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Arslan Bozdag L, Inan S, Elif Gultekin S. Microsatellite Instability and Loss of Heterozygosity as Prognostic Markers in Oral Squamous Cell Carcinoma: Molecular Mechanisms, Detection Techniques, and Therapeutic Strategies. Genes Chromosomes Cancer 2024; 63:e70002. [PMID: 39470253 DOI: 10.1002/gcc.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 10/05/2024] [Indexed: 10/30/2024] Open
Abstract
The aim of this study was to conduct a systematic review of research investigating the potential role of microsatellite instability (MSI) and loss of heterozygosity (LOH) in oral squamous cell carcinoma (OSCC), with a focus on molecular mechanisms, detection methods, and therapeutic approaches. Search for articles involved the PubMed and Scopus. Previous retrospective and prospective studies identified variations between oral cancers that exhibit microsatellite stability and LOH. In this search, 294 articles were initially retrieved. Of these, 70 were excluded due to duplication, 106 were identified as ineligible by automated tools, and 24 were excluded as they were published in languages other than English. An additional 94 articles were excluded, 32 of which focused on head and neck cancers broadly, and 8 could not be accessed due to withdrawal. Ultimately, a systematic review was conducted based on 54 selected articles. Among the chromosomes analyzed for MSI and LOH, the highest frequency of LOH was observed on chromosome 9p. The MSI subtype is particularly susceptible to immunotherapeutic methods, such as the use of anti-PD-L1 and anti-CTLA4 antibodies, owing to its strong immunogenicity and ubiquitous expression of immune checkpoint ligands. Given the distinct characteristics and clinical behavior of oral cancer with MSI compared to microsatellite stable disease, it is advisable to incorporate MSI testing into the diagnostic process for all stages of tumor development. This ensured that each patient had received precise and effective treatment.
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Affiliation(s)
- Leyla Arslan Bozdag
- Faculty of Science, Department of Biology, Gazi University, Ankara, Turkey
- Faculty of Dentistry, Department of Oral Pathology, Gazi University, Ankara, Turkey
| | - Sevinç Inan
- Tepebasi Oral Dental Health Centre, Ankara, Turkey
| | - Sibel Elif Gultekin
- Faculty of Dentistry, Department of Oral Pathology, Gazi University, Ankara, Turkey
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2
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Abbasi SF, Mahjabeen I, Parveen N, Qamar I, Haq MFU, Shafique R, Saeed N, Ashraf NS, Kayani MA. Exploring homologous recombination repair and base excision repair pathway genes for possible diagnostic markers in hematologic malignancies. Mol Genet Genomics 2023; 298:1527-1543. [PMID: 37861816 DOI: 10.1007/s00438-023-02078-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 10/04/2023] [Indexed: 10/21/2023]
Abstract
Hematologic malignancies (HMs) are a collection of malignant transformations, originating from the cells in the bone marrow and lymphoid organs. HMs comprise three main types; leukemia, lymphoma, and multiple myeloma. Globally, HMS accounts for approximately 10% of newly diagnosed cancer. DNA repair pathways defend the cells from recurrent DNA damage. Defective DNA repair mechanisms such as homologous recombination repair (HRR), nucleotide excision repair (NER), and base excision repair (BER) pathways may lead to genomic instability, which initiates HM progression and carcinogenesis. Expression deregulation of HRR, NER, and BER has been investigated in various malignancies. However, no studies have been reported to assess the differential expression of selected DNA repair genes combinedly in HMs. The present study was designed to assess the differential expression of HRR and BER pathway genes including RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 in blood cancer patients to highlight their significance as diagnostic/ prognostic marker in hematological malignancies. The study cohort comprised of 210 blood cancer patients along with an equal number of controls. For expression analysis, q-RT PCR was performed. DNA damage was measured in blood cancer patients and controls using the comet assay and LORD Q-assay. Data analysis showed significant downregulation of selected genes in blood cancer patients compared to healthy controls. To check the diagnostic value of selected genes, the Area under curve (AUC) was calculated and 0.879 AUC was observed for RAD51 (p < 0.0001) and 0.830 (p < 0.0001) for APEX1. Kaplan-Meier analysis showed that downregulation of RAD51 (p < 0.0001), XRCC3 (p < 0.02), and APEX1 (p < 0.0001) was found to be associated with a significant decrease in survival of blood cancer patients. Cox regression analysis showed that deregulation of RAD51 (p < 0.0001), XRCC2 (p < 0.02), XRCC3 (p < 0.003), and APEX1 (p < 0.00001) was found to be associated with the poor prognosis of blood cancer patients. Comet assay showed an increased number of comets in blood cancer patients compared to controls. These results are confirmed by performing the LORD q-assay and an increased frequency of lesions/Kb was observed in selected genes in cancer patients compared to controls. Our results showed significant downregulation of RAD51, XRCC2, XRCC3, APEX1, FEN1, PARP1, and XRCC1 genes with increased DNA damage in blood cancer patients. The findings of the current research suggested that deregulated expression of HRR and BER pathway genes can act as a diagnostic/prognostic marker in hematologic malignancies.
