|
1
|
Lyu X, Xu W, Zhou J, Chen X, Yi W, Chen L, Wang Z, Wang S, Wu B. Molecular changes of cellular senescence in dental pulp stem cells during in vitro culture: A potential role of PSG4. Tissue Cell 2025; 93:102758. [PMID: 39893742 DOI: 10.1016/j.tice.2025.102758] [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: 10/16/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/04/2025]
Abstract
Cellular senescence prevents the application of mesenchymal stem cells in tissue engineering and stem cell therapy. Effective regulation of senescence is the key to maintain the functional stability of mesenchymal stem cells and improve their clinical application. This study aims to explore the molecular mechanism changes in human dental pulp stem cells (hDPSCs) during replicative senescence, focusing on the potential role of pregnancy-specific glycoprotein (PSGs) family member PSG4 in modulating cellular senescence. RNA sequencing was performed on hDPSCs at different passages and with PSG4 overexpression to reveal changes in gene expression during the process. Gain- and loss-of-function studies suggested that PSG4 regulated cellular senescence. PSG4 expression levels were significantly elevated during cellular senescence and closely correlated with cell cycle regulation. This study provides new insights into the molecular mechanisms underlying of hDPSCs' replicative senescence. PSG4 acts as a pivotal regulator of replicative senescence in hDPSCs by impacting cell cycle process.
Collapse
Affiliation(s)
- Xiaolin Lyu
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China
| | - Wenan Xu
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China
| | - Jian Zhou
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of VIP Dental Service, School of Stomatology, Capital Medical University, Beijing, China; Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiaohang Chen
- Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China; Genetics Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, China
| | - Wenjing Yi
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China
| | - Leyi Chen
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China
| | - Ziting Wang
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China
| | - Songlin Wang
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
| | - Buling Wu
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, Guangdong, China; Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, Guangdong, China.
| |
Collapse
|
|
2
|
Bollig KJ, Senapati S, Takacs P, Robins JC, Haisenleder DJ, Beer LA, Speicher DW, Koelper NC, Barnhart KT. Evaluation of novel biomarkers for early pregnancy outcome prediction†. Biol Reprod 2024; 110:548-557. [PMID: 38011676 PMCID: PMC10941089 DOI: 10.1093/biolre/ioad162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/19/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023] Open
Abstract
OBJECTIVE To assess performance and discriminatory capacity of commercially available enzyme-linked immunosorbent assays of biomarkers for predicting first trimester pregnancy outcome in a multi-center cohort. DESIGN In a case-control study at three academic centers of women with pain and bleeding in early pregnancy, enzyme-linked immunosorbent assays of biomarkers were screened for assay performance. Performance was assessed via functional sensitivity, assay reportable range, recovery/linearity, and intra-assay precision (%Coefficient of Variation). Top candidates were analyzed for discriminatory capacity for viability and location among 210 women with tubal ectopic pregnancy, viable intrauterine pregnancy, or miscarriage. Assay discrimination was assessed by visual plots, area under the curve with 95% confidence intervals, and measures of central tendency with two-sample t-tests. RESULTS Of 25 biomarkers evaluated, 22 demonstrated good or acceptable assay performance. Transgelin-2, oviductal glycoprotein, and integrin-linked kinase were rejected due to poor performance. The best biomarkers for discrimination of pregnancy location were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 1, insulin-like growth factor binding protein 1, kisspeptin (KISS1), pregnancy-specific beta-1-glycoprotein 3, and beta parvin (PARVB). The best biomarkers for discrimination of pregnancy viability were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 3, EH domain-containing protein 3, KISS1, WAP four-disulfide core domain protein 2 (HE4), quiescin sulfhydryl oxidase 2, and pregnancy-specific beta-1-glycoprotein 1. CONCLUSION Performance of commercially available enzyme-linked immunosorbent assays was acceptable for a panel of novel biomarkers to predict early pregnancy outcome. Of these, six and seven candidates demonstrated good discriminatory capacity of pregnancy location and viability, respectively, when validated in a distinct external population. Four markers demonstrated good discrimination for both location and viability.
