endometriosis remains to be elucidated. In order to investigate the influence of S100A6 protein, recombinant lentivirus siS100A6 was used to transfect the eutopic endometrial stromal cells. CCK-8 assay was performed to identify the proliferation ability of cell and the cell migration was detected by Transwell assay. Flow cytometry was performed to detect cell apoptosis, and western blotting and reverse transcription-quantitative polymerase chain reaction were performed to identify the expression of β-catenin. The present study investigated the role of S100A6 in endometriosis and its interaction with β-catenin by transfecting eutopic endometrial stromal cells with a recombinant lentivirus containing S100A6-specific small interfering RNA. Inhibition of S100A6 expression had a significant antiproliferative effect and reduced the migratory ability of eutopic endometrial stromal cells, and induced their apoptosis. In addition, inhibition of S100A6 expression suppressed β-catenin expression. These results suggested that inhibition of S100A6 may represent a promising novel approach for the targeted therapy of endometriosis.
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Affiliation(s)
- Xiaoling Zhang
- Department of Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zequn Liu
- Department of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Meihong Chen
- Department of Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qing Cao
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Donghua Huang
- Department of Gynecology, Jiangxi Maternal and Child Health Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Li A, Shi D, Xu B, Wang J, Tang YL, Xiao W, Shen G, Deng W, Zhao C. S100A6 promotes cell proliferation in human nasopharyngeal carcinoma via the p38/MAPK signaling pathway. Mol Carcinog 2016; 56:972-984. [PMID: 27596819 DOI: 10.1002/mc.22563] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 08/25/2016] [Accepted: 09/04/2016] [Indexed: 01/15/2023]
Abstract
An elevated level of S100A6 is associated with poor outcomes of many tumor types, but, how S100A6 contributes to nasopharyngeal carcinoma (NPC) progression remains unknown. Here, we investigated the expression and prognostic significance of S100A6 in NPC and explored the molecular mechanisms under-lying the role of S100A6 in NPC development. The results showed that S100A6 was markedly up-regulated in NPC tissues and cell lines compared to paired peritumoral normal tissues and a normal nasopharyngeal epithelial cell line, respectively. In tissues from 92 NPC patients, high S100A6 expression was associated with advanced N stage, locoregional failure and disease progression and was predictive of poor locoregional recurrence-free survival (LRRFS, P = 0.001) and progression-free survival (PFS, P = 0.001). Multivariate analysis showed that S100A6 is an independent prognostic factor for LRRFS and PFS. Silencing S100A6 using siRNA or shRNA significantly suppressed NPC cell proliferation, colony formation and p38/mitogen-activated protein kinase (MAPK) activity in vitro and inhibited tumor growth in a xenograft mouse model of NPC. In contrast, overexpressing S100A6 via plasmid transfection resulted in increased NPC cell proliferation and p38/MAPK activation. S100A6-induced proliferation was abolished by a p38 inhibitor. In summary, S100A6 may be a new prognostic marker of NPC and may promote NPC development via the activation of p38/MAPK signaling pathways. These findings suggest S100A6/p38/MAPK signaling as a potential therapeutic target for NPC. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Anchuan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Dingbo Shi
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Benhua Xu
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jingshu Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan-Lai Tang
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - WeiWei Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guanzhu Shen
- Department of Radiation Oncology, Cancer Center of Guangzhou Medical University, Guangzhou, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chong Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Loosen SH, Benz F, Niedeggen J, Schmeding M, Schüller F, Koch A, Vucur M, Tacke F, Trautwein C, Roderburg C, Neumann UP, Luedde T. Serum levels of S100A6 are unaltered in patients with resectable cholangiocarcinoma. Clin Transl Med 2016; 5:39. [PMID: 27709523 PMCID: PMC5052241 DOI: 10.1186/s40169-016-0120-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/10/2016] [Indexed: 02/12/2023] Open
