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Batan D, Tseropoulos G, Kirkpatrick BE, Bishop C, Bera K, Khang A, Weiser-Evans M, Anseth KS. PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells Based on Subcellular Localization. Adv Biol (Weinh) 2025:e2400540. [PMID: 40229965 DOI: 10.1002/adbi.202400540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 03/03/2025] [Indexed: 04/16/2025]
Abstract
Aortic valve stenosis (AVS) is characterized by altered mechanics of the valve leaflets, which disrupts blood flow through the aorta and can cause left ventricle hypotrophy. These changes in the valve tissue result in the activation of resident valvular interstitial cells (VICs) into myofibroblasts, which have increased levels of αSMA in their stress fibers. The persistence of VIC myofibroblast activation is a hallmark of AVS. In recent years, the tumor suppressor gene phosphatase and tensin homolog (PTEN) has emerged as an important player in the regulation of fibrosis in various tissues (e.g., lung, skin), which motivated to investigate PTEN as a potential protective factor against matrix-induced myofibroblast activation in VICs. In aortic valve samples from humans, high levels of PTEN are found in healthy tissue and low levels of PTEN in diseased tissue. Then, using pharmacological inducers to treat VIC cultures, it is observed that PTEN overexpression prevented stiffness-induced myofibroblast activation, whereas genetic and pharmacological inhibition of PTEN further activated myofibroblasts. The increased nuclear PTEN localization is also observed in VICs cultured on stiff matrices, and nuclear PTEN also correlated with smaller nuclei, altered expression of histones, and a quiescent fibroblast phenotype. Together, these results suggest that PTEN not only suppresses VIC activation, but functions to promote quiescence, and can serve as a potential pharmacological target for the treatment of AVS.
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Affiliation(s)
- Dilara Batan
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
| | - Georgios Tseropoulos
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
| | - Bruce E Kirkpatrick
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
- Medical Scientist Training Program, School of Medicine, University of Colorado, Aurora, Colorado, 80045, USA
| | - Carrie Bishop
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
| | - Kaustav Bera
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
| | - Alex Khang
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
| | - Mary Weiser-Evans
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, C281, Research Complex 2, Room 7101, Aurora, Colorado, 80045, USA
- Center for Fibrosis Research and Translation, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, 80045, USA
- Department of Medicine, Cardiovascular Pulmonary Research Program, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, 80045, USA
| | - Kristi S Anseth
- Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, 80303, USA
- The BioFrontiers Institute, University of Colorado, Boulder, Colorado, 80303, USA
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Tucker DR, Lee AF, Orr NL, Alotaibi FT, Noga HL, Williams C, Allaire C, Bedaiwy MA, Huntsman DG, Köbel M, Anglesio MS, Yong PJ. Somatic PTEN and ARID1A loss and endometriosis disease burden: a longitudinal study. Hum Reprod 2025; 40:296-309. [PMID: 39701665 PMCID: PMC11788214 DOI: 10.1093/humrep/deae269] [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: 07/16/2024] [Revised: 10/07/2024] [Indexed: 12/21/2024] Open
Abstract
STUDY QUESTION Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes? SUMMARY ANSWER Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity. WHAT IS KNOWN ALREADY Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear. STUDY DESIGN, SIZE, DURATION This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013-2017), with a follow-up period of 5-9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS PTEN and ARID1A loss was assessed using established immunohistochemistry (IHC) methods as proxies for somatic loss by two independent raters. PTEN and ARID1A status for each participant was defined as loss (loss in at least one sample for a participant) or retained (no loss in all samples for a participant). Primary analyses examined associations between PTEN and ARID1A loss and disease burden based on anatomic subtype (superficial peritoneal endometriosis (SUP), deep endometriosis (DE), ovarian endometrioma (OMA)) and rASRM stage (I-IV). Secondary analyses explored associations of PTEN and ARID1A loss with demographics, surgical difficulty, and pain scores (baseline and follow-up). Additionally, using previously published data on KRAS codon 12 mutations for this cohort, we investigated associations between variables in the primary and secondary analyses and acquiring two or more somatic events (PTEN loss, ARID1A loss, or KRAS mutation) in this cohort. The risk of reoperation over the 5-9 years was also examined. MAIN RESULTS AND THE ROLE OF CHANCE PTEN loss (68.3%; 86 participants) exceeded ARID1A loss (24.6%; 31 participants). Inter-rater reliability was substantial for PTEN (k = 0.69; 95% CI: 0.62-0.77) and ARID1A (k = 0.64; 95% CI: 0.51-0.77). PTEN loss was significantly associated with more severe anatomic subtypes (P < 0.001; participants with SUP only = 46.4%; participants with DE only or OMA only = 72.7%; participants with mixed subtypes = 85.1%), and higher stages (P = 0.024; Stage I = 47.8%; Stage II = 73.7%; Stage III = 80.8%; Stage IV = 81.0%). Results were similar for ARID1A loss, albeit with smaller sample size limiting power. PTEN loss was further associated with non-White ethnicities (P = 0.017) and greater surgical difficulty (more frequent need for ureterolysis) (P = 0.02). There were no differences in pain scores (baseline or follow-up) based on PTEN or ARID1A status. Reoperation was uncommon (13.5% of the cohort), and patterns in reoperation rates based on the presence of somatic alterations did not reach statistical significance. LIMITATIONS, REASONS FOR CAUTION Sequencing was not performed to determine the type of PTEN and ARID1A somatic mutations resulting in loss of expression. WIDER IMPLICATIONS OF THE FINDINGS These results demonstrate a link between PTEN somatic loss and greater endometriosis disease burden. These findings underscore the potential relevance of PTEN loss and other somatic driver mutations in a future molecular classification of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Canadian Institutes of Health Research (CIHR) project grant (MOP-142273 and PJT-156084). P.J.Y. was supported by a Health Professional Investigator award from Michael Smith Health Research BC, Canada, and a Canada Research Chair (Tier 2) in Endometriosis and Pelvic Pain. M.S.A. was supported by a Michael Smith Health Research BC Scholar award, and CIHR project grants (369990, 462997, and 456767). The sponsors did not play any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. C.A. declares receiving payment from Pfizer for a symposium; being on advisory boards for AbbVie and Pfizer; being President and past President of the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE), co-lead of EndoAct Canada, and a board member of IPPS. M.A.B. has received consulting fees from AbbVie and Pfizer and grants from Ferring outside the scope of this work. D.G.H. is the founder of Canxeia Health but has no current affiliation. M.K. has received consulting fees from Helix Biopharma outside the scope of this work. M.S.A. received reimbursement of travel and registration fees to attend and present at the 2023 and 2024 annual meetings for the Society for Reproductive Investigation (SRI). P.J.Y. declares receiving: payment for a lecture from the International Society for the Study of Women's Sexual Health (ISSWSH); honoraria from the CIHR; support to attend meetings from CanSAGE, ISSWSH, the International Pelvic Pain Society, the World Endometriosis Society (WES), the Society for the Study of Reproduction, and the Vulvodynia Summit; and discounted devices from Ohnut Wearable for a clinical trial. P.J.Y. is a data safety monitoring board member of a clinical trial funded by CIHR; and a strategic advisory board member for the Women's Health Research Institute. P.J.Y. served as a board of directors member for CanSAGE and ISSWSH; was a junior board of directors member for WES; is a current board of directors member for WES; and was a committee chair for the Society of Obstetricians and Gynaecologists of Canada. A subset of these results was presented by the first author at the 71st Society for Reproductive Investigation Annual Scientific Meeting on 15 March 2024. Other authors have nothing to declare. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Dwayne R Tucker
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Anna F Lee
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Natasha L Orr
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Fahad T Alotaibi
- Department of Physiology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Heather L Noga
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Christina Williams
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Catherine Allaire
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Mohamed A Bedaiwy
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - David G Huntsman
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
| | - Michael S Anglesio
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
| | - Paul J Yong
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- BC Women’s Hospital and Health Centre, Vancouver, BC, Canada
- Women’s Health Research Institute, Vancouver, BC, Canada
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Chong ZX. Roles of miRNAs in regulating ovarian cancer stemness. Biochim Biophys Acta Rev Cancer 2024; 1879:189191. [PMID: 39353485 DOI: 10.1016/j.bbcan.2024.189191] [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: 07/12/2024] [Revised: 09/02/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Ovarian cancer is one of the gynaecology malignancies with the highest mortality rate. Ovarian cancer stem cell (CSC) is a subpopulation of ovarian cancer cells with increased self-renewability, aggression, metastatic potentials, and resistance to conventional anti-cancer therapy. The emergence of ovarian CSC is a critical factor that promotes treatment resistance and frequent relapse among ovarian cancer patients, leading to poor clinical outcomes. MicroRNA (miRNA) is a short, non-protein-coding RNA that regulates ovarian CSC development. Although multiple original research articles have discussed the CSC-regulatory roles of different miRNAs in ovarian cancer, there is a deficiency of a review article that can summarize the findings from different research papers. To narrow the gap in the literature, this review aimed to provide an up-to-date summary of the CSC-regulatory roles of various miRNAs in modulating ovarian cancer cell stemness. This review will begin by giving an overview of ovarian CSC and the pathways responsible for driving its appearance. Next, the CSC-regulatory roles of miRNAs in controlling ovarian CSC development will be discussed. Overall, more than 60 miRNAs have been reported to play CSC-regulatory roles in the development and progression of ovarian cancer. By targeting various downstream targets, these miRNAs can control the signaling activities of PI3K/AKT, EGFR/ERK, WNT/ß-catenin, NF-kß, Notch, Hippo/YAP, EMT, and DNA repair pathways. Hence, these CSC-modulatory miRNAs have the potential to be used as prognostic biomarkers in predicting the clinical outcomes of ovarian cancer patients. Targeting CSC-promoting miRNAs or increasing the expressions of CSC-repressing miRNAs can help slow ovarian cancer progression. However, more in-depth functional and clinical trials must be carried out to evaluate the suitability, safety, sensitivity, and specificity of these CSC-regulating miRNAs as prognostic biomarkers or therapeutic targets.
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Affiliation(s)
- Zhi-Xiong Chong
- Faculty of Science and Engineering, University of Nottingham Malaysia, Jalan Broga, 43500 Semenyih, Selangor, Malaysia; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599; Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
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Chen M, Wang T, Tian D, Hai C, Qiu Z. Induction, growth, drug resistance, and metastasis: A comprehensive summary of the relationship between STAT3 and gastric cancer. Heliyon 2024; 10:e37263. [PMID: 39309860 PMCID: PMC11416542 DOI: 10.1016/j.heliyon.2024.e37263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
Gastric cancer is a prevalent and highly lethal malignancy that poses substantial challenges to healthcare systems globally. Owing to its often asymptomatic nature in early stages, diagnosis frequently occurs at advanced stages when surgical intervention is no longer a viable option, forcing most patients to rely on nonsurgical treatments such as chemotherapy, targeted therapies, and emerging immunotherapies. Unfortunately, the therapeutic response rates for these treatments are suboptimal, and even among responders, the eventual development of drug resistance remains a significant clinical hurdle. Signal transducer and activator of transcription 3 (STAT3) is a widely expressed cellular protein that plays crucial roles in regulating cellular processes such as growth, metabolism, and immune function. Aberrant activation of the STAT3 pathway has been implicated in the initiation, progression, and therapeutic resistance of several cancers, with gastric cancer being particularly affected. Dysregulated STAT3 signaling not only drives tumorigenesis but also facilitates the development of resistance to chemotherapy and targeted therapies, as well as promotes metastatic dissemination. In this study, we explored the critical role of the STAT3 signaling cascade in the pathogenesis of gastric cancer, its contribution to drug resistance, and its involvement in the metastatic process. Furthermore, we assess recent advances in the development of STAT3 inhibitors and their potential application as therapeutic agents in the treatment of gastric cancer. This work provides a comprehensive overview of the current understanding of STAT3 in gastric cancer and offers a foundation for future research aimed at improving therapeutic outcomes in this challenging disease.