Collapse
Affiliation(s)
- Kassie J Bollig
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| | - Suneeta Senapati
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter Takacs
- Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Jared C Robins
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA
| | - Daniel J Haisenleder
- Department of Internal Medicine and the Center for Research in Reproduction, University of Virginia, Charlottesville, VA, USA
| | - Lynn A Beer
- Center for Systems & Computational Biology, The Wistar Institute, Philadelphia, PA, USA
| | - David W Speicher
- Center for Systems & Computational Biology, The Wistar Institute, Philadelphia, PA, USA
| | - Nathanael C Koelper
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| | - Kurt T Barnhart
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
3
|
Chowdhary S, Deka R, Panda K, Kumar R, Solomon AD, Das J, Kanoujiya S, Gupta AK, Sinha S, Ruokolainen J, Kesari KK, Gupta PK. Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities. Mol Pharm 2023; 20:3698-3740. [PMID: 37486263 PMCID: PMC10410670 DOI: 10.1021/acs.molpharmaceut.2c01080] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/25/2023]
Abstract
Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.
Collapse
Affiliation(s)
- Shivam Chowdhary
- Department
of Industrial Microbiology, Sam Higginbottom
University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh India
| | - Rahul Deka
- Department
of Bioengineering and Biotechnology, Birla
Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Kingshuk Panda
- Department
of Applied Microbiology, Vellore Institute
of Technology, Vellore 632014, Tamil Nadu, India
| | - Rohit Kumar
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Abhishikt David Solomon
- Department
of Molecular & Cellular Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India
| | - Jimli Das
- Centre
for
Biotechnology and Bioinformatics, Dibrugarh
University, Assam 786004, India
| | - Supriya Kanoujiya
- School
of
Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ashish Kumar Gupta
- Department
of Biophysics, All India Institute of Medical
Sciences, New Delhi 110029, India
| | - Somya Sinha
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
- Division
of Research and Development, Lovely Professional
University, Phagwara 144411, Punjab, India
| | - Piyush Kumar Gupta
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
- Faculty
of Health and Life Sciences, INTI International
University, Nilai 71800, Malaysia
| |
Collapse
|
|
4
|
Feng ML, Sun MJ, Xu BY, Liu MY, Zhang HJ, Wu C. Mechanism of ELL-associated factor 2 and vasohibin 1 regulating invasion, migration, and angiogenesis in colorectal cancer. World J Gastroenterol 2023; 29:3770-3792. [PMID: 37426316 PMCID: PMC10324531 DOI: 10.3748/wjg.v29.i24.3770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/08/2023] [Accepted: 05/12/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1 (VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer (CRC). Knockdown of VASH1 enhanced transforming growth factor-β1 (TGF-β1)/Smad3 pathway activity and type I/III collagen production. Our previous findings suggest that ELL-associated factor 2 (EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3 (STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.
AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.
METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.
RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was up-regulated in advanced CRC tissue compared to normal colorectal tissue. Kaplan-Meier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.
CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cell-derived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
Collapse
Affiliation(s)
- Ming-Liang Feng
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ming-Jun Sun
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bo-Yang Xu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Meng-Yuan Liu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hui-Jing Zhang
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Can Wu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| |
Collapse
|
|
5
|
Feng Z, Hom ME, Bearrood TE, Rosenthal ZC, Fernández D, Ondrus AE, Gu Y, McCormick AK, Tomaske MG, Marshall CR, Kline T, Chen CH, Mochly-Rosen D, Kuo CJ, Chen JK. Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1. Nat Chem Biol 2022; 18:1065-1075. [PMID: 35788181 PMCID: PMC9529790 DOI: 10.1038/s41589-022-01048-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 04/26/2022] [Indexed: 12/21/2022]
Abstract
Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.