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Affiliation(s)
- Sumaira Fida Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan.
| | - Neelam Parveen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Imama Qamar
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Maria Fazal Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Rabia Shafique
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Nida Sarosh Ashraf
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road, Islamabad, Pakistan
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Wang F, Gouttia OG, Wang L, Peng A. PARP1 Upregulation in Recurrent Oral Cancer and Treatment Resistance. Front Cell Dev Biol 2022; 9:804962. [PMID: 35071239 PMCID: PMC8769238 DOI: 10.3389/fcell.2021.804962] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
First-line treatments for oral cancer typically include surgery, radiation, and in some cases, chemotherapy. Radiation and oral cancer chemotherapeutics confer cytotoxicity largely by inducing DNA damage, underscoring the importance of the cellular DNA damage repair and response pathways in cancer therapy. However, tumor recurrence and acquired resistance, following the initial response to treatment, remains as a major clinical challenge. By analyzing oral tumor cells derived from the primary and recurrent tumors of the same patient, our study revealed upregulated PARP1 expression in the recurrent tumor cells. Cisplatin and 5-fluorouracil treatment further augmented PARP1 expression in the recurrent, but not the primary, tumor cells. Post-treatment upregulation of PARP1 was dependent on the catalytic activities of PARP and CDK7. Consistent with the established function of PARP1 in DNA repair, we showed that overexpression of PARP1 rendered the primary tumor cells highly resistant to DNA damage treatment. Conversely, PARP inhibition partially reversed the treatment resistance in the recurrent tumor cells; combinatorial treatment using a PARP inhibitor and cisplatin/5-fluorouracil significantly sensitized the tumor response in vivo. Taken together, we reported here PARP1 upregulation as a clinically relevant mechanism involved in oral cancer recurrence, and suggested the clinical benefit of PARP inhibitors, currently approved for the treatment of several other types of cancer, in oral cancer.
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Affiliation(s)
- Feifei Wang
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Odjo G Gouttia
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Ling Wang
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Aimin Peng
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
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Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics. Oral Oncol 2021; 121:105451. [PMID: 34329869 DOI: 10.1016/j.oraloncology.2021.105451] [Citation(s) in RCA: 235] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Oral cavity squamous cell carcinoma (OCSCC) is the most common malignancy of the oral cavity. The substantial risk factors for OCSCC are the consumption of tobacco products, alcohol, betel quid, areca nut, and genetic alteration. However, technological advancements have occurred in treatment, but the survival decreases with late diagnosis; therefore, new methods are continuously being investigated for treatment. In addition, the rate of secondary tumor formation is 3-7% yearly, which is incomparable to other malignancies and can lead to the disease reoccurrence. Oral cavity cancer (OCC) arises from genetic alterations, and a complete understanding of the molecular mechanism involved in OCC is essential to develop targeted treatments. This review aims to update the researcher on oral cavity cancer, risk factors, genetic alterations, molecular mechanism, classification, diagnostic approaches, and treatment.
