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Martins PR, dos Santos TPM, Menezes LM, Froede AG, Gomes MDS, Nogueira L, Braga LDC, do Amaral LR, Salles PGDO. Association of human papillomavirus (HPV), p16, p53 and p63 expression with non-bilharzia-associated squamous cell carcinoma of the bladder and algorithm construction for histopathological grading prediction. EINSTEIN-SAO PAULO 2023; 21:eAO0109. [PMID: 37132663 PMCID: PMC10124586 DOI: 10.31744/einstein_journal/2023ao0109] [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: 03/28/2022] [Accepted: 08/30/2022] [Indexed: 05/04/2023] Open
Abstract
OBJECTIVE To investigate the expression of human papillomavirus (HPV), p16, p53, and p63 in non-schistosomiasis-related squamous cell carcinoma of the bladder and to develop an accurate and automated tool to predict histological classification based on clinicopathological features. METHODS Twenty-eight patients with primary bladder pure squamous cell carcinoma who underwent cystectomy or transurethral resection of bladder tumor (TURBT) for bladder cancer between January 2011 and July 2017 were evaluated. Clinical data and follow-up information were obtained from medical records. Formalin-fixed, paraffin-embedded surgical specimens were used for immunohistochemical staining for p16, p53, and p63. Human papillomavirus detection was evaluated by PCR. Statistical analysis was performed, and statistical significance was set at p<0.05. Finally, decision trees were built to classify patients' prognostic features. Leave-one-out cross-validation was used to test the generalizability of the model. RESULTS Neither direct HPV detection nor its indirect marker (p16 protein) was identified in most cases. The absence of p16 was correlated with less aggressive histological grading (p=0.040). The positive p16 staining detection found only in pT1 and pT2 cases in our sample suggests a possible role for this tumor suppressor protein in the initial stages of bladder squamous cell carcinoma. The decision trees constructed described the relationship between clinical features, such as hematuria/dysuria, the level of tumor invasion, HPV status, lymphovascular invasion, gender, age, compromised lymph nodes, and tumor degree differentiation, with high classification accuracy. CONCLUSION The algorithm classifier approach established decision pathways for semi-automatic tumor histological classification, laying the foundation for tailored semi-automated decision support systems for pathologists.
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Affiliation(s)
- Patrícia Rocha Martins
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
| | - Tálita Pollyanna Moreira dos Santos
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
| | - Letícia Mattos Menezes
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
| | - Astaruth Guimarães Froede
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
| | - Matheus de Souza Gomes
- Universidade Federal de UberlândiaPatos de MinasMGBrazil Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil.
| | - Lucas Nogueira
- Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Letícia da Conceição Braga
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
| | - Laurence Rodrigues do Amaral
- Universidade Federal de UberlândiaUberlândiaMGBrazil Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
| | - Paulo Guilherme de Oliveira Salles
- Núcleo de Ensino e PesquisaInstituto Mário PennaBelo HorizonteMGBrazil Núcleo de Ensino e Pesquisa, Instituto Mário Penna, Belo Horizonte, MG, Brazil.
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Yu YC, Shi TM, Gu SL, Li YH, Yang XM, Fan Q, Wang YD. A novel cervix carcinoma biomarker: Pathological-epigenomics, integrated analysis of MethylMix algorithm and pathology for predicting response to cancer immunotherapy. Front Oncol 2022; 12:1053800. [PMID: 36408176 PMCID: PMC9667097 DOI: 10.3389/fonc.2022.1053800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/21/2022] [Indexed: 11/05/2022] Open
Abstract
Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future.
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Affiliation(s)
- Yu-Chong Yu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tian-Ming Shi
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Lan Gu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Hong Li
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Ming Yang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiong Fan
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yu-Dong Wang, ; Qiong Fan,
| | - Yu-Dong Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Municipal Key Clinical Specialty of Gynecologic Oncology Affiliated to The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yu-Dong Wang, ; Qiong Fan,
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Yoon J, Kim H, Jeong YIL, Yang HS. CD44 Receptor-Mediated/Reactive Oxygen Species-Sensitive Delivery of Nanophotosensitizers against Cervical Cancer Cells. Int J Mol Sci 2022; 23:ijms23073594. [PMID: 35408970 PMCID: PMC8998256 DOI: 10.3390/ijms23073594] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/17/2022] [Accepted: 03/22/2022] [Indexed: 12/10/2022] Open
Abstract