Collapse
Affiliation(s)
- Zhiping Feng
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Marisa E Hom
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
- Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thomas E Bearrood
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Zachary C Rosenthal
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Daniel Fernández
- Macromolecular Structure Knowledge Center, Stanford University, Stanford, CA, USA
- Stanford ChEM-H, Stanford University, Stanford, CA, USA
| | - Alison E Ondrus
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Yuchao Gu
- Department of Medicine, Stanford University, Stanford, CA, USA
- Department of Biochemistry, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | | | | | - Cody R Marshall
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Toni Kline
- SPARK at Stanford, Stanford University, Stanford, CA, USA
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Calvin J Kuo
- Department of Medicine, Stanford University, Stanford, CA, USA
| | - James K Chen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
- Department of Developmental Biology, Stanford University, Stanford, CA, USA.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
| |
Collapse
|
|
6
|
Kandel M, MacDonald TM, Walker SP, Cluver C, Bergman L, Myers J, Hastie R, Keenan E, Hannan NJ, Cannon P, Nguyen TV, Pritchard N, Tong S, Kaitu'u-Lino TJ. PSG7 and 9 (Pregnancy-Specific β-1 Glycoproteins 7 and 9): Novel Biomarkers for Preeclampsia. J Am Heart Assoc 2022; 11:e024536. [PMID: 35322669 PMCID: PMC9075453 DOI: 10.1161/jaha.121.024536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Preeclampsia is pregnancy specific, involving significant maternal endothelial dysfunction. Predictive biomarkers are lacking. We evaluated the biomarker potential, expression, and function of PSG7 (pregnancy‐specific β‐1 glycoprotein 7) and PSG9 (pregnancy‐specific β‐1 glycoprotein 9) in preeclampsia. Methods and Results At 36 weeks gestation preceding term preeclampsia diagnosis, PSG7 and PSG9 (in Australian cohorts of n=918 and n=979, respectively) were significantly increased before the onset of term preeclampsia (PSG7, P=0.013; PSG9, P=0.0011). In samples collected at 28 to 32 weeks from those with preexisting cardiovascular disease and at high risk of preeclampsia (Manchester Antenatal Vascular Service, UK cohort, n=235), both PSG7 and PSG9 were also significantly increased preceding preeclampsia onset (PSG7, P<0.0001; PSG9, P=0.0003) relative to controls. These changes were validated in the plasma and placentas of patients with established preeclampsia who delivered at <34 weeks gestation (PSG7, P=0.0008; PSG9, P<0.0001). To examine whether PSG7 and PSG9 are associated with increasing disease severity, we measured them in a cohort from South Africa stratified for this outcome, the PROVE (Preeclampsia Obstetric Adverse Events) cohort (n=72). PSG7 (P=0.0027) and PSG9 (P=0.0028) were elevated among patients who were preeclamptic with severe features (PROVE cohort), but not significantly changed in those without severe features or with eclampsia. In syncytialized first trimester cytotrophoblast stem cells, exposure to TNFα (tumor necrosis factor α) or IL‐6 (interleukin 6) significantly increased the expression and secretion of PSG7 and PSG9. In contrast, when we treated primary endothelial cells with recombinant PSG7 and PSG9, we only observed modest changes in Flt‐1 (FMS‐like tyrosine kinase‐1) expression and Plgf (placental growth factor) expression, and no other effects on proangiogenic/antiangiogenic or endothelial dysfunction markers were observed. Conclusions Circulating PSG7 and PSG9 are increased before preeclampsia onset and among those with established disease with their production and release potentially driven by placental inflammation.
Collapse
Affiliation(s)
- Manju Kandel
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia
| | - Teresa M MacDonald
- Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| | - Susan P Walker
- Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| | - Catherine Cluver
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia.,Department of Obstetrics and Gynecology Stellenbosch University Cape Town South Africa
| | - Lina Bergman
- Department of Obstetrics and Gynecology Stellenbosch University Cape Town South Africa.,Department of Women's and Children's Health Uppsala University Uppsala Sweden.,Department of Obstetrics and Gynecology Institute of clinical sciencesSahlgrenska AcademyUniversity of Gothenburg Gothenburg Sweden
| | - Jenny Myers
- Division of Developmental Biology and Medicine University of ManchesterManchester Academic Health Science CentreSt Mary's Hospital Manchester United Kingdom
| | - Roxanne Hastie
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia
| | - Emerson Keenan
- Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia
| | - Natalie J Hannan
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| | - Ping Cannon
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia
| | - Tuong-Vi Nguyen
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia
| | - Natasha Pritchard
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| | - Stephen Tong
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| | - Tu'uhevaha J Kaitu'u-Lino
- Translational Obstetrics Group Mercy Hospital for Women Heidelberg Victoria Australia.,Department of Obstetrics and Gynaecology Mercy Hospital for Women University of Melbourne Heidelberg Victoria Australia.,Mercy PerinatalMercy Hospital for Women Victoria Australia
| |
Collapse
|
|
7
|
McNulty SN, Schwetye KE, Ferguson C, Storer CE, Ansstas G, Kim AH, Gutmann DH, Rubin JB, Head RD, Dahiya S. BRAF mutations may identify a clinically distinct subset of glioblastoma. Sci Rep 2021; 11:19999. [PMID: 34625582 PMCID: PMC8501013 DOI: 10.1038/s41598-021-99278-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/09/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM.