Abstract
Background Elevated expression levels of S100A6, a calcium-binding low-molecular-weight protein, were demonstrated in various malignancies. Moreover, increased serum levels of S100A6 were suggested as a novel biomarker for various inflammatory and malignant diseases including lung and gastric cancer. However, up to now, serum concentrations of S100A6 have not been analyzed in patients with cholangiocarcinoma (CCA). Methods S100A6 mRNA expression levels were analyzed in human and murine CCA tumor samples, using semi-quantitative reverse transcriptase PCR. S100A6 serum concentrations were measured using an enzyme-linked immunosorbent assay in 112 patients with CCA referred to surgery for curative resection and were compared to those of 42 healthy controls. Results were correlated with clinical data. Results S100A6 mRNA expression levels were significantly up-regulated in tumor samples of CCA patients and in tumor tissue of a CCA mouse model. In contrast, serum levels of S100A6 were not significantly altered in patients with CCA compared to healthy controls. Whereas no differences became apparent within the different clinical subgroups of CCA, patients with primary sclerosing cholangitis (PSC)-based CCA displayed higher levels of S100A6 compared to the other patients. Nevertheless, patients with higher S100A6 serum concentrations showed a trend towards an impaired prognosis compared to patients with lower levels. Finally, within our cohort of patients both the diagnostic and prognostic potentials of S100A6 were similar to those of the clinically established biomarkers CEA and CA19-9. Conclusion Although S100A6 was expressed at significantly higher levels in human and murine CCA tumor samples, S100A6 serum levels were not regulated in patients with CCA and are thus not suitable for diagnosis of CCA. However, CCA-patients with elevated S100A6 displayed a trend toward an impaired prognosis compared to patients with lower S100A6 levels, supporting its further evaluation as a prognostic biomarker in CCA. Electronic supplementary material The online version of this article (doi:10.1186/s40169-016-0120-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sven H Loosen
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Fabian Benz
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jennifer Niedeggen
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Maximilian Schmeding
- Department of Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Florian Schüller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .,Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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Meng D, Chen Y, Yun D, Zhao Y, Wang J, Xu T, Li X, Wang Y, Yuan L, Sun R, Song X, Huai C, Hu L, Yang S, Min T, Chen J, Chen H, Lu D. High expression of N-myc (and STAT) interactor predicts poor prognosis and promotes tumor growth in human glioblastoma. Oncotarget 2016; 6:4901-19. [PMID: 25669971 PMCID: PMC4467123 DOI: 10.18632/oncotarget.3208] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 12/25/2014] [Indexed: 12/20/2022] Open
Abstract
Glioma is the most malignant brain tumor and glioblastoma (GBM) is the most aggressive type. The involvement of N-myc (and STAT) interactor (NMI) in tumorigenesis was sporadically reported but far from elucidation. This study aims to investigate roles of NMI in human glioma. Three independent cohorts, the Chinese tissue microarray (TMA) cohort (N = 209), the Repository for Molecular Brain Neoplasia Data (Rembrandt) cohort (N = 371) and The Cancer Genome Atlas (TCGA) cohort (N = 528 or 396) were employed. Transcriptional or protein levels of NMI expression were significantly increased according to tumor grade in all three cohorts. High expression of NMI predicted significantly unfavorable clinical outcome for GBM patients, which was further determined as an independent prognostic factor. Additionally, expression and prognostic value of NMI were associated with molecular features of GBM including PTEN deletion and EGFR amplification in TCGA cohort. Furthermore, overexpression or depletion of NMI revealed its regulation on G1/S progression and cell proliferation (both in vitro and in vivo), and this effect was partially dependent on STAT1, which interacted with and was regulated by NMI. These data demonstrate that NMI may serve as a novel prognostic biomarker and a potential therapeutic target for glioblastoma.