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Kabzinski J, Maczynska M, Kaczmarczyk D, Majsterek I. Influence of Arg399Gln, Arg280His and Arg194Trp XRCC1 gene polymorphisms of Base Excision Repair pathway on the level of 8-oxo-guanine and risk of head and neck cancer in the Polish population. Cancer Biomark 2021; 32:317-326. [PMID: 34151836 DOI: 10.3233/cbm-203163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Reduced efficiency of DNA repair systems has long been a suspected factor in increasing the risk of cancer. OBJECTIVE In this work we investigate influence of three selected polymorphisms of DNA repair gene XRCC1 and level of oxidative damage (measured as level of 8-oxo-guanine) on modulation of the risk of HNSCC. METHODS In group of 359 patients with HNSCC (diagnosed with OSCC) the occurrence of polymorphic variants in Arg399Gln, Arg280His and Arg194Trp of XRCC1 were studied with TaqMan technique. In addition we determined level of 8-oxo-guanine with ELISA. RESULTS Arg399Gln polymorphism and Arg194Trp polymorphism of XRCC1 gene increases the risk of HNSCC. The coexistence of Arg399Gln and Arg194Trp simultaneously enhances this effect. At the same time, their coexistence with His280His raises the risk to a level higher than in the absence of such coexistence, although the His280His itself is not associated with an increased risk of HNSCC. Patients have higher levels of 8-oxo-guanine than control group, and His280His is polymorphism with highest mean value of 8-oxoG level among studied. CONCLUSION Patients with HNSCC not only have an increased level of 8-oxoguanine and the Arg399Gln and Arg/Trp of XRCC1 modulate risk of cancer, but there is also a relationship between these two phenomena, and it can be explained using intragenic combinations revealing that a high level of 8-oxoG could be a potential mechanism behind the modulation of HNSCC risk by the polymorphisms studied.
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Affiliation(s)
- Jacek Kabzinski
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łodz, Poland
| | - Monika Maczynska
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łodz, Poland
| | - Dariusz Kaczmarczyk
- Department of Head and Neck Neoplasm Surgery, Medical University of Lodz, Łodz, Poland
| | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Łodz, Poland
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Gutiérrez-Díez PJ, Gomez-Pilar J, Hornero R, Martínez-Rodríguez J, López-Marcos MA, Russo J. The role of gene to gene interaction in the breast's genomic signature of pregnancy. Sci Rep 2021; 11:2643. [PMID: 33514799 PMCID: PMC7846553 DOI: 10.1038/s41598-021-81704-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/18/2020] [Indexed: 12/20/2022] Open
Abstract
Full-term pregnancy at an early age confers long-term protection against breast cancer. Published data shows a specific transcriptomic profile controlling chromatin remodeling that could play a relevant role in the pregnancy-induced protection. This process of chromatin remodeling, induced by the breast differentiation caused by the first full-term pregnancy, has mainly been measured by the expression level of genes individually considered. However, genes equally expressed during the process of chromatin remodeling may behave differently in their interaction with other genes. These changes at the gene cluster level could constitute an additional dimension of chromatin remodeling and therefore of the pregnancy-induced protection. In this research, we apply Information and Graph Theories, Differential Co-expression Network Analysis, and Multiple Regression Analysis, specially designed to examine structural and informational aspects of data sets, to analyze this question. Our findings demonstrate that, independently of the changes in the gene expression at the individual level, there are significant changes in gene-gene interactions and gene cluster behaviors. These changes indicate that the parous breast, through the process of early full-term pregnancy, generates more modules in the networks, with higher density, and a genomic structure performing additional and more complex functions than those found in the nulliparous breast.
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Affiliation(s)
- Pedro J Gutiérrez-Díez
- IMUVA Mathematical Institute, University of Valladolid, Valladolid, Spain
- Faculty of Economics, University of Valladolid, Valladolid, Spain
| | - Javier Gomez-Pilar
- Biomedical Engineering Group, University of Valladolid, Paseo de Belén, 15, 47011, Valladolid, Spain.
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Valladolid, Spain.
| | - Roberto Hornero
- IMUVA Mathematical Institute, University of Valladolid, Valladolid, Spain
- Biomedical Engineering Group, University of Valladolid, Paseo de Belén, 15, 47011, Valladolid, Spain
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Valladolid, Spain
| | - Julia Martínez-Rodríguez
- IMUVA Mathematical Institute, University of Valladolid, Valladolid, Spain
- Faculty of Economics, University of Valladolid, Valladolid, Spain
| | - Miguel A López-Marcos
- IMUVA Mathematical Institute, University of Valladolid, Valladolid, Spain
- Faculty of Science, University of Valladolid, Valladolid, Spain
| | - Jose Russo
- The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center - Temple University Health System, Philadelphia, USA
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Usman S, Jamal A, Teh MT, Waseem A. Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance. FRONTIERS IN ORAL HEALTH 2021; 1:603160. [PMID: 35047986 PMCID: PMC8757854 DOI: 10.3389/froh.2020.603160] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
Oral cancer is a sub-category of head and neck cancers that primarily initiates in the oral cavity. The primary treatment option for oral cancer remains surgery but it is associated with massive disfigurement, inability to carry out normal oral functions, psycho-social stress and exhaustive rehabilitation. Other treatment options such as chemotherapy and radiotherapy have their own limitations in terms of toxicity, intolerance and therapeutic resistance. Immunological treatments to enhance the body's ability to recognize cancer tissue as a foreign entity are also being used but they are new and underdeveloped. Although substantial progress has been made in the treatment of oral cancer, its complex heterogeneous nature still needs to be explored, to elucidate the molecular basis for developing resistance to therapeutic agents and how to overcome it, with the aim of improving the chances of patients' survival and their quality of life. This review provides an overview of up-to-date information on the complex role of the major molecules and associated signaling, epigenetic changes, DNA damage repair systems, cancer stem cells and micro RNAs in the development of therapeutic resistance and treatment failure in oral cancer. We have also summarized the current strategies being developed to overcome these therapeutic challenges. This review will help not only researchers but also oral oncologists in the management of the disease and in developing new therapeutic modalities.