Collapse
Affiliation(s)
- Samantha N McNulty
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA
| | - Katherine E Schwetye
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA
| | - Cole Ferguson
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA
| | - Chad E Storer
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA
| | - George Ansstas
- Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Albert H Kim
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.,Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
| | - Joshua B Rubin
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.,Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.,Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
| | - Richard D Head
- Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA.
| | - Sonika Dahiya
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, 63110, USA. .,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
| |
Collapse
|
|
8
|
Whole exome sequencing and establishment of an organoid culture of the carcinoma showing thymus-like differentiation (CASTLE) of the parotid gland. Virchows Arch 2021; 478:1149-1159. [PMID: 33415446 DOI: 10.1007/s00428-020-02981-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/04/2020] [Accepted: 11/25/2020] [Indexed: 10/22/2022]
Abstract
Carcinoma showing thymus-like differentiation (CASTLE) is a rare tumor, especially in the parotid gland. We encountered a CASTLE of the parotid gland and analyzed its clinicopathological features, as well as the genotype using whole exome sequencing (WES). Moreover, we successfully established an organoid culture cell line from the primary tumor tissue. The patient was a 23-year-old woman who underwent superficial parotidectomy with peripheral neck dissection, followed by radiotherapy. Pathologically, the resected specimen showed atypical epithelioid nests and trabeculae with squamous differentiation, separated by thick fibrous septa, accompanied by dense lymphocytes and plasma cell infiltration. Immunohistochemistry revealed that the tumor cells were positive for AE1/AE3, p40, p63, p16, CK5/6, and CD5, and the background lymphocytes were positive for CD5 and CD99. Based on these findings, the tumor was diagnosed as CASTLE. WES uncovered five nonsynonymous and splicing somatic mutations, namely, FREM2 p.Val861Phe, CLK3 p.Phe376Leu, DLGAP1 p.Lys294Asn, NOX1 p.Val165Met, and PSG9 c.430 + 4A > T. Organoid culture cells preserved the histopathological characteristics of the epithelioid component of CASTLE and harbored all five somatic mutations detected in the primary tumor. In conclusion, for the first time to the best of our knowledge, we successfully analyzed a comprehensive genotype and established an organoid culture cell line of a parotid gland CASTLE, which should serve for analyzing the nature of this rare tumor.
Collapse
|
|
9
|
Liu Y, Zhang S, Yu T, Zhang F, Yang F, Huang Y, Ma D, Liu G, Shao Z, Li D. Pregnancy-specific glycoprotein 9 acts as both a transcriptional target and a regulator of the canonical TGF-β/Smad signaling to drive breast cancer progression. Clin Transl Med 2020; 10:e245. [PMID: 33377651 PMCID: PMC7733318 DOI: 10.1002/ctm2.245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/16/2020] [Accepted: 11/27/2020] [Indexed: 12/24/2022] Open
Abstract
Pregnancy-specific glycoprotein 9 (PSG9) is a placental glycoprotein essential for the maintenance of normal gestation in mammals. Bioinformatics analysis of multiple publicly available datasets revealed aberrant PSG9 expression in breast tumors, but its functional and mechanistic role in breast cancer remains unexplored. Here, we report that PSG9 expression levels were elevated in tumor tissues and plasma specimens from breast cancer patients, and were associated with poor prognosis. Gain- or loss-of-function studies demonstrated that PSG9 promoted breast cancer cell proliferation, migration, and invasionin vitro, and enhanced tumor growth and lung colonization in vivo. Mechanistically, transforming growth factor-β1 (TGF-β1) transcriptionally activated PSG9 expression through enhancing the enrichment of Smad3 and Smad4 onto PSG9 promoter regions containing two putative Smad-binding elements (SBEs). Mutation of both SBEs in the PSG9 promoter, or knockdown of TGF-β receptor 1 (TGFBR1), TGFBR2, Smad3, or Smad4 impaired the ability of TGF-β1 to induce PSG9 expression. Consequently, PSG9 contributed to TGF-β1-induced epithelial-mesenchymal transition (EMT) and breast cancer cell migration and invasion. Moreover, PSG9 enhanced the stability of Smad2, Smad3, and Smad4 proteins by blocking their proteasomal degradation, and regulated the expression of TGF-β1 target genes involved in EMT and breast cancer progression, thus further amplifying the canonical TGF-β/Smad signaling in breast cancer cells. Collectively, these findings establish PSG9 as a novel player in breast cancer progressionvia hijacking the canonical TGF-β/Smad signaling, and identify PSG9 as a potential plasma biomarker for the early detection of breast cancer.