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Affiliation(s)
- Delong Meng
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuanyuan Chen
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Dapeng Yun
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yingjie Zhao
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Jingkun Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Tao Xu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoying Li
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuqi Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Li Yuan
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Ruochuan Sun
- The Eighth Department of General Surgery and Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao Song
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Cong Huai
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Lingna Hu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Song Yang
- The Eighth Department of General Surgery and Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Taishan Min
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Juxiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hongyan Chen
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
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Otsuka Y, Satoh S, Naito J, Kyogaku M, Hashimoto H. Visualization of cancer-related chemical components in mouse pancreas tissue by tapping-mode scanning probe electrospray ionization mass spectrometry. JOURNAL OF MASS SPECTROMETRY : JMS 2015; 50:1157-1162. [PMID: 26456785 DOI: 10.1002/jms.3634] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/10/2015] [Accepted: 07/10/2015] [Indexed: 06/05/2023]
Abstract
Mass spectrometry imaging is an informative approach for the comprehensive analysis of multiple components inside biological specimens. We used novel tapping-mode scanning probe electrospray ionization mass spectrometry method to visualize cancer-related chemical components in the mouse pancreas tissue section at a sampling pitch of 100 µm. Positive ion mode measurements from m/z 100 to 1500 resulted in the visualization of multiple components that are tentatively assigned as polyamines, lipids and proteins. Their signal intensities inside the cancerous and the non-cancerous regions were found to be significantly different by the two-sample t-test.
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Affiliation(s)
- Yoichi Otsuka
- Frontier Research Center, Canon Inc., 30-2 Shimomaruko 3-chome, Ohta-ku, Tokyo, 146-8501, Japan
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1, Machikaneyama-cho, Toyonaka, Osaka, 560-0043, Japan
| | - Shuya Satoh
- Frontier Research Center, Canon Inc., 30-2 Shimomaruko 3-chome, Ohta-ku, Tokyo, 146-8501, Japan
| | - Junpei Naito
- Frontier Research Center, Canon Inc., 30-2 Shimomaruko 3-chome, Ohta-ku, Tokyo, 146-8501, Japan
| | - Masafumi Kyogaku
- Frontier Research Center, Canon Inc., 30-2 Shimomaruko 3-chome, Ohta-ku, Tokyo, 146-8501, Japan
| | - Hiroyuki Hashimoto
- Frontier Research Center, Canon Inc., 30-2 Shimomaruko 3-chome, Ohta-ku, Tokyo, 146-8501, Japan
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Wang T, Liang Y, Thakur A, Zhang S, Yang T, Chen T, Gao L, Chen M, Ren H. Diagnostic significance of S100A2 and S100A6 levels in sera of patients with non-small cell lung cancer. Tumour Biol 2015; 37:2299-304. [PMID: 26361956 DOI: 10.1007/s13277-015-4057-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/04/2015] [Indexed: 12/14/2022] Open
Abstract
Biochemical markers play a significant role in the diagnosis of lung cancer. Recent studies have demonstrated a link involving S100 Calcium Binding Proteins (S100A2, S100A6) and non-small cell lung cancer (NSCLC), but the expediency of their serum levels in NSCLC has not been established. In this study, we evaluate the potential of serum S100A2 and S100A6 levels as diagnostic markers for NSCLC. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of S100A2 and S100A6 in 141 NSCLC patients and 150 healthy subjects. Serum levels of the two proteins in patients with NSCLC were higher compared to healthy controls (P = 0.0002 for S100A2 and P < 0.0001 for S100A6). Moreover, the levels of S100A2 and S100A6 were higher in the sera of stage I/II NSCLC patients compared to healthy controls with P = 0.01 and <0.0001, respectively. Receiver operating characteristic (ROC) analysis showed that S100A2 could distinguish NSCLC patients from healthy controls (AUC = 0.646), and S100A6 could also identify NSCLC (AUC = 0.668). Meanwhile, these two proteins showed notable capabilities for distinguishing stage I/II NSCLC from healthy controls (AUC = 0.708 for S100A2 and AUC = 0.702 for S100A6). Our results indicate that serum levels of S100A2 and S100A6 are significantly elevated in early stage NSCLC and may have the potential for NSCLC biomarker. Further studies with large sample population would help validate our findings.