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Affiliation(s)
- Muyang Chen
- School of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Tongshan Wang
- Gastric Cancer Center, Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dianzhe Tian
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chaorui Hai
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Zixuan Qiu
- School of Public Health, Xiangya School of Medicine, Central South University, Changsha, China
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Cook SR, Hugen S, Hayward JJ, Famula TR, Belanger JM, McNiel E, Fieten H, Oberbauer AM, Leegwater PA, Ostrander EA, Mandigers PJ, Evans JM. Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.14.604426. [PMID: 39372775 PMCID: PMC11451740 DOI: 10.1101/2024.08.14.604426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.
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Affiliation(s)
- Shawna R. Cook
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Sanne Hugen
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jessica J. Hayward
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Thomas R. Famula
- Department of Animal Science, University of California, Davis, CA, USA
| | | | - Elizabeth McNiel
- Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA
| | - Hille Fieten
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | | | - Peter A.J. Leegwater
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Elaine A. Ostrander
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Center, National Institutes of Health, Bethesda, MD, USA
| | - Paul J.J. Mandigers
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jacquelyn M. Evans
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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Miratashi Yazdi SA, Hoseini F, Eftekhar Javadi A, Nazar E. Evaluation of phosphatase and tensin homologue (PTEN) expression in gastric cancer and its relationship with histopathological findings. REVISTA ESPANOLA DE PATOLOGIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ANATOMIA PATOLOGICA Y DE LA SOCIEDAD ESPANOLA DE CITOLOGIA 2024; 57:3-8. [PMID: 38246708 DOI: 10.1016/j.patol.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 11/15/2023] [Accepted: 11/23/2023] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Phosphatase and tensin homologue (PTEN) is an important tumour suppressor in multi-step tumorigenesis. To establish the role of PTEN in gastric cancer progression, we examined the PTEN expression degree in gastric cancer tissues. We also explained the connection between PTEN expression and histopathological findings. MATERIALS AND METHODS Our study was cross-sectional and made up of 50 patients with known gastric cancer. Immunohistochemical staining for PTEN was done on gastric cancer tissues. Tumour behaviour was estimated by histopathological assessments. RESULTS Twenty-seven (54%) of the 50 patients had PTEN staining. The evaluation of the connection between PTEN expression and demographic data and tumour behaviours revealed no meaningful relationship between PTEN expression and patients' age, gender, tumour site and size, tumour type, tumour grade and stage, neural, and lymphovascular invasion (P-value>0.05). CONCLUSION PTEN expression level is expected to be a significant molecular event in the progression of gastric cancer and may be a predictive marker for gastric cancer behaviours dependent on society.
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Affiliation(s)
| | - Fatemeh Hoseini
- Department of Pathology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezoo Eftekhar Javadi
- Department of Pathology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Nazar
- Department of Pathology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Androutsopoulos G, Styliara I, Zarogianni E, Lazurko N, Valasoulis G, Michail G, Adonakis G. The ErbB Signaling Network and Its Potential Role in Endometrial Cancer. EPIGENOMES 2023; 7:24. [PMID: 37873809 PMCID: PMC10594534 DOI: 10.3390/epigenomes7040024] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/25/2023] Open
Abstract
Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/β-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.
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Affiliation(s)
- Georgios Androutsopoulos
- Gynaecological Oncology Unit, Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
| | - Ioanna Styliara
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
| | - Evgenia Zarogianni
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
| | - Nadia Lazurko
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
| | - George Valasoulis
- Department of Obstetrics and Gynaecology, Medical School, University of Thessaly, 41334 Larisa, Greece;
- Hellenic National Public Health Organization—ECDC, 15123 Athens, Greece
| | - Georgios Michail
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
| | - Georgios Adonakis
- Department of Obstetrics and Gynaecology, School of Medicine, University of Patras, 26504 Rion, Greece; (I.S.); (E.Z.); (N.L.); (G.M.); (G.A.)
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Singh P, Ali SA, Kumar S, Mohanty AK. CRISPR-Cas9 based knockout of S100A8 in mammary epithelial cells enhances cell proliferation and triggers oncogenic transformation via the PI3K-Akt pathway: Insights from a deep proteomic analysis. J Proteomics 2023; 288:104981. [PMID: 37544501 DOI: 10.1016/j.jprot.2023.104981] [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: 04/25/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/08/2023]
Abstract
S100A8 is a calcium-binding protein with multiple functions, including being a chemoattractant for phagocytes and playing a key role in the inflammatory response. Its expression has been shown to influence epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer. However, the role of S100A8 in cell proliferation and differentiation remains unknown. In this study, we used the CRISPR-Cas9 system to knock out S100A8 in healthy mammary epithelial cells and investigated the resulting changes in proteome profiling and signaling pathways. Our results showed that S100A8 knockout led to an increase in cell proliferation and migration, reduced cell-cell adhesion, and increased apoptosis compared to wildtype cells. Proteomics data indicated that S100A8 significantly affects cell cycle progression, cell proliferation, and cell survival through the PI3K-Akt pathway. Furthermore, our findings suggest that S100A8 function is associated with Pten expression, a negative regulator of the PI3K-Akt pathway. These results indicate that S100A8 dysregulation in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, maintaining S100A8 expression is critical for preserving healthy cell physiology. This study provides novel insights into the role of S100A8 in cell proliferation and differentiation and its potential relevance to cancer biology. SIGNIFICANCE: The study suggests that maintaining S100A8 expression is critical for preserving healthy cell physiology, and dysregulation of S100A8 in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, targeting the PI3K-Akt pathway or regulating Pten expression, a negative regulator of the PI3K-Akt pathway, may be potential strategies for cancer treatment by controlling S100A8 dysregulation. Additionally, S100A8 and S100A9 have been shown to promote metastasis of breast carcinoma by forming a metastatic milieu. However, the differential expression of S100A8 in tumors and its dual effects of antitumor and protumor make the relationship between S100A8 and tumors complicated. Currently, most research focuses on the function of S100A8 as a secretory protein in the microenvironment of tumors, and its function inside healthy cells without forming dimers remains unclear. Furthermore, the study provides insight into the role of S100A8 in cell proliferation and differentiation, which may have implications for other diseases beyond cancer. The functional role of S100A8 in normal mammary epithelial cells remains completely uncertain. Therefore, the objective of this study is to investigate the function of S100A8 on proliferation in mammary epithelial cells after its deletion and to elucidate the underlying proteins involved in downstream signaling. Our findings indicate that the deletion of S100A8 leads to excessive proliferation in normal mammary epithelial cells, reduces apoptosis, and affects cell-cell adhesion molecules required for cellular communication, resulting in a cancer-like phenotype.
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Affiliation(s)
- Parul Singh
- Proteomics and Cell Biology Lab, Animal Biotechnology Center, National Dairy Research Institute, Karnal, 132001, Haryana, India
| | - Syed Azmal Ali
- Proteomics and Cell Biology Lab, Animal Biotechnology Center, National Dairy Research Institute, Karnal, 132001, Haryana, India; Proteomics of Stem Cells and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany.
| | - Sudarshan Kumar
- Proteomics and Cell Biology Lab, Animal Biotechnology Center, National Dairy Research Institute, Karnal, 132001, Haryana, India
| | - Ashok Kumar Mohanty
- Proteomics and Cell Biology Lab, Animal Biotechnology Center, National Dairy Research Institute, Karnal, 132001, Haryana, India; Indian Veterinary Research Institute, Mukteshwar, 263138 Nainital, Uttarakhand, India.
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Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, Kulke MH, Baird RD, Prabhu JS, Carbone D, Pecoraro C, Teh DBL, Sethi G, Cavalieri V, Lin KH, Javidi-Sharifi NR, Toska E, Davids MS, Brown JR, Diana P, Stebbing J, Fruman DA, Kumar AP. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer 2023; 22:138. [PMID: 37596643 PMCID: PMC10436543 DOI: 10.1186/s12943-023-01827-6] [Citation(s) in RCA: 662] [Impact Index Per Article: 331.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/18/2023] [Indexed: 08/20/2023] Open
Abstract
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Aaron S C Foo
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
| | - Hiu Y Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Kenneth C H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - William Jacot
- Department of Medical Oncology, Institut du Cancer de Montpellier, Inserm U1194, Montpellier University, Montpellier, France
| | - Robert H Jones
- Cardiff University and Velindre Cancer Centre, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Huiyan Eng
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Pooyan Makvandi
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, Zhejiang, China
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Inserm U1015, Université Paris-Saclay, Paris, France
| | - Matthew H Kulke
- Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, Boston, MA, USA
| | - Richard D Baird
- Cancer Research UK Cambridge Centre, Hills Road, Cambridge, CB2 0QQ, UK
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Camilla Pecoraro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Daniel B L Teh
- Departments of Ophthalmology and Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, and Neurobiology Programme, National University of Singapore, Singapore, Singapore
| | - Gautam Sethi
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Vincenzo Cavalieri
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kevin H Lin
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Eneda Toska
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Justin Stebbing
- Division of Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, 216 Sprague Hall, Irvine, CA, USA
| | - Alan P Kumar
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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10
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Bhokisham N, Laudermilch E, Traeger LL, Bonilla TD, Ruiz-Estevez M, Becker JR. CRISPR-Cas System: The Current and Emerging Translational Landscape. Cells 2023; 12:cells12081103. [PMID: 37190012 DOI: 10.3390/cells12081103] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
CRISPR-Cas technology has rapidly changed life science research and human medicine. The ability to add, remove, or edit human DNA sequences has transformative potential for treating congenital and acquired human diseases. The timely maturation of the cell and gene therapy ecosystem and its seamless integration with CRISPR-Cas technologies has enabled the development of therapies that could potentially cure not only monogenic diseases such as sickle cell anemia and muscular dystrophy, but also complex heterogenous diseases such as cancer and diabetes. Here, we review the current landscape of clinical trials involving the use of various CRISPR-Cas systems as therapeutics for human diseases, discuss challenges, and explore new CRISPR-Cas-based tools such as base editing, prime editing, CRISPR-based transcriptional regulation, CRISPR-based epigenome editing, and RNA editing, each promising new functionality and broadening therapeutic potential. Finally, we discuss how the CRISPR-Cas system is being used to understand the biology of human diseases through the generation of large animal disease models used for preclinical testing of emerging therapeutics.
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Affiliation(s)
| | - Ethan Laudermilch
- Corporate Research Material Labs, 3M Center, 3M Company, Maplewood, MN 55144, USA
| | - Lindsay L Traeger
- Corporate Research Material Labs, 3M Center, 3M Company, Maplewood, MN 55144, USA
| | - Tonya D Bonilla
- Corporate Research Material Labs, 3M Center, 3M Company, Maplewood, MN 55144, USA
| | | | - Jordan R Becker
- Corporate Research Material Labs, 3M Center, 3M Company, Maplewood, MN 55144, USA
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11
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Boyd DC, Zboril EK, Olex AL, Leftwich TJ, Hairr NS, Byers HA, Valentine AD, Altman JE, Alzubi MA, Grible JM, Turner SA, Ferreira-Gonzalez A, Dozmorov MG, Harrell JC. Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs. Cancers (Basel) 2023; 15:cancers15051582. [PMID: 36900375 PMCID: PMC10001201 DOI: 10.3390/cancers15051582] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/23/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways.