Collapse
Affiliation(s)
- Ying‐Ying Liu
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Sa Zhang
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Tian‐Jian Yu
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Fang‐Lin Zhang
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
| | - Fan Yang
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Yan‐Ni Huang
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Ding Ma
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Guang‐Yu Liu
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
| | - Zhi‐Ming Shao
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Key Laboratory of Breast CancerShanghai Medical College, Fudan UniversityShanghaiChina
| | - Da‐Qiang Li
- Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical EpigeneticsInternational Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
- Cancer InstituteShanghai Medical College, Fudan UniversityShanghaiChina
- Department of OncologyShanghai Medical College, Fudan UniversityShanghaiChina
- Department of Breast SurgeryShanghai Medical College, Fudan UniversityShanghaiChina
- Shanghai Key Laboratory of Breast CancerShanghai Medical College, Fudan UniversityShanghaiChina
| |
Collapse
|
|
10
|
Expression of Pregnancy Specific β-1 Glycoprotein 1 in Cervical Cancer Cells. Arch Med Res 2020; 51:504-514. [PMID: 32546445 DOI: 10.1016/j.arcmed.2020.05.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/25/2020] [Accepted: 05/07/2020] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cervical Cancer (CC) is a worldwide public health concern associated with genetic alterations, among these the gain of the 19q chromosome harboring the Pregnancy Specific Glycoproteins (PSG) gene family. These proteins play a critical role in pregnancy, with participation in immunotolerance, angiogenesis, and invasion processes, which are also observed in carcinogenesis. The aim of this study was to determine the molecular alterations of PSG1 and its relationship with CC. METHODS PSG1 Copy Number Variation (CNV) was evaluated in 31 CC and eight normal cervical tissues by qPCR. PSG1 expression was correlated with HPV detection and IL-10 and TGF-β expression in CC samples. Finally, PSG1 protein expression was evaluated by immunofluorescence in CC cell lines, by immunohistochemistry in a tissue microarray, and by immunoblotting in the sera of women with normal cervix, pre-invasive lesions, and CC. RESULTS PSG1 showed a gain of 25.6% in CNV and gene expression in CC. There was a lack of PSG1 expression in normal cervical epithelium and positive immunostaining in 57% of CC tissues, while all CC cell lines expressed PSG1. Finally, PSG1 was immunodetected in 90% of pre-invasive lesions and in all CC serum samples, but not in healthy women. PSG1 expression correlates with the expression of IL-10 and TGF-β in CC tissues, but not with the presence of HPV. CONCLUSION These data show evidence of the differential expression of PSG1 in CC that could explain its participation in tumor-biology and immunotolerance mechanisms. Further, its immunodetection could provide early detection of this cancer.
Collapse
|
|
11
|
Li MY, Fan H, Hu DS. Angiogenesis-promoting factors in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2020; 28:435-442. [DOI: 10.11569/wcjd.v28.i11.435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the common malignant tumors, accounting for about 10% and 9.4% of malignancies in males and females, respectively. The number of patients who die from CRC reaches 700000 each year. In addition, there are about 1.4 million new patients every year. Angiogenesis is involved in a variety of physiological and pathological processes and is an important pathological marker for many diseases such as tumor, ischemia, atherosclerosis, inflammation, wound healing, and tissue regeneration. Angiogenesis plays a crucial role in the occurrence, development, and metastasis of CRC. In this review, we summarize our current knowledge of tumor-associated angiogenesis, the factors that promote angiogenesis in CRC, and future directions in this field, with an aim to provide a theoretical basis for better understanding the role of angiogenesis in the pathogenesis of CRC.