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Affiliation(s)
- Ting Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China.,Department of Respiratory Medicine, Xi'an No.4 Hospital, Xi'an, 710004, People's Republic of China
| | - Yiqian Liang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China
| | - Asmitananda Thakur
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China.,Department of Internal Medicine, Life Guard Hospital, Biratnagar, Nepal.,S.R. Laboratory and Diagnostic Center, Biratnagar, Nepal
| | - Shuo Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China
| | - Tian Yang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China
| | - Tianjun Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China
| | - Lei Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China
| | - Mingwei Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China.
| | - Hui Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, 277 Yanta West Street, Xi'an, 710061, People's Republic of China.
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Lyu X, Li H, Ma X, Li X, Gao Y, Ni D, Shen D, Gu L, Wang B, Zhang Y, Zhang X. High-level S100A6 promotes metastasis and predicts the outcome of T1-T2 stage in clear cell renal cell carcinoma. Cell Biochem Biophys 2015; 71:279-90. [PMID: 25120023 DOI: 10.1007/s12013-014-0196-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
S100A6 (calcyclin), functions in cell cycle progression and differentiation, has been reported to promote the tumorigenesis and malignancy of many types of cancers. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, lacking both promising prognostic markers and effective therapeutic targets. In our previous study, we have found the elevated S100A6 in the ccRCC tumor tissues, and the differentially expressed genes determined by microarray analysis were found to be strongly related to tumor metastasis after S100A6 knockdown and overexpression in the ccRCC cell line 786-O. The mRNA expression of S100A6 detected by RT-PCR in 6 cell lines and 174 tumor tissues, including 58 metastatic ccRCC and 116 clinicopathological features paired non-metastatic ccRCC (1:2), indicated S100A6 was elevated in the metastatic cells and tumor tissues. The protein expression was consistent with mRNA expression. The biological function of S100A6 in promoting metastasis was determined through overexpression and knockdown of S100A6 in the ccRCC cell lines 786-O, caki-1, and ACHN. In the scratch wound migration assay as well as migration and invasion assays, S100A6 knockdown significantly suppressed the migratory and invasive abilities of tumor cells, whereas overexpression enhanced the malignancy. Further research with the follow-up data of 129 ccRCC patients were analyzed by the Cox regression and survival analysis. The expression of S100A6 was up-regulated in metastatic ccRCC cells. In the metastatic tumor tissues, the expression of S100A6 was also higher than in the non-metastatic tissues. High S100A6 expression might be crucial to promote metastasis in ccRCC by enhancing the ability of tumor cells migration and invasion. In addition, the quantitative mRNA expression of S100A6 in the tumor tissues was an independent risk factor and might be used as a prognostic marker for the metastatic risk of the localized T1-T2 stage ccRCC.