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Affiliation(s)
- David C. Boyd
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Integrative Life Sciences Program, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Emily K. Zboril
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Amy L. Olex
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Tess J. Leftwich
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Nicole S. Hairr
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Holly A. Byers
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Aaron D. Valentine
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Julia E. Altman
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Mohammad A. Alzubi
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Integrative Life Sciences Program, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Jacqueline M. Grible
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Scott A. Turner
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | | | - Mikhail G. Dozmorov
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23219, USA
| | - J. Chuck Harrell
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence:
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12
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Apurva, Abdul Sattar RS, Ali A, Nimisha, Kumar Sharma A, Kumar A, Santoshi S, Saluja SS. Molecular pathways in periampullary cancer: An overview. Cell Signal 2022; 100:110461. [PMID: 36096460 DOI: 10.1016/j.cellsig.2022.110461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022]
Abstract
Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves differently from pancreatic carcinoma both in prognosis and outcome, therefore it needs special attention. Pancreatic cancer have higher incidence of nodal spread and perineural &lymphovascular invasion suggesting it biologically more aggressive tumor compared to periampullary cancer. Since PAC tumors consist of heterogenous tissue of origin, they might contain different mutations in tumor associated genes and other changes in tissue composition among different subgroups clubbed together. Significant progress has been made in understanding the molecular nature of PAC in the previous two decades, and a large number of mutations and other genetic changes have been identified as being responsible for the disease. This review article targets to collate and discuss the molecular evolution of PAC and their implication in its outcome. As per literature, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Wnt signaling are the most common pathways involved in PAC. Mutations in KRAS, TP53, CTNNB1, SMAD4 and APC genes were the most frequently reported. I-subtype resembles colorectal cancer while the morphology of PB-type shows close resemblance to pancreatic tumors. The frequency of driver gene mutations is higher in I-type compared to PB-type of PAC indicating I-type to be genetically more unstable. The genetic landscape of PAC obtained from WES data highlighted PI3/AKT pathway to be a primary target in I-type and RAS/RAF in PB-type.
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Affiliation(s)
- Apurva
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Amity University, Noida, India
| | - Real Sumayya Abdul Sattar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | | | - Sundeep Singh Saluja
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, GovindBallabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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13
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Perevalova AM, Kobelev VS, Sisakyan VG, Gulyaeva LF, Pustylnyak VO. Role of Tumor Suppressor PTEN and Its Regulation in Malignant Transformation of Endometrium. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:1310-1326. [PMID: 36509719 DOI: 10.1134/s0006297922110104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Tumor-suppressive effects of PTEN are well-known, but modern evidence suggest that they are not limited to its ability to inhibit pro-oncogenic PI3K/AKT signaling pathway. Features of PTEN structure facilitate its interaction with substrates of different nature and display its activity in various ways both in the cytoplasm and in cell nuclei, which makes it possible to take a broader look at its ability to suppress tumor growth. The possible mechanisms of the loss of PTEN effects are also diverse - PTEN can be regulated at many levels, leading to change in the protein activity or its amount in the cell, while their significance for the development of malignant tumors has yet to be studied. Here we summarize the current data on the PTEN structure, its functions and changes in its regulatory mechanisms during malignant transformation of the cells, focusing on one of the most sensitive to the loss of PTEN types of malignant tumors - endometrial cancer.
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Affiliation(s)
| | - Vyacheslav S Kobelev
- Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia
| | - Virab G Sisakyan
- Novosibirsk Regional Oncology Center, Novosibirsk, 630108, Russia
| | - Lyudmila F Gulyaeva
- Novosibirsk State University, Novosibirsk, 630090, Russia.,Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia
| | - Vladimir O Pustylnyak
- Novosibirsk State University, Novosibirsk, 630090, Russia.,Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia
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14
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Disciglio V, Sanese P, Fasano C, Lotesoriere C, Valentini AM, Forte G, Lepore Signorile M, De Marco K, Grossi V, Lolli I, Cariola F, Simone C. Identification and Somatic Characterization of the Germline PTEN Promoter Variant rs34149102 in a Family with Gastrointestinal and Breast Tumors. Genes (Basel) 2022; 13:644. [PMID: 35456450 PMCID: PMC9025445 DOI: 10.3390/genes13040644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 02/04/2023] Open
Abstract
Genetic variants located in non-coding regions can affect processes that regulate protein expression, functionally contributing to human disease. Germline heterozygous mutations in the non-coding region of the PTEN gene have been previously identified in patients with PTEN hamartoma tumor syndrome (PHTS) diagnosed with breast, thyroid, and/or endometrial cancer. In this study, we report a PTEN promoter variant (rs34149102 A allele) that was identified by direct sequencing in an Italian family with a history of gastroesophageal junction (GEJ) adenocarcinoma and breast cancer. In order to investigate the putative functional role of the rs34149102 A allele variant, we evaluated the status of PTEN alterations at the somatic level. We found that PTEN protein expression was absent in the GEJ adenocarcinoma tissue of the index case. Moreover, we detected the occurrence of copy number loss involving the PTEN rs34149102 major C allele in tumor tissue, revealing that the second allele was somatically inactivated. This variant is located within an active regulatory region of the PTEN core promoter, and in silico analysis suggests that it may affect the binding of the nuclear transcription factor MAZ and hence PTEN expression. Overall, these results reveal the functional role of the PTEN promoter rs34149102 A allele variant in the modulation of PTEN protein expression and highlight its contribution to hereditary cancer risk.
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Affiliation(s)
- Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Claudio Lotesoriere
- Oncology Unit, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (C.L.); (I.L.)
| | - Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy;
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Ivan Lolli
- Oncology Unit, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (C.L.); (I.L.)
| | - Filomena Cariola
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology—IRCCS “S. de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (V.D.); (P.S.); (C.F.); (G.F.); (M.L.S.); (K.D.M.); (V.G.); (F.C.)
- Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy
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15
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Bagheri S, Rahban M, Bostanian F, Esmaeilzadeh F, Bagherabadi A, Zolghadri S, Stanek A. Targeting Protein Kinases and Epigenetic Control as Combinatorial Therapy Options for Advanced Prostate Cancer Treatment. Pharmaceutics 2022; 14:515. [PMID: 35335890 PMCID: PMC8949110 DOI: 10.3390/pharmaceutics14030515] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 02/02/2023] Open
Abstract
Prostate cancer (PC), the fifth leading cause of cancer-related mortality worldwide, is known as metastatic bone cancer when it spreads to the bone. Although there is still no effective treatment for advanced/metastatic PC, awareness of the molecular events that contribute to PC progression has opened up opportunities and raised hopes for the development of new treatment strategies. Androgen deprivation and androgen-receptor-targeting therapies are two gold standard treatments for metastatic PC. However, acquired resistance to these treatments is a crucial challenge. Due to the role of protein kinases (PKs) in the growth, proliferation, and metastases of prostatic tumors, combinatorial therapy by PK inhibitors may help pave the way for metastatic PC treatment. Additionally, PC is known to have epigenetic involvement. Thus, understanding epigenetic pathways can help adopt another combinatorial treatment strategy. In this study, we reviewed the PKs that promote PC to advanced stages. We also summarized some PK inhibitors that may be used to treat advanced PC and we discussed the importance of epigenetic control in this cancer. We hope the information presented in this article will contribute to finding an effective treatment for the management of advanced PC.
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Affiliation(s)
- Soghra Bagheri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran;
| | - Mahdie Rahban
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran; (M.R.); (F.B.)
| | - Fatemeh Bostanian
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417614335, Iran; (M.R.); (F.B.)
| | - Fatemeh Esmaeilzadeh
- Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom 7414785318, Iran;
| | - Arash Bagherabadi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil 5619911367, Iran;
| | - Samaneh Zolghadri
- Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom 7414785318, Iran;
| | - Agata Stanek
- Department of Internal Medicine, Angiology and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St, 41-902 Bytom, Poland
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16
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Cai S, Yao D, Zhang Y, Li Z, Li X, Li L. Cautions should be taken when using cell models for gastric cancer research. Gene 2022; 806:145922. [PMID: 34454032 DOI: 10.1016/j.gene.2021.145922] [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: 04/30/2021] [Revised: 08/11/2021] [Accepted: 08/23/2021] [Indexed: 11/25/2022]
Abstract
Gastric cancer (GC)-derived cell lines were generally used in basic cancer research and drug screening. However, it is always concerned about the difference between cultured cells and primary tumor by oncologists. To address this question, we compared differentially expressed genes (DEGs) in primary cancers, healthy tissues, and cell lines both in vitro and in silico. Seven reported genes with decreased expression in GCs by DNA methylation were analyzed in our cohort studies and experimentally validation. Selected datasets from TCGA (The Cancer Genome Atlas), CCLE (The Broad Institute Cancer Cell Line Encyclopedia), and GTEx (The Genotype-Tissue Expression project) were used to represent GCs, GC-derived cell lines, and healthy tissues respectively in the in silico analysis. Thirty gastric tissues together with six cell lines were used for validations. Unexpectedly, we experimentally found that reported cancer-related downregulated genes were only found in cancer cell lines but not in biopsies. The unchanged gene expressions in primary GCs were generally consistent with our cohort study, using information from cancerous (TCGA) and healthy tissues (GETx). Substantial differences were also found between DEGs of cancer tissues (TGCA)/ healthy tissues (GTEx) pair and cell lines (CCLE)/ healthy tissues (GTEx) pair, which confirmed the significant differences between primary cancer and cancer cell lines. Moreover, elevated expression of YWHAQ (14-3-3 δ) and THBS1 were observed in the GC biopsies, which might be potential biomarkers for GC diagnosis, considering the increased YWHAQ and THBS1 associated with poor survival rates in gastric cancer patients. In sum, it is suggested that cautions should be taken when using GC cell lines to study genes that show great differences between cell lines and tissues.
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Affiliation(s)
- Siqi Cai
- Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology (Qingdao), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Dan Yao
- Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology (Qingdao), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Yuqi Zhang
- Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology (Qingdao), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Zhaohe Li
- Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology (Qingdao), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China
| | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
| | - Li Li
- Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology (Qingdao), School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
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17
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Samanta S, Mahata R, Santra MK. The Cross-Talk between Epigenetic Gene Regulation and Signaling Pathways Regulates Cancer Pathogenesis. Subcell Biochem 2022; 100:427-472. [PMID: 36301502 DOI: 10.1007/978-3-031-07634-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Cancer begins due to uncontrolled cell division. Cancer cells are insensitive to the signals that control normal cell proliferation. This uncontrolled cell division is due to the accumulation of abnormalities in different factors associated with the cell division, including different cyclins, cell cycle checkpoint inhibitors, and cellular signaling. Cellular signaling pathways are aberrantly activated in cancer mainly due to epigenetic regulation and post-translational regulation. In this chapter, the role of epigenetic regulation in aberrant activation of PI3K/AKT, Ras, Wnt, Hedgehog, Notch, JAK/STAT, and mTOR signaling pathways in cancer progression is discussed. The role of epigenetic regulators in controlling the upstream regulatory proteins and downstream effector proteins responsible for abnormal cellular signaling-mediated cancer progression is covered in this chapter. Similarly, the role of signaling pathways in controlling epigenetic gene regulation-mediated cancer progression is also discussed. We have tried to ascertain the current status of potential epigenetic drugs targeting several epigenetic regulators to prevent different cancers.