Collapse
Affiliation(s)
- Ming-Yue Li
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Heng Fan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - De-Sheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| |
Collapse
|
|
12
|
Bahia W, Soltani I, Abidi A, Haddad A, Ferchichi S, Menif S, Almawi WY. Identification of genes and miRNA associated with idiopathic recurrent pregnancy loss: an exploratory data mining study. BMC Med Genomics 2020; 13:75. [PMID: 32487076 PMCID: PMC7268288 DOI: 10.1186/s12920-020-00730-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 05/12/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Recurrent pregnancy loss (RPL) is a significant adverse pregnancy complication, with an incompletely understood pathology. While many entities were proposed to elucidate the pathogenic basis of RPL, only few were significant enough to warrant investigation in all affected couples.. The aim of this study was to provide novel insights into the biological characteristics and related pathways of differentially expressed miRNA (DEMs) and genes (DEGs), in RPL, and construct a molecular miRNAs-mRNAs network. METHODS miRNAs and gene expression data were collected, and a number of DEMs and (DEGs) were obtained, and regulatory co-expression network were constructed. Function and enrichment analyses of DEMs were conducted using DIANA-miRPath. DEGs were screened, and were used in generation of protein-protein interaction (PPI) network, using STRING online database. Modularity analysis, and pathway identification operations were used in identifying graph clusters and associated pathways. DEGs were also used for further gene ontology (GO) analysis, followed by analysis of KEGG pathway. RESULTS A total of 34 DEMs were identified, and were found to be highly enriched in TGF-β signaling pathway, Fatty acid metabolism and TNF signaling pathway. Hub miRNAs were selected and were found to be involved in several functional pathways including progesterone-mediated oocyte maturation and Thyroid hormone signaling pathway. Five dysregulated feedback loops involving miRNA and TFs were identified and characterized. Most notably, PPI network analysis identified hub-bottleneck protein panel. These appear to offer potential candidate biomarker pattern for RPL diagnosis and treatment. CONCLUSIONS The present study provides novel insights into the molecular mechanisms underlying RPL.
Collapse
Affiliation(s)
- Wael Bahia
- Research Unit of Clinical and Molecular Biology, Department of Biochemistry, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Faculty of Science of Bizerte, University of Carthage, Bizerte, Tunisia
| | - Ismael Soltani
- Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia
| | - Anouar Abidi
- Laboratory of Physiology, Faculty of Medicine of Tunis, la Rabta, 1007, Tunis, Tunisia
| | - Anis Haddad
- Department of Obstetrics and Gynecology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Salima Ferchichi
- Research Unit of Clinical and Molecular Biology, Department of Biochemistry, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Samia Menif
- Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia
| | - Wassim Y Almawi
- Faculty of Sciences, El Manar University, Tunis, Tunisia.
- College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates.
| |
Collapse
|
|
13
|
Yang Z, Chen Y, Wu D, Min Z, Quan Y. Analysis of risk factors for colon cancer progression. Onco Targets Ther 2019; 12:3991-4000. [PMID: 31190895 PMCID: PMC6535430 DOI: 10.2147/ott.s207390] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 04/24/2019] [Indexed: 12/13/2022] Open
Abstract
Purpose: This study aimed to find risk factors for colon cancer progression with bioinformatics methods, and validated by clinical patients. Methods: Differentially expressed genes (DEGs) between colon cancer tissues and normal colon tissues were extracted from The Cancer Genome Atlas (TCGA) database using R software, amounted to 8,051. DEGs between pathologic stage I+II and stage III+IV amounted to 373, and were compared with DEGs of cancer/normal analyzed above to get the intersection of both. Ninety-six intersected DEGs were identified and defined as progressive DEGs of colon cancer. Then these 96 progressive DEGs were studied by Gene ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis using the DAVID database and visualizing by R software. A protein–protein interaction (PPI) network and functional modules were established using the STRING database. Further, an overall survival (OS) curve was drawn via the GEPIA website based on the CGA database and six progressive DEGs were found to be involved with OS of colon cancer patients. The Linkedomics website was used for detailed analysis of specific subsets of TNM. Results: Pregnancy specific glycoprotein (PSG), vitamin digestion, and absorption were confirmed to promote the progression of colon cancer. Furthermore, NTF4 was found to be associated with both OS and each subset of TNM; therefore, defined as a key risk factor for colon cancer progression. Further analysis of NTF4 expression using clinical data showed it acted as a key risk factor and diagnosis marker for colon cancer progression. Conclusion: NTF4 is a risk factor contributing to colon cancer progression and associated with overall survival.