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Affiliation(s)
| | | | | | - Ahmad Waseem
- Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Ramesh PS, Devegowda D, Singh A, Thimmulappa RK. NRF2, p53, and p16: Predictive biomarkers to stratify human papillomavirus associated head and neck cancer patients for de-escalation of cancer therapy. Crit Rev Oncol Hematol 2020; 148:102885. [PMID: 32062315 DOI: 10.1016/j.critrevonc.2020.102885] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/09/2020] [Accepted: 01/25/2020] [Indexed: 01/18/2023] Open
Abstract
Patients with HPV associated (HPV+ve) head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal cancer, show better treatment response, higher survival rates, and lower risks of recurrence as compared to HPV-ve HNSCC patients. Despite increased sensitivity to treatment modality, HPV+ve HNSCC patients are subjected to the same intensive anti-cancer therapy as HPV-ve HNSCC patients and thus subjecting them to unwarranted long-term toxicity. To identify predictive biomarkers for risk-stratification, we have analyzed the mutational spectrum, and the evidence suggests that gain-of-function mutations in the NRF2 pathway are highly prevalent in HPV-ve HNSCC. At the same time, it is rare in HPV+ve HNSCC tumors. We have reviewed the importance of gain-of-NRF2 function and loss of p53 in the prognosis of HNSCC patients and discussed a predictive scoring system using a combination of HPV status (p16), NRF2 pathway and p53 to stratify HPV+ve HNSCC into good versus poor responders, which could immensely help in guiding future de-escalation treatment approaches in patients with HPV+ve HNSCC.
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Affiliation(s)
- Pushkal S Ramesh
- Centre of Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, India
| | - Devananda Devegowda
- Centre of Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, India
| | - Anju Singh
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, United States
| | - Rajesh K Thimmulappa
- Centre of Excellence in Molecular Biology & Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, India.
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Lu H, Lu Y, Xie Y, Qiu S, Li X, Fan Z. Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma. JCI Insight 2019; 4:131106. [PMID: 31578313 DOI: 10.1172/jci.insight.131106] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/31/2019] [Indexed: 12/28/2022] Open
Abstract
Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.
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Affiliation(s)
- Haiquan Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Yang Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yangyiran Xie
- Program in Neuroscience, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, USA
| | - Songbo Qiu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xinqun Li
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhen Fan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
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PARP1: A potential biomarker for gastric cancer. Pathol Res Pract 2019; 215:152472. [DOI: 10.1016/j.prp.2019.152472] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/13/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022]
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Sarkar S, Panda CK. Preferential allelic deletion of RBSP3, LIMD1 and CDC25A in head and neck squamous cell carcinoma: Implication in cancer screening and early detection. Cancer Biol Ther 2018; 19:631-635. [PMID: 29624473 DOI: 10.1080/15384047.2018.1449615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Abstract
Head and neck squamous cell carcinoma is one of the leading cancers in terms of incidence and mortality. However, no reliable marker till date accurately predicts its progression when altered in healthy tissues. The study aims to identify alleles of microsatellites adjacent to important cell cycle regulatory, tumor suppressor genes altered in early head and neck lesions, viz. RBSP3, LIMD1 and CDC25A, which undergo frequent deletion and can be used for population screening and early detection. DNA for tumors and normal tissues was isolated from 143 patients in different stages of head and neck squamous cell carcinoma. The size of microsatellite present in normal tissues and their deletion in the corresponding tumor was identified, along with the correlation of expression in normal epithelium with respect to allele size. The results revealed a range of alleles (CA9 to CA32) for the different microsatellites of the genes in normal tissues. The larger alleles were significantly deleted with differential deletion of alleles observed in tumors, except for LIMD1, in which the smaller allele was significantly deleted. In normal tissues, some alleles represented as stable alleles with high prevalence, while in tumours, specific sizes showed greater propensity for deletion. However, similar expression of the proteins in normal epithelium adjacent to tumors was observed despite variations in allele size, possibly due to the location of the microsatellites. Thus, those alleles when present in normal tissues and undergoing persistent deletion in tumours could be used as markers for screening and early identification of populations at risk of developing head and neck lesions.