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Affiliation(s)
- Snigdha Samanta
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Rumpa Mahata
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Manas Kumar Santra
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India.
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Nguyen TTD, Tran TA, Le NQK, Pham DM, Ou YY. An Extensive Examination of Discovering 5-Methylcytosine Sites in Genome-Wide DNA Promoters Using Machine Learning Based Approaches. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2022; 19:87-94. [PMID: 34014828 DOI: 10.1109/tcbb.2021.3082184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
It is well-known that the major reason for the rapid proliferation of cancer cells are the hypomethylation of the whole cancer genome and the hypermethylation of the promoter of particular tumor suppressor genes. Locating 5-methylcytosine (5mC) sites in promoters is therefore a crucial step in further understanding of the relationship between promoter methylation and the regulation of mRNA gene expression. High throughput identification of DNA 5mC in wet lab is still time-consuming and labor-extensive. Thus, finding the 5mC site of genome-wide DNA promoters is still an important task. We compared the effectiveness of the most popular and strong machine learning techniques namely XGBoost, Random Forest, Deep Forest, and Deep Feedforward Neural Network in predicting the 5mC sites of genome-wide DNA promoters. A feature extraction method based on k-mers embeddings learned from a language model were also applied. Overall, the performance of all the surveyed models surpassed deep learning models of the latest studies on the same dataset employing other encoding scheme. Furthermore, the best model achieved AUC scores of 0.962 on both cross-validation and independent test data. We concluded that our approach was efficient for identifying 5mC sites of promoters with high performance.
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19
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Rascio F, Spadaccino F, Rocchetti MT, Castellano G, Stallone G, Netti GS, Ranieri E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers (Basel) 2021; 13:3949. [PMID: 34439105 PMCID: PMC8394096 DOI: 10.3390/cancers13163949] [Citation(s) in RCA: 239] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.
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Affiliation(s)
- Federica Rascio
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Federica Spadaccino
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Maria Teresa Rocchetti
- Cell Biology Unit, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Giuseppe Castellano
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giuseppe Stefano Netti
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Elena Ranieri
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
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20
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Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2021; 13:877-919. [PMID: 34050894 PMCID: PMC9243210 DOI: 10.1007/s13238-021-00846-7] [Citation(s) in RCA: 347] [Impact Index Per Article: 86.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
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Affiliation(s)
- Linchong Sun
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Huafeng Zhang
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China. .,CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. .,School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
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21
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Evaluation of the PTEN and circRNA-CDR1as Gene Expression Changes in Gastric Cancer and Normal Cell Lines Following the Exposure to Weak and Moderate 50 Hz Electromagnetic Fields. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2021. [DOI: 10.5812/ijcm.111079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background: Attention to the electromagnetic exposure as a targeted tumor therapy has been recently increasing. Objectives: The aim of the current study was to investigate the effect of continuous and discontinuous electromagnetic fields on cell viability as well as phosphatase and tensin homolog (PTEN) and circular (circ)-RNA CDR1as genes expression in the normal and gastric cancer (GC) cell lines. Methods: After preparing gastric cancer cell lines (AGS) and normal cells (HU02 line), they were exposed to magnetic flux densities of 0.25, 0.5, 1, and 2 mT continuously and discontinuously (1h on/1h off) for 18 hours. The 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell viability. In addition, after designing the primers, the expression of the PTEN and circ-CDR1as genes was studied using the real-time polymerase chain reaction (real-time-PCR) technique. The results were analyzed using SPSS software version 25. Results: The exposed normal and tumor cells to discontinuous electromagnetic fields resulted in increasing of cell survival rate in both normal and tumor cells. In contrast, the exposure of continuous electromagnetic field showed no effect on the viability of the normal and tumor cells at intensities of 0.25, 0.5, and 1 mT. The electromagnetic field showed a significant effect on the expression of the circ-CDR1as gene and this effect depended on the intensity of the electromagnetic field used and the cell type. We have found that the activity of PTEN gene in the normal and tumor cells increased and decreased with increasing intensity of discontinuous electromagnetic field, respectively. Conclusions: In general, the effect of electromagnetic field on gastric cancer seems to depend on the kind of exposure as well as an extent of intensity and can be used for cancer therapeutic purposes. However, more research is needed on this subject.
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22
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Swellam M, Saad EA, Sabry S, Denewer A, Abdel Malak C, Abouzid A. Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay. J Genet Eng Biotechnol 2021; 19:54. [PMID: 33825073 PMCID: PMC8024427 DOI: 10.1186/s43141-021-00154-x] [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] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/26/2021] [Indexed: 12/22/2022]
Abstract
Background Diagnosis of breast cancer is more complicated due to lack of minimal invasive biomarker with sufficient precision. DNA methylation is a promising marker for cancer diagnosis. In this study, authors evaluated methylation patterns for PTEN and SMAD4 in blood samples using EpiTect Methyl II QPCR assay quantitative PCR technology. Results Methylation status for PTEN and SMAD4 were statistically significant as breast cancer patients reported hypermethylation compared to benign and control groups (77.1 ± 17.9 vs. 24.9 ± 4.5 and 15.1 ± 1.4 and 70.1 ± 14.4 vs. 28.2 ± 0.61 and 29.5 ± 3.6, respectively). ROC curve analysis revealed that both PTEN (AUC = 0.992) and SMAD4 (AUC = 0.853) had good discriminative power for differentiating BC from all non-cancer individuals (benign and healthy combined) compared to routine tumor markers CEA (AUC = 0.538) and CA15.3 (AUC = 0.686). High PTEN methylation degree was associated with late stages (84.2 ± 17.4), positive lymph node (84.2 ± 18.5), positive ER (81.3 ± 19.7), positive PgR (79.5 ± 19.1), and positive HER2 (80.7 ± 19.0) vs. 67.4 ± 13.8, 70.6 ± 14.8, 72.8 ± 14.9, 72.5 ± 14.7, and 70.2 ± 13.5 in early stages, negative lymph node, negative ER, negative PgR, and negative HER2, respectively. Similar results were obtained regarding SMAD4 methylation. Sensitivity, specificity, positive and negative predictive values, and accuracy for methylated PTEN were 100%, 95%, 99.1%, 100%, and 95%, respectively when differentiated BC from all-non cancer controls. Interestingly, PTEN could distinguish early BC stages with good sensitivity 84.4%, 51.4%, 69.1%, 72%, and 70%, respectively. Conclusion Methylation status of PTEN and SMAD4 is a promising blood marker for early detection of breast cancer. Future studies are needed for their role as prognostic markers.
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Affiliation(s)
- Menha Swellam
- Biochemistry Department, Genetic Engineering and Biotechnology Research Division, High Throughput Molecular and Genetic Laboratory, Center for Excellences for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
| | - Entsar A Saad
- Chemistry Department, Faculty of Science, Damietta University, Damietta, 34517, Egypt
| | - Shimaa Sabry
- Chemistry Department, Faculty of Science, Damietta University, Damietta, 34517, Egypt.
| | - Adel Denewer
- Surgical Oncology Department, Mansoura Oncology Centre, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Camelia Abdel Malak
- Chemistry Department, Faculty of Science, Damietta University, Damietta, 34517, Egypt
| | - Amr Abouzid
- Surgical Oncology Department, Mansoura Oncology Centre, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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23
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Sar P, Dalai S. CRISPR/Cas9 in epigenetics studies of health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2021; 181:309-343. [PMID: 34127198 DOI: 10.1016/bs.pmbts.2021.01.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Epigenetics is the heritable phenotypic changes without altering the genotype. Epigenetic processes are such as histone methylation, acetylation, ubiquitination, sumoylation, phosphorylation, ADP ribosylation, DNA methylation and non-coding RNAs interactions associated with structural changes in chromatin. The change of structure is either open chromatin for "active" state or closed chromatin for "inactive" state, that regulates important biological phenomenon like chromatin condensation, gene expression, DNA repair, cellular development, differentiation and homeostasis, etc. However, dysregulation of epigenetic patterns causes diseases like cancer, diabetes, neurological disorder, infectious diseases, autoimmunity etc. Besides, the most important clinical uses of Epigenetics studies are i. identification of disease biomarkers and ii. development of their therapeutics. Epigenetic therapies include epi-drugs, combinatorial therapy, nanocarriers, plant-derived products that are being used for changing the epigenetic pattern to reverse gene expression. However, the developed epi- drugs cause off-target gene and transposable elements activation; promote mutagenesis and carcinogenesis in normal cells, are the major hurdles regarding their clinical use. Therefore, advanced epigenetic therapeutics are required to develop target-specific epigenetic modifications to reverse gene expression pattern. CRISPR-Cas9 (Clustered Regularly Interspaced Palindrome Repeats-associated protein 9) system-mediated gene activation mechanism paves new methods of target-specific epigenetic therapeutics to cure diseases. In this chapter, we discuss how CRISPR/Cas9 and dCas9 have recently been engineered for epigenome editing. Different strategies have been discussed used for epigenome editing based on their efficacy and complexity. Last but not least we have discussed the limitations, different uses of CRISPR/Cas9 and dCas9 in the area of genetic engineering.
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Affiliation(s)
- Pranati Sar
- Institute of Science, NIRMA University, Ahmedabad, India.
| | - Sarat Dalai
- Institute of Science, NIRMA University, Ahmedabad, India.
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24
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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25
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Clerici SP, Oliveira PFDS, Akagi EM, Cordeiro HG, Azevedo-Martins JM, Faria AVDS, Ferreira-Halder CV. A comprehensive review on the role of protein tyrosine phosphatases in gastric cancer development and progression. Biol Chem 2021; 402:663-674. [PMID: 33544466 DOI: 10.1515/hsz-2020-0355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/15/2021] [Indexed: 12/09/2022]
Abstract
The main post-translational reversible modulation of proteins is phosphorylation and dephosphorylation, catalyzed by protein kinases (PKs) and protein phosphatases (PPs) which is crucial for homeostasis. Imbalance in this crosstalk can be related to diseases, including cancer. Plenty of evidence indicates that protein tyrosine phosphatases (PTPs) can act as tumor suppressors and tumor promoters. In gastric cancer (GC), there is a lack of understanding of the molecular aspects behind the tumoral onset and progression. Here we describe several members of the PTP family related to gastric carcinogenesis. We discuss the associated molecular mechanisms which support the down or up modulation of different PTPs. We emphasize the Helicobacter pylori (H. pylori) virulence which is in part associated with the activation of PTP receptors. We also explore the involvement of intracellular redox state in response to H. pylori infection. In addition, some PTP members are under influence by genetic mutations, epigenetics mechanisms, and miRNA modulation. The understanding of multiple aspects of PTPs in GC may provide new targets and perspectives on drug development.