Collapse
Affiliation(s)
- Zhou Yang
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| | - Yusheng Chen
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| | - Dejun Wu
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| | - Zhijun Min
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| | - Yingjun Quan
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China
| |
Collapse
|
|
14
|
Yang L, Liu Z, Wen T. Multiplex fluorescent immunohistochemistry quantitatively analyses microvascular density (MVD) and the roles of TGF-β signalling in orchestrating angiogenesis in colorectal cancer. Transl Cancer Res 2019; 8:429-438. [PMID: 35116775 PMCID: PMC8797362 DOI: 10.21037/tcr.2019.02.09] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 12/07/2018] [Indexed: 12/28/2022]
Abstract
Background Advances in multiplex fluorescent immunohistochemistry (mfIHC) techniques and digital pathology platforms allow the quantification of multiple proteins in the same tissue section and produce continuous data. Previously, we used mfIHC to establish the expressed profiles of proteins involved in TGF-β signalling in colorectal cancer (CRC). Methods We used mfIHC to show microvascular density (MVD) by staining CD31 in the tissues from CRC patients. We further investigated the relationship between MVD and TGF-β signalling. Results We found that the levels of MVD were significantly higher in cancer tissues than in paired normal tissues. Prognostic analysis revealed that the survival time for CRC patients with high levels of MVD was significantly shorter than that for those with low levels of MVD. Systematic analysis of the levels of MVD and TGF-β signalling proteins revealed that TGF-β signalling showed contradictory roles in sustained tumour angiogenesis. In CRC cells, the expression of VEGFA was increased by low concentrations of TGFB1 but decreased by high concentrations of TGFB1. Vessel-forming assays demonstrated that low-dose TGFB1 stimulated but high-dose TGFB1 inhibited HUVECs to form vessel tubes. Conclusions Our analysis based on mfIHC staining in CRC tissues supports the concept that TGF-β signalling either promotes or inhibits tumour angiogenesis.
Collapse
Affiliation(s)
- Lei Yang
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zheng Liu
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tao Wen
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| |
Collapse
|
|
15
|
Yang L, Liu Z, Tan J, Dong H, Zhang X. Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer. Cancer Biol Ther 2017; 19:105-112. [PMID: 29219668 DOI: 10.1080/15384047.2017.1395116] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections. Quantitative analysis was carried out by a scoring system by InForm software. It revealed that TGF-β signaling was hyper active. The levels of TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD1/5/9 and p-SMAD2/3 were significantly increased in cancer tissues when compared their levels in normal tissues. Furthermore, the levels of eight proteins in stroma were significantly lower than the levels that in cancer tissues. Clinical pathological relevant analysis exhibited that TGF-β signaling inclined to suppress the progression of tumor. SMAD1/5/9, TGFBRII, SMAD2/3 were confirmed as significant predictors for overall survival. In conclusion, we established a method based on multispectral imaging to extensively explore the clinical relevant of TGF-β signaling proteins. These results provided an opportunity to consider the novel application for proteins involving TGF-β signaling that used as diagnostic or prognostic biomarkers to conduct tumor therapy.
Collapse
Affiliation(s)
- Lei Yang
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Zheng Liu
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Jinjing Tan
- b Department of Cellular and Molecular Biology, Beijing Chest Hospital , Capital Medical University , Beijing , P.R. China
| | - Hongwei Dong
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Xiaojing Zhang
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| |
Collapse
|
|
16
|
Ma Y, Xue Y, Liu X, Qu C, Cai H, Wang P, Li Z, Li Z, Liu Y. SNHG15 affects the growth of glioma microvascular endothelial cells by negatively regulating miR-153. Oncol Rep 2017; 38:3265-3277. [DOI: 10.3892/or.2017.5985] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/11/2017] [Indexed: 11/06/2022] Open
|
|
17
|
Liu J, Liu F, Li X, Song X, Zhou L, Jie J. Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing. Tumour Biol 2017; 39:1010428317714899. [PMID: 28714374 DOI: 10.1177/1010428317714899] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA-target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR-548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA-sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may make a contribution for developing new diagnostic and therapeutic strategies for early-stage colon adenocarcinoma.
Collapse
Affiliation(s)
- Jixi Liu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Fang Liu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoou Li
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Xin Song
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Lei Zhou
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Jianzheng Jie
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| |
Collapse
|