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Affiliation(s)
- Shreya Sarkar
- a Department of Oncogene Regulation , Chittaranjan National Cancer Institute , Kolkata , India
| | - Chinmay Kumar Panda
- a Department of Oncogene Regulation , Chittaranjan National Cancer Institute , Kolkata , India
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12
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Gorska M, Zmijewski MA, Kuban-Jankowska A, Wnuk M, Rzeszutek I, Wozniak M. Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line. Mol Neurobiol 2015; 53:5030-40. [PMID: 26381428 DOI: 10.1007/s12035-015-9434-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023]
Abstract
2-methoxyestradiol, metabolite of 17β-estradiol, is considered a potential anticancer agent, currently investigated in several clinical trials. This natural compound was found to be effective towards great number of cancers, including colon, breast, lung, and osteosarcoma and has been reported to be relatively non-toxic towards non-malignant cells. The aim of the study was to determine the potential neurotoxicity and genotoxicity of 2-methoxyestradiol at physiological and pharmacological relevant concentrations in hippocampal HT22 cell line. Herein, we determined influence of 2-methoxyestradiol on proliferation, inhibition of cell cycle, induction of apoptosis, and DNA damage in the HT22 cells. The study was performed using imaging cytometry and comet assay techniques. Herein, we demonstrated that 2-methoxyestradiol, at pharmacologically and also physiologically relevant concentrations, increases nuclear localization of neuronal nitric oxide synthase. It potentially results in DNA strand breaks and increases in genomic instability in hippocampal HT22 cell line. Thus, we are postulating that naturally occurring 2-methoxyestradiol may be considered a physiological modulator of neuron survival.
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Affiliation(s)
- Magdalena Gorska
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland.
| | | | - Alicja Kuban-Jankowska
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland
| | - Maciej Wnuk
- Department of Genetics, University of Rzeszow, Rzeszow, Poland
| | - Iwona Rzeszutek
- Department of Genetics, University of Rzeszow, Rzeszow, Poland
| | - Michal Wozniak
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk 80-211, Debinki 1 St, Poland
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Gorska M, Kuban-Jankowska A, Zmijewski M, Gammazza AM, Cappello F, Wnuk M, Gorzynik M, Rzeszutek I, Daca A, Lewinska A, Wozniak M. DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol. Oncotarget 2015; 6:15449-63. [PMID: 25972363 PMCID: PMC4558163 DOI: 10.18632/oncotarget.3913] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/24/2015] [Indexed: 12/11/2022] Open
Abstract
2-Methoxyestradiol (2-ME) is a physiological metabolite of 17β-estradiol. At pharmacological concentrations, 2-ME inhibits colon, breast and lung cancer in tumor models. Here we investigated the effect of physiologically relevant concentrations of 2-ME in osteosarcoma cell model. We demonstrated that 2-ME increased nuclear localization of neuronal nitric oxide synthase, resulting in nitro-oxidative DNA damage. This in turn caused cell cycle arrest and apoptosis in osteosarcoma cells. We suggest that 2-ME is a naturally occurring hormone with potential anti-cancer properties.