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Affiliation(s)
- Stefano Piatto Clerici
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | | | - Erica Mie Akagi
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Helon Guimarães Cordeiro
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Jordana Maria Azevedo-Martins
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Alessandra Valéria de Sousa Faria
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
| | - Carmen Veríssima Ferreira-Halder
- Department of Biochemistry and Tissue Biology, University of Campinas, UNICAMP, Rua Monteiro Lobato 255, 13083-862Campinas, São Paulo, Brazil
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Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci 2020; 262:118513. [PMID: 33011222 DOI: 10.1016/j.lfs.2020.118513] [Citation(s) in RCA: 236] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Sadegh Fattahi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; North Research Center, Pasteur Institute, Amol, Iran
| | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Reza Tabaripour
- Department of Cellular and Molecular Biology, Islamic Azad University Babol-Branch, Iran
| | - Gholam Hossein Ashrafi
- Kingston University London, Cancer theme, School of Life Science, Pharmacy and Chemistry, SEC Faculty, Kingston upon Thames, KT12EE, London, UK
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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27
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Kadian LK, Yadav R, Nanda S, Gulshan G, Sharma S, Yadav C. High-risk HPV infection modulates the promoter hypermethylation of APC, SFRP1, and PTEN in cervical cancer patients of North India. Mol Biol Rep 2020; 47:9725-9732. [PMID: 33230782 DOI: 10.1007/s11033-020-05960-z] [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: 05/08/2020] [Accepted: 10/29/2020] [Indexed: 12/18/2022]
Abstract
Persistent infection with oncogenic HPV and downregulation of tumor suppressor genes play an essential role in the development and progression of cervical cancer. The present study aimed to identify the promoter methylation status of APC, SFRP1, and PTEN which are important regulators of Wnt pathway and their association with high-risk HPV infection and gene expression. Methylation Specific PCR (MSP) and quantitative reverse transcription PCR (RT-qPCR) were used to detect methylation status and gene expression levels of APC, SFRP1, and PTEN in cervical cancer biopsies (110) and paired non-cancerous biopsies (28). APC promoter was methylated in 38%, SFRP1 in 95%, and PTEN in 55% of the cervical cancer biopsies. Our data showed a trend of a higher rate of methylation of the gene promoters in cervical cancer biopsies while; they were majorly un-methylated in non-cancerous biopsies. Corresponding to a higher rate of methylation in cancer biopsies, the gene expression levels of APC, SFRP1, and PTEN were reduced in cervical cancer samples in comparison to normal cervix tissues. Further, we observed that 97% cancer biopsies were HPV infected and high-risk type HPV16 and 18 infections were significantly positively associated with APC (p = 0.008 and p = 0.007), SFRP1 (p = 0.003 and p = 0.0067), and PTEN (p = 0.049 and p = 0.008) promoter methylation. APC, SFRP1, and PTEN promoter hyper-methylation is positively associated with high-risk HPV infection and inversely associated with gene expression. Our findings show that high-risk HPV infection promotes methylation of these genes and further promotes their silencing.
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Affiliation(s)
- Lokesh Kumari Kadian
- Department of Genetics, Maharishi Dayanand University, Rohtak, 124001, Haryana, India
| | - Ritu Yadav
- Department of Genetics, Maharishi Dayanand University, Rohtak, 124001, Haryana, India.
| | - Smiti Nanda
- Departments of Obstetrics and Gynaecology, PGIMS, Rohtak, Haryana, India
| | - Gulshan Gulshan
- Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, Maharashtra, India
| | - Shivkant Sharma
- Department of Genetics, Maharishi Dayanand University, Rohtak, 124001, Haryana, India
| | - Chetna Yadav
- Department of Genetics, Maharishi Dayanand University, Rohtak, 124001, Haryana, India
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28
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Zhang L, Xiao X, Xu ZC. iPromoter-5mC: A Novel Fusion Decision Predictor for the Identification of 5-Methylcytosine Sites in Genome-Wide DNA Promoters. Front Cell Dev Biol 2020; 8:614. [PMID: 32850787 PMCID: PMC7399635 DOI: 10.3389/fcell.2020.00614] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 06/22/2020] [Indexed: 11/29/2022] Open
Abstract
The hypomethylation of the whole cancer genome and the hypermethylation of the promoter of specific tumor suppressor genes are the important reasons for the rapid proliferation of cancer cells. Therefore, obtaining the distribution of 5-methylcytosine (5mC) in promoters is a key step to further understand the relationship between promoter methylation and mRNA gene expression regulation. Large-scale detection of DNA 5mC through wet experiments is still time-consuming and laborious. Therefore, it is urgent to design a method for identifying the 5mC site of genome-wide DNA promoters. Based on promoter methylation data of the small cell lung cancer (SCLC) from the database named cancer cell line Encyclopedia (CCLE), we built a fusion decision predictor called iPromoter-5mC for identifying methylation modification sites in promoters using deep neural network (DNN). One-Hot Encoding (One-hot) was used to encode the promoter samples for the classification. The method achieves average AUC of 0.957 on the independent testing dataset, indicating that our predictor is robust and reliable. A user-friendly web-server called iPromoter-5mC could be freely accessible at http://www.jci-bioinfo.cn/iPromoter-5mC, which will provide simple and effective means for users to study promoter 5mC modification. The source code of the proposed methods is freely available for academic research at https://github.com/zlwuxi/iPromoter-5mC.
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Affiliation(s)
- Lei Zhang
- Computer Department, Jing-De-Zhen Ceramic Institute, Jingdezhen, China
| | - Xuan Xiao
- Computer Department, Jing-De-Zhen Ceramic Institute, Jingdezhen, China
| | - Zhao-Chun Xu
- Computer Department, Jing-De-Zhen Ceramic Institute, Jingdezhen, China
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29
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Kim B, Kang SY, Kim D, Heo YJ, Kim KM. PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression. Cancers (Basel) 2020; 12:cancers12071724. [PMID: 32610572 PMCID: PMC7407887 DOI: 10.3390/cancers12071724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 12/21/2022] Open
Abstract
Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein–Barr virus (EBV), HER2 overexpression, and PD-L1 expression on PTEN mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic PTEN mutations, of which 19 (55.9%) showed PTEN protein loss. The most common PTEN variants associated with protein loss were p.R130 (n = 4) followed by p.R335, p.L265fs, and deletions (n = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type PTEN, protein loss was found in 35 cases (12.2%). Thus, PTEN mutations were significantly associated with PTEN protein loss (p = 5.232 × 10−10), high MSI (p = 3.936 × 10−8), and EBV-positivity (p = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in PTEN are a frequent genetic mechanism of PTEN inactivation in GC.
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Affiliation(s)
- Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
| | - Deokgeun Kim
- Department of Clinical Genomics, Samsung Medical Center, Seoul 06351, Korea;
| | - You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Correspondence: ; Tel.: +82-2-3410-2807; Fax: +82-2-3410-6396
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The Combination of Transient Receptor Potential Vanilloid Type 1 (TRPV1) and Phosphatase and Tension Homolog (PTEN) is an Effective Prognostic Biomarker in Cervical Cancer. Int J Gynecol Pathol 2020; 40:214-223. [PMID: 32287115 DOI: 10.1097/pgp.0000000000000677] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Transient receptor potential vanilloid type 1 (TRPV1) has been reported to play an important role in human cancers. However, the knowledge about TRPV1 in cervical cancer is sparse. Therefore, we evaluated the expression and clinical significance of TRPV1 in cervical cancer. Immunohistochemical analyses were performed for TRPV1 and phosphatase and tension homolog (PTEN) to delineate clinical significance using 150 cervical cancers, 230 cervical intraepithelial neoplasias, and 312 normal cervical epithelial tissues in a tissue microarray. Furthermore, the role of TRPV1 in cell growth was assessed in a cervical cancer cell line. The TRPV1 expression was significantly higher in cervical cancer tissues than in cervical intraepithelial neoplasias, and normal epithelial tissues (P<0.001). In cervical cancer tissues, TRPV1 expression negatively correlated with PTEN expression (Spearman ρ=-0.121, P=0.009). Multivariate survival analysis revealed high TRPV1 expression (hazard ratio=3.41, 95% confidence interval: 1.25-9.27, P=0.016) as an independent prognostic factor for overall survival. Notably. the high TRPV1/low PTEN expression showed the highest hazard ratio (5.87; 95% confidence interval: 2.18-15.82, P<0.001) for overall survival. In vitro results demonstrated that the overexpression of TRPV1 was associated with increased cell viability and colony formation. Overexpression of TRPV1 could be a good biomarker for the prediction of chemoradiation response. Our result suggested promising potential of high TRPV1/low PTEN as prognostic and survival makers. The possible link between the biologic function of TRPV1 and PTEN in cervical cancer warrants further studies.
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Ji C, Yue S, Gu J, Kong Y, Chen H, Yu C, Sun Z, Zhao M. 2,7-Dibromocarbazole interferes with tube formation in HUVECs by altering Ang2 promoter DNA methylation status. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 697:134156. [PMID: 32380619 DOI: 10.1016/j.scitotenv.2019.134156] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/24/2019] [Accepted: 08/27/2019] [Indexed: 06/11/2023]
Abstract
2,7-Dibromocarbazole (2,7-DBCZ) is one of the most frequently detected polyhalogenated carbazoles (PHCZs) in the environmental media. 2,7-DBCZ has attracted public attention for its potential for dioxin-like toxicity and cardiovascular toxicity. However, researches on the potential mechanism of angiogenesis inhibition by 2,7-DBCZ is still insufficient. Herein, human umbilical vein endothelial cells (HUVECs) were applied to explore the angiogenic effect of 2,7-DBCZ and the potential underlying mechanisms. 2,7-DBCZ significantly inhibited tube formation in HUVECs in the non-toxic concentration range. PCR array showed that 2,7-DBCZ reduced the expression proportion between VEGFs and Ang2, thereby inhibiting tube formation in HUVECs. Then, small RNA interference and DNA methylation assays were adopted to explore the potential mechanisms. It has been found that angiopoietin2 (Ang2)-silencing recovered the tube formation inhibited by 2,7-DBCZ. The DNA methylation status of Ang2 promoter also showed a demethylation tendency after exposure. In conclusion, 2,7-DBCZ could demethylate the Ang2 promoter to potentiate Ang2 expression, thus altering angiogenic phenotype of HUVECs by reducing the proportion between Ang2 and VEGFs. The data presented here can help to guide safety measures on the use of dioxin-like PHCZs for their potential adverse effects and provide a method for identifying the relevant biomarkers to assess their cardiovascular toxicity.
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Affiliation(s)
- Chenyang Ji
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China
| | - Siqing Yue
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China
| | - Jinping Gu
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yuan Kong
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China
| | - Haofeng Chen
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China
| | - Chang Yu
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhe Sun
- Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Meirong Zhao
- College of Environment, Zhejiang University of Technology, Hangzhou 310032, China.