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Affiliation(s)
- Xiangjun Lyu
- Department of Urology, State Key Laboratory of Kidney Diseases, Chinese People's Liberation Army General Hospital, Chinese PLA Medical School, Beijing, 100853, People's Republic of China
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SUN ERLIN, FAN XIAODONG, WANG LINING, LEI MINGDE, ZHOU XIAODONG, LIU CHUNYU, LU BINGXIN, NIAN XUEWU, SUN YAN, HAN RUIFA. Recombinant h IFN-α2b-BCG inhibits tumor growth in a mouse model of bladder cancer. Oncol Rep 2015; 34:183-94. [DOI: 10.3892/or.2015.3985] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 04/20/2015] [Indexed: 11/06/2022] Open
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Chen X, Liu X, Lang H, Zhang S, Luo Y, Zhang J. S100 calcium-binding protein A6 promotes epithelial-mesenchymal transition through β-catenin in pancreatic cancer cell line. PLoS One 2015; 10:e0121319. [PMID: 25799022 PMCID: PMC4370615 DOI: 10.1371/journal.pone.0121319] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/30/2015] [Indexed: 01/31/2023] Open
Abstract
The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. S100 calcium-binding protein A6 (S100A6) has been associated with PDAC; however, the effect of S100A6 on PDAC migration and invasion has not yet been explored. In this study, Panc-1 cells were transfected with a plasmid to induce overexpression of S100A6, and β-catenin was knocked down using a specific short hairpin RNA (shRNA). The wound-healing and Transwell assays demonstrated that S100A6 promoted PDAC cell migration and invasion. Furthermore, β-catenin shRNA inhibited the migration and invasion of PDAC cells. We confirmed that S100A6 induces PDAC cell migration and invasion via activation of β-catenin in vitro. Assessment of mRNA and protein levels revealed that S100A6 induces increased expression of β-catenin, N-cadherin and vimentin, and decreased expression of E-cadherin in PDAC cells. β-catenin shRNA also altered the expression of epithelial-mesenchymal transition (EMT)-related markers in PDAC cells. Specifically, expression of E-cadherin was increased, whereas expression of N-cadherin and vimentin was decreased. Finally, we demonstrated that S100A6 alters the expression of EMT-related markers via β-catenin activation. In conclusion, S100A6 induces EMT and promotes cell migration and invasion in a β-catenin-dependent manner. S100A6 may therefore represent a novel potential therapeutic target for the treatment of pancreatic cancer.
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Affiliation(s)
- Xue Chen
- Department of Gastroenterology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Haibo Lang
- Department of Gastroenterology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
| | - Shiqi Zhang
- Department of Gastroenterology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
| | - Yanlin Luo
- Department of neurobiology and Beijing institute for brain disorders, School of basic medical science, Capital Medical University, Beijing, China
| | - Jie Zhang
- Department of Gastroenterology, Beijing An Zhen Hospital, Capital Medical University, Beijing, China
- * E-mail:
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Mizuuchi Y, Aishima S, Ohuchida K, Shindo K, Fujino M, Hattori M, Miyazaki T, Mizumoto K, Tanaka M, Oda Y. Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial-mesenchymal transition. J Transl Med 2015; 95:193-206. [PMID: 25418581 DOI: 10.1038/labinvest.2014.138] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 08/28/2014] [Accepted: 09/22/2014] [Indexed: 12/24/2022] Open
Abstract
Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.
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Affiliation(s)
- Yusuke Mizuuchi
- 1] Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [2] Reserch Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Shinichi Aishima
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- 1] Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [2] Reserch Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Minoru Fujino
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masami Hattori
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuyuki Miyazaki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Masao Tanaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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A loss of FUS/TLS function leads to impaired cellular proliferation. Cell Death Dis 2014; 5:e1572. [PMID: 25501833 PMCID: PMC4649830 DOI: 10.1038/cddis.2014.508] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 09/12/2014] [Accepted: 10/21/2014] [Indexed: 12/13/2022]
Abstract
Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional RNA/DNA-binding protein that is pathologically associated with cancer and neurodegeneration. To gain insight into the vital functions of FUS and how a loss of FUS function impacts cellular homeostasis, FUS expression was reduced in different cellular models through RNA interference. Our results show that a loss of FUS expression severely impairs cellular proliferation and leads to an increase in phosphorylated histone H3, a marker of mitotic arrest. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with multiple processes, some of which influence cell proliferation including cell cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. FUS knockdown also correlated with increased expression of the closely related protein EWS (Ewing's sarcoma). We demonstrate that the maladaptive phenotype resulting from FUS knockdown is reversible and can be rescued by re-expression of FUS or partially rescued by the small-molecule rolipram. These results provide insight into the pathways and processes that are regulated by FUS, as well as the cellular consequences for a loss of FUS function.
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