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Affiliation(s)
- Magdalena Gorska
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
| | | | - Michal Zmijewski
- Department of Histology, Medical University of Gdansk, Gdansk, Poland
| | - Antonella Marino Gammazza
- Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy “Emerico Luna”, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Francesco Cappello
- Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy “Emerico Luna”, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Maciej Wnuk
- Department of Genetics, University of Rzeszow, Rzeszow, Poland
| | - Monika Gorzynik
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
| | - Iwona Rzeszutek
- Department of Genetics, University of Rzeszow, Rzeszow, Poland
| | - Agnieszka Daca
- Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland
- Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdansk, Poland
| | - Anna Lewinska
- Department of Biochemistry and Cell Biology, University of Rzeszow, Poland
| | - Michal Wozniak
- Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland
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Tseng SH, Yang CC, Yu EH, Chang C, Lee YS, Liu CJ, Chang KW, Lin SC. K14-EGFP-miR-31 transgenic mice have high susceptibility to chemical-induced squamous cell tumorigenesis that is associating with Ku80 repression. Int J Cancer 2014; 136:1263-75. [PMID: 25082302 DOI: 10.1002/ijc.29106] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 07/24/2014] [Indexed: 12/18/2022]
Abstract
Squamous cell carcinoma (SCC) occurring in the head and neck region and the esophagus causes tremendous cancer mortality around the world. miR-31 is among the most eminently upregulated MicroRNAs in SCC, when it occurs in the head and neck region and the esophagus. We established miR-31 transgenic mouse lines, in which miR-31 is under the control of the K14 promoter. 4-nitroquinoline 1-oxide (4NQO) is a mutagen that causes double strand breaks. The transgenic mice exhibited a higher potential for tumor induction than wild-type (Wt) mice of the tongue and esophagus after 4NQO treatment. After 4NQO treatment or irradiation, p-γH2AX expression in squamous epithelium of transgenic mice was increased more than in Wt mice. Exogenous expression of miR-31 was also found to be associated with the higher p-γH2AX expression induced by 4NQO in human oral SCC (OSCC) cell lines. The repair genes PARP1 and Ku80 were validated as new targets of miR-31 in human OSCC cell lines, and were found to be downregulated in the squamous epithelium of the tongue in transgenic mice. However, only the downregulation of Ku80 was essential for maintaining the high level of p-γH2AX induced by 4NQO in OSCC cells. Inverse expression profiles for miR-31 and Ku80 were noted in human OSCC tissue. Our study identifies the high sensitivity of K14-EGFP-miR-31 transgenic mice to chemical carcinogen-induced squamous cell tumorigenesis and shows that this seems to be associated with the downregulation of Ku80 and an impairment of repair activity in squamous cells, which are mediated by miR-31.
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Affiliation(s)
- Ssu-Hsueh Tseng
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
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15
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Sun CK, Luo XB, Gou YP, Hu L, Wang K, Li C, Xiang ZT, Zhang P, Kong XL, Zhang CL, Yang Q, Li J, Xiao LY, Li Y, Chen QM. TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas. Mol Cancer 2014; 13:180. [PMID: 25070141 PMCID: PMC4118648 DOI: 10.1186/1476-4598-13-180] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Background WRAP53, including α, β and γ isoforms, plays an important role not only in the stability of p53 mRNA, but also in the assembly and trafficking of the telomerase holoenzyme. It has been considered an oncogene and is thought to promote the survival of cancer cells. The aim of this study was to detect the role of TCAB1 (except WRAP53α) in the occurrence and development of head and neck carcinomas. Methods Immunohistochemistry was used to detect the TCAB1 expression in clinical specimen sections and performed western blotting to check the TCAB1 expression levels in cell lines. TCAB1 was depleted using shRNA lentivirus and the knockdown efficiency was assessed using q-PCR and Western blotting. We performed CCK-8 assays and flow cytometry to check the cell proliferation potential and used the trans-well assay to test the invasion ability in vitro. Xenografts were used to detect the tumor formation potential in vivo. Moreover, we performed cDNA microarray to investigate the candidate factors involved in this process. Results We observed a notable overexpression of TCAB1 in head and neck carcinoma clinical specimens as well as in carcinoma cell lines. Knockdown of TCAB1 decreased the cellular proliferation potential and invasion ability in vitro. cDNA microarray analysis suggested the possible involvement of several pathways and factors associated with tumorigenesis and carcinoma development in the TCAB1-mediated regulation of cancers. Furthermore, the xenograft assay confirmed that the depletion of TCAB1 would inhibit tumor formation in nude mice. The immunohistochemistry results of the mice tumor tissue sections revealed that the cells in shTCAB1 xenografts showed decreased proliferation potential and increased apoptotic trend, meanwhile, the angiogenesis was inhibited in the smaller tumors form shTCAB1 cells. Conclusions Our study demonstrated that depletion of TCAB1 decreased cellular proliferation and invasion potential both in vitro and in vivo. The data indicated that TCAB1 might facilitate the occurrence and development of head and neck carcinomas. In future, TCAB1 might be useful as a prognostic biomarker or a potential target for the diagnosis and therapy of head and neck carcinomas.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Li-ying Xiao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
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Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
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Meta analysis of XRCC3 Thr241Met polymorphism and lung cancer susceptibility of populations in East Asia. ASIAN PAC J TROP MED 2014; 7:483-7. [DOI: 10.1016/s1995-7645(14)60079-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/15/2014] [Accepted: 05/15/2014] [Indexed: 11/20/2022] Open
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