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Crispo F, Condelli V, Lepore S, Notarangelo T, Sgambato A, Esposito F, Maddalena F, Landriscina M. Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression. Cells 2019; 8:E798. [PMID: 31366176 PMCID: PMC6721562 DOI: 10.3390/cells8080798] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/24/2019] [Accepted: 07/29/2019] [Indexed: 02/07/2023] Open
Abstract
Cancer has been considered, for a long time, a genetic disease where mutations in keyregulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, theadvent of high-throughput technologies has revolutionized cancer research, allowing to investigatemolecular alterations at multiple levels, including genome, epigenome, transcriptome, proteome,and metabolome and showing the multifaceted aspects of this disease. The multi-omics approachesrevealed an intricate molecular landscape where different cellular functions are interconnected andcooperatively contribute to shaping the malignant phenotype. Recent evidence has brought to lighthow metabolism and epigenetics are highly intertwined, and their aberrant crosstalk can contributeto tumorigenesis. The oncogene-driven metabolic plasticity of tumor cells supports the energeticand anabolic demands of proliferative tumor programs and secondary can alter the epigeneticlandscape via modulating the production and/or the activity of epigenetic metabolites. Conversely,epigenetic mechanisms can regulate the expression of metabolic genes, thereby altering themetabolome, eliciting adaptive responses to rapidly changing environmental conditions, andsustaining malignant cell survival and progression in hostile niches. Thus, cancer cells takeadvantage of the epigenetics-metabolism crosstalk to acquire aggressive traits, promote cellproliferation, metastasis, and pluripotency, and shape tumor microenvironment. Understandingthis bidirectional relationship is crucial to identify potential novel molecular targets for theimplementation of robust anti-cancer therapeutic strategies.
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Affiliation(s)
- Fabiana Crispo
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Valentina Condelli
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Silvia Lepore
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Tiziana Notarangelo
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Alessandro Sgambato
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Franca Esposito
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II,80131 Naples, Italy.
| | - Francesca Maddalena
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
| | - Matteo Landriscina
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata,85028 Rionero in Vulture, PZ, Italy.
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia,71100 Foggia, Italy.
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Im SA, Lee KE, Nam E, Kim DY, Lee JH, Han HS, Seoh JY, Park HY, Cho MS, Han WS, Lee SN. Potential Prognostic Significance of p185HER2 Overexpression with Loss of PTEN Expression in Gastric Carcinomas. TUMORI JOURNAL 2019; 91:513-21. [PMID: 16457151 DOI: 10.1177/030089160509100612] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Aims and Background The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185HER2) that has partial homology with the epidermal growth factor receptor and shares intrinsic tyrosine kinase activity. The phosphatase and tensin homolog mutated on chromosome ten (PTEN) gene product is a protein tyrosine phosphatase that participates in modulating the phosphoinositide 3-kinase pathway which has antagonizing activity to protein tyrosine kinase. The authors investigated the correlation between clinicopathologic variables including survival and the overexpression of the p185HER2 with loss of PTEN expression in gastric adenocarcinoma patients. Methods The protein expression of p185HER2 and PTEN was examined by immunohistochemical stain in paraffin-embedded tissues of 94 (M:F, 52:42) gastric adenocarcinoma patients by using monoclonal antibody, and the results were related to clinicopathological variables and survival. Results p185HER2 overexpression correlated positively with lymph node metastasis, distant metastasis, AJCC classification, higher relapse rate. Patients with overexpression of p185HER2 were found to have significantly lower disease-free survival ( P = 0.003) and overall survival ( P = 0.0004). Loss of PTEN expression correlated positively with depth of invasion (T stage) and was more frequent in the advanced stage. The patient group with p185HER2 overexpression and loss of PTEN expression showed significantly shorter disease-free and overall survival ( P = 0.03, P = 0.01) than the other groups. Conclusions Our observations suggest potential prognostic significance of p185HER2 overexpression with PTEN loss in gastric adenocarcinoma patients. This opens up the possibility of considering p185HER2 and PTEN as a therapeutic target in gastric cancer.
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Affiliation(s)
- Seock-Ah Im
- Section of Oncology/Hematology, Department of Internal Medicine, Seoul National University, College of Medicine, 28 Yongondong Chongnogu, Seoul, 110-744, Korea.
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Ghasabi M, Majidi J, Mansoori B, Mohammadi A, Shomali N, Shirafkan N, Baghbani E, Kazemi T, Baradaran B. The effect of combined miR‐200c replacement and cisplatin on apoptosis induction and inhibition of gastric cancer cell line migration. J Cell Physiol 2019; 234:22581-22592. [DOI: 10.1002/jcp.28823] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/06/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Mehri Ghasabi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Jafar Majidi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Mansoori
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine University of Southern Denmark Odense Denmark
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Mohammadi
- Aging Research Institute, Physical Medicine and Rehabilitation Research Center Tabriz University of Medical Sciences Tabriz Iran
| | - Navid Shomali
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Naghmeh Shirafkan
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Elham Baghbani
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
| | - Behzad Baradaran
- Immunology Research Center TabrizUniversity of Medical Sciences Tabriz Iran
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Naseem A, Bhat ZI, Kalaiarasan P, Kumar B, Bin Hafeez Z, Tiwari RR, Wahabi K, Gandhi G, Alam Rizvi MM. Assessment of epigenetic alterations and in silico analysis of mutation affecting PTEN expression among Indian cervical cancer patients. J Cell Biochem 2019; 120:15851-15866. [PMID: 31074114 DOI: 10.1002/jcb.28856] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 02/06/2019] [Accepted: 02/21/2019] [Indexed: 02/04/2023]
Abstract
Genetic and epigenetic anomalies accountable for genetic dysregulation are the most common aberrations that determine the underlying heterogeneity of the tumor cells. Currently, phosphatase and tensin homolog (PTEN) incongruity has emerged as potent and persuasive malfunctioning in varied human malignancies. In this study, we have analysed the promoter hypermethylation and expression status of PTEN. We identified different mutations in the exonic region of PTEN. Functional consequences of these mutations were explored using in silico techniques. Promoter hypermethylation of PTEN was detected using methylation-specific polymerase chain reaction (MS-PCR), expression analysis was performed with immunohistochemistry (IHC) and mutation by direct sequencing in a total of 168 uterine cervix tumor cases. The findings were statistically correlated with the clinical parameters. In addition, the effect of nonsynonymous mutations was studied with molecular dynamics simulations. PTEN promoter hypermethylation (45.8%) was found to be significantly associated with the of PTEN loss (57.14%, P < 0.0001). Tumor stages, tumor size, lymph node (LN) were found to be significantly correlated with both PTEN promoter hypermethylation and PTEN loss. Histological grade, however, showed a significant association with only PTEN loss. In total, 11.76% of tumors exhibited mutations in exon 5 and 7, out of which E150K of exon 5 showed the highest deviations in the crystal structure of PTEN by in silico analysis. This study provides valuable insights into oncology and paves the path in the development of efficient biomarker and/or imperative therapeutic tool for cervical cancer treatment.
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Affiliation(s)
- Afreen Naseem
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Zafar Iqbal Bhat
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | | | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Zubair Bin Hafeez
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Raj Ranjan Tiwari
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Khushnuma Wahabi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Gauri Gandhi
- Department of Obstetrics & Gynecology, LNJP/MAMC Campus, New Delhi, India
| | - M Moshahid Alam Rizvi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
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Chai C, Wu H, Wang B, Eisenstat DD, Leng RP. MicroRNA-498 promotes proliferation and migration by targeting the tumor suppressor PTEN in breast cancer cells. Carcinogenesis 2019; 39:1185-1196. [PMID: 29985991 DOI: 10.1093/carcin/bgy092] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 07/03/2018] [Indexed: 12/13/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and high mortality rate. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and cell migration by negatively regulating the PI3K/Akt pathway. PTEN is downregulated by microRNAs in multiple cancers. However, few microRNAs have been reported to directly target PTEN in TNBC. In this study, microRNAs predicted to target PTEN were screened by immunoblotting and luciferase reporter assays. Expression levels of microRNA-498 (miR-498) were measured by TaqMan microRNA assays. We performed clonogenic, cell cycle and scratch wound assays to examine the oncogenic role of miR-498. We demonstrated that miR-498 directly targeted the 3'untranslated region of PTEN mRNA and reduced PTEN protein levels in TNBC cells. Compared with the non-tumorigenic breast epithelial cell line MCF-10A, TNBC cell lines overexpressed miR-498. Moreover, miR-498 promoted cell proliferation and cell cycle progression in TNBC cells in a PTEN-dependent manner. Suppressing miR-498 overexpression impaired the oncogenic effects of miR-498 on cell proliferation and cell migration. This study identified a novel microRNA (miR-498) overexpressed in TNBC cells and its oncogenic role in suppressing PTEN. These results provide new insight into the downregulation of PTEN and indicate a potential therapeutic target for treating TNBC.
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Affiliation(s)
- Chengsen Chai
- Department of Laboratory Medicine and Pathology, Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada
| | - Hong Wu
- Department of Laboratory Medicine and Pathology, Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada
| | - Benfan Wang
- Department of Laboratory Medicine and Pathology, Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada
| | - David D Eisenstat
- Department of Oncology, Cross Cancer Institute, University Ave., University of Alberta, Edmonton, Alberta, Canada
| | - Roger P Leng
- Department of Laboratory Medicine and Pathology, Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada
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Álvarez-Garcia V, Tawil Y, Wise HM, Leslie NR. Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol 2019; 59:66-79. [PMID: 30738865 DOI: 10.1016/j.semcancer.2019.02.001] [Citation(s) in RCA: 265] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/22/2019] [Accepted: 02/05/2019] [Indexed: 01/04/2023]
Abstract
PTEN is a phosphatase which metabolises PIP3, the lipid product of PI 3-Kinase, directly opposing the activation of the oncogenic PI3K/AKT/mTOR signalling network. Accordingly, loss of function of the PTEN tumour suppressor is one of the most common events observed in many types of cancer. Although the mechanisms by which PTEN function is disrupted are diverse, the most frequently observed events are deletion of a single gene copy of PTEN and gene silencing, usually observed in tumours with little or no PTEN protein detectable by immunohistochemistry. Accordingly, with the exceptions of glioblastoma and endometrial cancer, mutations of the PTEN coding sequence are uncommon (<10%) in most types of cancer. Here we review the data relating to PTEN loss in seven common tumour types and discuss mechanisms of PTEN regulation, some of which appear to contribute to reduced PTEN protein levels in cancers.
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Affiliation(s)
- Virginia Álvarez-Garcia
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Yasmine Tawil
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Helen M Wise
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Nicholas R Leslie
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK.
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Giles KM, Rosenbaum BE, Berger M, Izsak A, Li Y, Illa Bochaca I, Vega-Saenz de Miera E, Wang J, Darvishian F, Zhong H, Osman I. Revisiting the Clinical and Biologic Relevance of Partial PTEN Loss in Melanoma. J Invest Dermatol 2019; 139:430-438. [PMID: 30148988 PMCID: PMC6342667 DOI: 10.1016/j.jid.2018.07.031] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/11/2018] [Accepted: 07/19/2018] [Indexed: 12/26/2022]
Abstract
The extent of PTEN loss that confers clinical and biological impact in melanoma is unclear. We evaluated the clinical and biologic relevance of PTEN dosage in melanoma and tested the postulate that partial PTEN loss is due to epigenetic mechanisms. PTEN expression was assessed by immunohistochemistry in a stage III melanoma cohort (n = 190) with prospective follow up. Overall, 21 of 190 (11%) tumors had strong PTEN expression, 51 of 190 (27%) had intermediate PTEN, 44 of 190 (23%) had weak PTEN, and 74 of 190 (39%) had absent PTEN. Both weak and absent PTEN expression predicted shorter survival in multivariate analyses (hazard ratio = 2.13, P < 0.01). We show a continuous negative correlation between PTEN and activated Akt in melanoma cells with titrated PTEN expression and in two additional independent tumor datasets. PTEN genomic alterations (deletion, mutation), promoter methylation, and protein destabilization did not fully explain PTEN loss in melanoma, whereas PTEN levels increased with treatment of melanoma cells with the histone deacetylase inhibitor LBH589. Our data indicate that partial PTEN loss is due to modifiable epigenetic mechanisms and drives Akt activation and worse prognosis, suggesting a potential approach to improve the clinical outcome for a subset of patients with advanced melanoma.
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Affiliation(s)
- Keith M Giles
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA.
| | - Brooke E Rosenbaum
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Marlies Berger
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Allison Izsak
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Yang Li
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Irineu Illa Bochaca
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Eleazar Vega-Saenz de Miera
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Jinhua Wang
- University of Minnesota Institute for Health Informatics, Minneapolis, Minnesota, USA; Masonic Cancer Center; Minneapolis, Minnesota, USA
| | - Farbod Darvishian
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - Hua Zhong
- Department of Population Health, New York University School of Medicine, New York, New York, USA
| | - Iman Osman
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA.
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Moses C, Nugent F, Waryah CB, Garcia-Bloj B, Harvey AR, Blancafort P. Activating PTEN Tumor Suppressor Expression with the CRISPR/dCas9 System. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 14:287-300. [PMID: 30654190 PMCID: PMC6348769 DOI: 10.1016/j.omtn.2018.12.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/05/2018] [Accepted: 12/06/2018] [Indexed: 12/22/2022]
Abstract
PTEN expression is lost in many cancers, and even small changes in PTEN activity affect susceptibility and prognosis in a range of highly aggressive malignancies, such as melanoma and triple-negative breast cancer (TNBC). Loss of PTEN expression occurs via multiple mechanisms, including mutation, transcriptional repression and epigenetic silencing. Transcriptional repression of PTEN contributes to resistance to inhibitors used in the clinic, such as B-Raf inhibitors in BRAF mutant melanoma. We aimed to activate PTEN expression using the CRISPR system, specifically dead (d) Cas9 fused to the transactivator VP64-p65-Rta (VPR). dCas9-VPR was directed to the PTEN proximal promoter by single-guide RNAs (sgRNAs), in cancer cells that exhibited low levels of PTEN expression. The dCas9-VPR system increased PTEN expression in melanoma and TNBC cell lines, without transcriptional regulation at predicted off-target sgRNA binding sites. PTEN activation significantly repressed downstream oncogenic pathways, including AKT, mTOR, and MAPK signaling. BRAF V600E mutant melanoma cells transduced with dCas9-VPR displayed reduced migration, as well as diminished colony formation in the presence of B-Raf inhibitors, PI3K/mTOR inhibitors, and with combined PI3K/mTOR and B-Raf inhibition. CRISPR-mediated targeted activation of PTEN may provide an alternative therapeutic approach for highly aggressive cancers that are refractory to current treatments.
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Affiliation(s)
- Colette Moses
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia; School of Human Sciences, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia
| | - Fiona Nugent
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia; School of Molecular Sciences, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia
| | - Charlene Babra Waryah
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia
| | - Benjamin Garcia-Bloj
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia; School of Medicine, Faculty of Science, Universidad Mayor, Camino la Piramide 5750, Huechuraba 8580745, Santiago, Chile
| | - Alan R Harvey
- School of Human Sciences, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia; Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA 6009, Australia
| | - Pilar Blancafort
- Cancer Epigenetics Laboratory, The Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, WA 6009, Australia; School of Human Sciences, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia.
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Miranda-Gonçalves V, Lameirinhas A, Henrique R, Jerónimo C. Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets. Front Genet 2018; 9:427. [PMID: 30356832 PMCID: PMC6190739 DOI: 10.3389/fgene.2018.00427] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/10/2018] [Indexed: 12/31/2022] Open
Abstract
Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. Modulation of histone and DNA modification enzymes occurs owing to metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes is, in turn, epigenetically regulated, promoting the well-known metabolic reprogramming of cancer cells and, consequently, altering the metabolome. Thus, several malignant traits are supported by the interplay between metabolomics and epigenetics, promoting neoplastic transformation. In this review we emphasize the importance of tumour metabolites in the activity of most chromatin-modifying enzymes and implication in neoplastic transformation. Furthermore, candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer.
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Affiliation(s)
- Vera Miranda-Gonçalves
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Ana Lameirinhas
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Master in Oncology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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41
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Zhang H, Liu J, Li G, Wei J, Chen H, Zhang C, Zhao J, Wang Y, Dang S, Li X, Fang X, Liu L, Liu M. Fresh red raspberry phytochemicals suppress the growth of hepatocellular carcinoma cells by PTEN/AKT pathway. Int J Biochem Cell Biol 2018; 104:55-65. [PMID: 30195065 DOI: 10.1016/j.biocel.2018.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 08/17/2018] [Accepted: 09/04/2018] [Indexed: 12/24/2022]
Abstract
The red raspberry (Rubus idaeus L.) is a common fruit worldwide and its extract has been found to inhibit the growth of many types of tumors, mainly because it is rich in bioactive phytochemicals. However, the mechanism underlying its anticancer activity in hepatocellular carcinoma (HCC) is not well understood. Herein, the aim of this study was to determine the effects of red raspberry phytochemicals on the proliferation of hepatocellular carcinoma cells and to elucidate its biochemical and molecular targets. CCK8 and colony formation, as well as flow cytometry assays, were employed to determine the effects of red raspberry extract (RRE) on cell proliferation and cell cycle distribution in HCC cells. Our results showed that RRE significantly inhibited cell proliferation and arrested cell cycle progression at the S phase in HCC cells. RRE increased the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) by reducing the methylation status of the PTEN gene promoter and inhibiting DNMT1 expression and regulated AKT signaling pathway. These findings show that red raspberry phytochemicals inhibit the proliferation of HCC cells by regulating PTEN/AKT signaling pathway, providing evidence that RRE may be used as a potential auxiliary therapy for patients with HCC.
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Affiliation(s)
- Haopeng Zhang
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Jiaren Liu
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Guodong Li
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Jiufeng Wei
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Hongsheng Chen
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chunpeng Zhang
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Jinlu Zhao
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yunfeng Wang
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Shuwei Dang
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xinglong Li
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xuan Fang
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Lianxin Liu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University & Key Laboratory of Hepatosplenic Surgery Ministry of Education, Harbin, 150001, China
| | - Ming Liu
- Department of General Surgery & Bio-Bank of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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Naderali E, Khaki AA, Rad JS, Ali-Hemmati A, Rahmati M, Charoudeh HN. Regulation and modulation of PTEN activity. Mol Biol Rep 2018; 45:2869-2881. [PMID: 30145641 DOI: 10.1007/s11033-018-4321-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 08/20/2018] [Indexed: 01/04/2023]
Abstract
PTEN (Phosphatase and tensin homolog deleted on chromosome ten) is a tumor suppressor that is frequently mutated in most human cancers. PTEN is a lipid and protein phosphatase that antagonizes PI3K/AKT pathway through lipid phosphatase activity at the plasma membrane. More recent studies showed that, in addition to the putative role of PTEN as a PI(3,4,5)P3 3-phosphatase, it is a PI(3,4)P2 3-phosphatase during stimulation of class I PI3K signaling pathway by growth factor. Although PTEN tumor suppressor function via it's lipid phosphatase activity occurs primarily in the plasma membrane, it can also be found in the nucleus, in cytoplasmic organelles and extracellular space. PTEN has also shown phosphatase independent functions in the nucleus. PTEN can exit from the cell through exosomal export or secretion and has a tumor suppressor function in adjacent cells. PTEN has a critical role in growth, the cell cycle, protein synthesis, survival, DNA repair and migration. Understanding the regulation of PTEN function, activity, stability, localization and its dysregulation outcomes and also the intracellular and extracellular role of PTEN and paracrine role of PTEN-L in tumor cells as an exogenous therapeutic agent can help to improve clinical conceptualization and treatment of cancer.
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Affiliation(s)
- Elahe Naderali
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Afshin Khaki
- Department of Anatomical sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleymani Rad
- Department of Anatomical sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Ali-Hemmati
- Department of Anatomical sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Rahmati
- Department of Clinical Biochemistry Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hojjatollah Nozad Charoudeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Cell Therapy Research Laboratory, Drug Applied Research Center, Tabriz University of Medical Sciences, P.O. Box: 51656-65811, Tabriz, Iran.
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43
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Catuogno S, Esposito CL, Ungaro P, de Franciscis V. Nucleic Acid Aptamers Targeting Epigenetic Regulators: An Innovative Therapeutic Option. Pharmaceuticals (Basel) 2018; 11:ph11030079. [PMID: 30149585 PMCID: PMC6161095 DOI: 10.3390/ph11030079] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/11/2022] Open
Abstract
Epigenetic mechanisms include DNA methylation, posttranslational modifications of histones, chromatin remodeling factors, and post transcriptional gene regulation by noncoding RNAs. All together, these processes regulate gene expression by changing chromatin organization and DNA accessibility. Targeting enzymatic regulators responsible for DNA and chromatin modifications hold promise for modulating the transcriptional regulation of genes that are involved in cancer, as well as in chronic noncommunicable metabolic diseases like obesity, diabetes, and cardiovascular diseases. Increasingly studies are emerging, leading to the identification of specific and effective molecules targeting epigenetic pathways involved in disease onset. In this regard, RNA interference, which uses small RNAs to reduce gene expression and nucleic acid aptamers are arising as very promising candidates in therapeutic approach. Common to all these strategies is the imperative challenge of specificity. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands, their high chemical flexibility as well as tissue penetration capability. In this review, we will focus on the recent progress in the field of aptamers used as targeting moieties able to recognize and revert epigenetics marks involved in diseases onset.
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Affiliation(s)
- Silvia Catuogno
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale del CNR "G. Salvatore", Via S. Pansini 5, 80131 Naples, Italy.
| | - Carla Lucia Esposito
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale del CNR "G. Salvatore", Via S. Pansini 5, 80131 Naples, Italy.
| | - Paola Ungaro
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale del CNR "G. Salvatore", Via S. Pansini 5, 80131 Naples, Italy.
| | - Vittorio de Franciscis
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale del CNR "G. Salvatore", Via S. Pansini 5, 80131 Naples, Italy.
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Xu W, Yang Z, Xie C, Zhu Y, Shu X, Zhang Z, Li N, Chai N, Zhang S, Wu K, Nie Y, Lu N. PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:198. [PMID: 30134988 PMCID: PMC6104022 DOI: 10.1186/s13046-018-0795-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023]
Abstract
Background Phosphatase and tensin homolog (PTEN) is an important tumor suppressor gene, and its encoded protein has activities of both a protein phosphatase and a lipid phosphatase. However, the substitution effect of protein phosphatase activity remains unclear. PI3K/Akt is the most common pathway negatively regulated by PTEN. The Hippo and PI3K/Akt pathways have a joint effect in regulating cell proliferation and apoptosis. Therefore, how PTEN lipid phosphatase inactivation contributes to the occurrence and development of gastric cancer and the potential role of the Hippo and PI3K/Akt pathways in PTEN lipid phosphatase inactivation mediated gastric tumorigenesis remain to be explored. Methods Immunohistochemical staining was performed to detect the expression of p-PTEN and YAP in a gastric cancer tissue microarray. Stable cell lines expressing a wild-type or dominant-negative mutant PTEN were established. The proliferation and migration of stable cells were detected by MTT, BrdU, and colony-formation, transwell assay and high content analysis in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the Hippo and Akt signaling pathways were detected by western blot. Nuclear-cytoplasm separation, immunofluorescence and coimmunoprecipitation analyses were conducted to explore the dysregulation of Hippo in the stable cell lines. Results PTEN lipid phosphatase inactivation strongly promoted the proliferation and migration of gastric cancer cells in vitro and tumor growth in vivo. A immunohistochemical analysis of gastric cancer tissues revealed a significant correlation between phosphorylated PTEN and nuclear YAP expression, and both were determined to be independent prognostic factors for gastric cancer. Mechanistically, PTEN lipid phosphatase inactivation abolished the MOB1-LATS1/2 interaction, decreased YAP phosphorylation and finally promoted YAP nuclear translocation, which enhanced the synergistic effect of YAP-TEAD, thus inducing cell proliferation and migration. Moreover, PTEN lipid phosphatase inactivation promoted the PI3K/Akt pathway, and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose-dependent manner. Conclusions Taken together, our findings indicate that PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to promote gastric tumorigenesis and cancer development. Electronic supplementary material The online version of this article (10.1186/s13046-018-0795-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Zhe Zhang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Na Chai
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Song Zhang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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45
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Emadi-Baygi M, Sedighi R, Nourbakhsh N, Nikpour P. Pseudogenes in gastric cancer pathogenesis: a review article. Brief Funct Genomics 2018; 16:348-360. [PMID: 28459995 DOI: 10.1093/bfgp/elx004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer burden rises globally at an alarming pace. According to GLOBOCAN 2012, gastric cancer (GC) is regarded as the fifth most common malignancy in the world. Being twice as high in men as in women, GC is the third leading cause of cancer mortality in both sexes globally. Being labeled as 'junk DNA', pseudogenes were considered as nonfunctional 'trash', which contribute nothing to survival of the organism; therefore, a number of strategies have been developed to circumvent their accidental detection. Recent progresses have confirmed that pseudogenes can have broad and multifaceted spectrum of activities in human cancers in general and GC in particular. Furthermore, the mentioned functions are parental gene-dependent and/or -independent. Therefore, pseudogenes can be regarded as the emerging class of elaborate modulators of gene expression involved in pathogenesis of human cancers including gastric adenocarcinoma.
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46
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Cruickshank B, Giacomantonio M, Marcato P, McFarland S, Pol J, Gujar S. Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy. Front Immunol 2018; 9:654. [PMID: 29666625 PMCID: PMC5891575 DOI: 10.3389/fimmu.2018.00654] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/16/2018] [Indexed: 12/13/2022] Open
Abstract
Immunogenic cell death (ICD) activates both innate and adaptive arms of the immune system during apoptotic cancer cell death. With respect to cancer immunotherapy, the process of ICD elicits enhanced adjuvanticity and antigenicity from dying cancer cells and consequently, promotes the development of clinically desired antitumor immunity. Cancer ICD requires the presentation of various "hallmarks" of immunomodulation, which include the cell-surface translocation of calreticulin, production of type I interferons, and release of high-mobility group box-1 and ATP, which through their compatible actions induce an immune response against cancer cells. Interestingly, recent reports investigating the use of epigenetic modifying drugs as anticancer therapeutics have identified several connections to ICD hallmarks. Epigenetic modifiers have a direct effect on cell viability and appear to fundamentally change the immunogenic properties of cancer cells, by actively subverting tumor microenvironment-associated immunoevasion and aiding in the development of an antitumor immune response. In this review, we critically discuss the current evidence that identifies direct links between epigenetic modifications and ICD hallmarks, and put forward an otherwise poorly understood role for epigenetic drugs as ICD inducers. We further discuss potential therapeutic innovations that aim to induce ICD during epigenetic drug therapy, generating highly efficacious cancer immunotherapies.
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Affiliation(s)
| | | | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Sherri McFarland
- Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, United States
- Department of Chemistry, Acadia University, Wolfville, NS, Canada
| | - Jonathan Pol
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- INSERM, U1138, Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie, Paris, France
| | - Shashi Gujar
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
- Department of Biology, Dalhousie University, Halifax, NS, Canada
- Centre for Innovative and Collaborative Health Services Research, IWK Health Centre, Halifax, NS, Canada
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Current Insights into Oral Cancer Epigenetics. Int J Mol Sci 2018; 19:ijms19030670. [PMID: 29495520 PMCID: PMC5877531 DOI: 10.3390/ijms19030670] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 02/20/2018] [Accepted: 02/22/2018] [Indexed: 12/30/2022] Open
Abstract
Epigenetic modifications have emerged into one of the cancer hallmarks, replacing the concept of malignant pathologies as being solely genetic-based conditions. The epigenetic landscape is responsible for normal development but also for the heterogeneity among tissues in terms of gene expression patterns. Dysregulation in these mechanisms has been associated with disease stage, and increased attention is now granted to cancer in order to take advantage of these modifications in terms of novel therapeutic strategies or diagnosis/prognosis tools. Oral cancer has also been subjected to epigenetic analysis with numerous studies revealing that the development and progression of this malignancy are partially induced by an altered epigenetic substrate together with genetic alterations and prolonged exposure to environmental risk factors. The present review summarizes the most important epigenetic modifications associated with oral cancer and also their potential to be used as new therapeutic targets.
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48
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Yang Z, Cao X, Xu W, Xie C, Chen J, Zhu Y, Lu N. Phosphorylation of phosphatase and tensin homolog induced by Helicobacter pylori promotes cell invasion by activation of focal adhesion kinase. Oncol Lett 2017; 15:1051-1057. [PMID: 29399165 PMCID: PMC5772772 DOI: 10.3892/ol.2017.7430] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 10/18/2017] [Indexed: 02/06/2023] Open
Abstract
Phosphorylation of the phosphatase and tensin homolog (PTEN) tumor suppressor at Ser380/Thr382/Thr383 residues is a novel mechanism underlying PTEN inactivation in gastric carcinogenesis, which may be triggered by Helicobacter pylori infection. To investigate this further, the effect of H. pylori infection on PTEN phosphorylation and the subsequent activation of focal adhesion kinase (FAK), were evaluated in gastric tissue samples from Mongolian gerbils and in the human gastric epithelial mucosa cell line GES-1 using immunohistochemistry, western blotting and Transwell assays. The in vivo and in vitro results of the present study demonstrated that H. pylori infection induced the phosphorylation and inactivation of PTEN at Ser380/Thr382/383, and the subsequent phosphorylation and activation of FAK at Tyr397. Gastric epithelial cell invasion was also increased. Furthermore, stable expression of a dominant-negative PTEN mutant inhibited the enhanced FAK activation and cell invasion induced by H. pylori infection. These results suggest that the mechanism underlying H. pylori-induced carcinogenesis may involve promoting cell invasion through the phosphorylation of PTEN and the activation of FAK.
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Affiliation(s)
- Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ximei Cao
- Department of Gastroenterology, First Peoples' Hospital of Jiujiang, Jiujiang, Jiangxi 332000, P.R. China
| | - Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Wang C, Li L, Duan Q, Wang Q, Chen J. Krüppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling. Oncotarget 2017; 8:100358-100370. [PMID: 29245984 PMCID: PMC5725026 DOI: 10.18632/oncotarget.22229] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 10/05/2017] [Indexed: 02/06/2023] Open
Abstract
Krüppel-like factors (KLFs) are a large family of DNA-binding transcriptional regulators that affect basic cellular processes such as growth, survival, migration and differentiation and serve a complicated function in cancers. KLF2, one member of the KLF family, is dysregulated in many tumors. However, the specific role of KLF2 in human gastric tumorigenesis is unknown. Here we show that the expression of KLF2 protein was lower in gastric tumors when compared with adjacent normal tissue. Moreover, downregulated KLF2 expression in primary gastric tumor was closely correlated with patients’ survival. Various cell experiments showed that ectopic KLF2 expression suppressed the proliferation, migration and invasion of gastric cancer cells. Moreover, KLF2 overexpression remarkably enhanced cell apoptosis and induced cell cycle arrest. Impaired expression of KLF2 markedly promoted cell growth in vitro and significantly expanded tumor size in vivo. Mechanically, the mRNA and protein level of PTEN was reduced in KLF2 deficient cells and xenograft tumors, suggesting that PTEN/AKT signaling was involved in the gastric tumor inhibitory effect of KLF2. Administration of AKT inhibitor AZD5363 or Insulin-like growth factor-1 (IGF-1) in KLF2 knockdown or ectopic expression cell lines, respectively, substantially reversed the proliferation phenotype. Collectively, our findings provide clinical evidence and a potential mechanism supporting that KLF2 suppresses human gastric tumorigenesis through inhibiting the PTEN/AKT axis.
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Affiliation(s)
- Chunmei Wang
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai 200241, China.,Department of Gastroenterology, Affiliated Fengxian Hospital of Southern Medical University, Shanghai 201499, China.,Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Liang Li
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai 200241, China
| | - Qiuhui Duan
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai 200241, China
| | - Qingqing Wang
- Department of Gastroenterology, Affiliated Fengxian Hospital of Anhui University of Science and Technology, Shanghai 201499, China
| | - Jinlian Chen
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai 200241, China.,Department of Gastroenterology, Affiliated Fengxian Hospital of Southern Medical University, Shanghai 201499, China
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50
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Ma Q, Wu X, Wu J, Wu H, Xiao Y, Wang L, Liang Z, Liu T. PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation. Oncotarget 2017; 8:72893-72909. [PMID: 29069834 PMCID: PMC5641177 DOI: 10.18632/oncotarget.20552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/31/2017] [Indexed: 01/26/2023] Open
Abstract
Phosphorylation is a recently established cause of phosphatase and tensin homolog (PTEN) gene inactivation, which leads to defect tumour-suppressor function. In pancreatic cancer, this phenomenon has not been reported. Based on database and clinical sample analyses, we found that PTEN phosphorylation occurs in pancreatic ductal adenocarcinoma patient tissues and cell lines, and we aimed to find a method for dephosphorylation. PDZ-containing 1 (PDZK1), a tumour-associated protein that shares its PDZ-binding sequence with the carboxyl-terminal domain of PTEN, was significantly down-regulated in pancreatic cancer as compared to adjacent non-tumour tissues. In vitro, PDZK1 overexpression reversed the proliferation and migration abilities of pancreatic cancer cells and led to significantly decreased PTEN phosphorylation and AKT phosphorylation by interacting with wild-type PTEN. In addition, a transcription factor-activation assay supported that PDZK1 overexpression enhanced the anti-oncogene function of PTEN by regulating the activities of its downstream transcription factors, including p53, NF-κB, and FOXO1. In vivo, nude mice stably over-expressing PDZK1 had lower tumour weights and volumes and showed significantly down-regulated PTEN phosphorylation in xenograft tumour tissues as compared to the control group. Moreover, low PDZK1 expression strongly correlated with advanced stage and poor prognosis of patients with pancreatic ductal adenocarcinoma. In conclusion, our study elucidated the tumour-suppressor role of PDZK1 in pancreatic cancer through down-regulating PTEN phosphorylation, and established PDZK1 as a potential novel prognostic marker for pancreatic cancer.
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Affiliation(s)
- Qiang Ma
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Xiuxiu Wu
- Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Jing Wu
- Department of Medical Imaging, Beijing Huairou Hospital, University of Chinese Academy of Science, Beijing, 101400, P.R. China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Ying Xiao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Lili Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
| | - Tonghua Liu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P. R. China
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