Stimulus-sensitive, nanomedicine-based photosensitizer delivery has an opportunity to target tumor tissues since oxidative stress and the expression of molecular proteins, such as CD44 receptors, are elevated in the tumor microenvironment. The aim of this study is to investigate the CD44 receptor- and reactive oxygen species (ROS)-sensitive delivery of nanophotosensitizers of chlorin e6 (Ce6)-conjugated hyaluronic acid (HA) against HeLa human cervical cancer cells. For the synthesis of nanophotosensitizers, thioketal diamine was conjugated with the carboxyl group in HA and then the amine end group of HA-thioketal amine conjugates was conjugated again with Ce6 (Abbreviated as HAthCe6). The HAthCe6 nanophotosensitizers were of small diameter, with sizes less than 200. Their morphology was round-shaped in the observations using a transmission electron microscope (TEM). The HAthCe6 nanophotosensitizers responded to oxidative stress-induced changes in size distribution when H2O2 was added to the nanophotosensitizer aqueous solution, i.e., their monomodal distribution pattern at 0 mM H2O2 was changed to dual- and/or multi-modal distribution patterns at higher concentrations of H2O2. Furthermore, the oxidative stress induced by the H2O2 addition contributed to the disintegration of HAthCe6 nanophotosensitizers in morphology, and this phenomenon accelerated the release rate of Ce6 from nanophotosensitizers. In a cell culture study using HeLa cells, nanophotosensitizers increased Ce6 uptake ratio, ROS generation and PDT efficacy compared to free Ce6. Since HA specifically bonds with the CD44 receptor of cancer cells, the pretreatment of free HA against HeLa cells decreased the Ce6 uptake ratio, ROS generation and PDT efficacy of HAthCe6 nanophotosensitizers. These results indicated that intracellular delivery of HAthCe6 nanophotosensitizers can be controlled by the CD44 receptor-mediated pathway. Furthermore, these phenomena induced CD44 receptor-controllable ROS generation and PDT efficacy by HAthCe6 nanophotosensitizers. During in vivo tumor imaging using HeLa cells, nanophotosensitizer administration showed that the fluorescence intensity of tumor tissues was relatively higher than that of other organs. When free HA was pretreated, the fluorescence intensity of tumor tissue was relatively lower than those of other organs, indicating that HAthCe6 nanophotosensitizers have CD44 receptor sensitivity and that they can be delivered by receptor-specific manner. We suggest that HAthCe6 nanophotosensitizers are promising candidates for PDT in cervical cancer.
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Affiliation(s)
- Jieun Yoon
- Department of Medicine, Graduate School, Dongguk University, Gyeongju 38067, Korea; (J.Y.); (H.K.)
| | - Howard Kim
- Department of Medicine, Graduate School, Dongguk University, Gyeongju 38067, Korea; (J.Y.); (H.K.)
| | - Young-IL Jeong
- Research Institute of Convergence of Biomedical Sciences, Pusan National University Yangsan Hospital, Gyeongnam 50612, Korea
- The Institute of Dental Science, Chosun University, Gwangju 61452, Korea
- Correspondence: (Y.-I.J.); (H.S.Y.)
| | - Hoe Saeng Yang
- Department of Obstetrics and Gynecology, Dongguk University College of Medicine, Gyeongju 38067, Korea
- Correspondence: (Y.-I.J.); (H.S.Y.)
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ΔN63 suppresses the ability of pregnancy-identified mammary epithelial cells (PIMECs) to drive HER2-positive breast cancer. Cell Death Dis 2021; 12:525. [PMID: 34023861 PMCID: PMC8141055 DOI: 10.1038/s41419-021-03795-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 02/04/2023]
Abstract
While pregnancy is known to reduce a woman's life-long risk of breast cancer, clinical data suggest that it can specifically promote HER2 (human EGF receptor 2)-positive breast cancer subtype (HER2+ BC). HER2+ BC, characterized by amplification of HER2, comprises about 20% of all sporadic breast cancers and is more aggressive than hormone receptor-positive breast cancer (the majority of cases). Consistently with human data, pregnancy strongly promotes HER2+ BC in genetic mouse models. One proposed mechanism of this is post-pregnancy accumulation of PIMECs (pregnancy-identified mammary epithelial cells), tumor-initiating cells for HER2+ BC in mice. We previously showed that p63, a homologue of the tumor suppressor p53, is required to maintain the post-pregnancy number of PIMECs and thereby promotes HER2+ BC. Here we set to test whether p63 also affects the intrinsic tumorigenic properties of PIMECs. To this end, we FACS-sorted YFP-labeled PIMECs from p63+/-;ErbB2 and control p63+/+;ErbB2 females and injected their equal amounts into immunodeficient recipients. To our surprise, p63+/- PIMECs showed increased, rather than decreased, tumorigenic capacity in vivo, i.e., significantly accelerated tumor onset and tumor growth, as well as increased self-renewal in mammosphere assays and proliferation in vitro and in vivo. The underlying mechanism of these phenotypes seems to be a specific reduction of the tumor suppressor TAp63 isoform in p63+/- luminal cells, including PIMECs, with concomitant aberrant upregulation of the oncogenic ΔNp63 isoform, as determined by qRT-PCR and scRNA-seq analyses. In addition, scRNA-seq revealed upregulation of several cancer-associated (Il-4/Il-13, Hsf1/HSP), oncogenic (TGFβ, NGF, FGF, MAPK) and self-renewal (Wnt, Notch) pathways in p63+/-;ErbB2 luminal cells and PIMECs per se. Altogether, these data reveal a complex role of p63 in PIMECs and pregnancy-associated HER2+ BC: maintaining the amount of PIMECs while suppressing their intrinsic tumorigenic capacity.
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Bispo S, Farias TDJ, de Araujo-Souza PS, Cintra R, Dos Santos HG, Jorge NAN, Castro MAA, Wajnberg G, Scherer NDM, Genta MLND, Carvalho JP, Villa LL, Sichero L, Passetti F. Dysregulation of Transcription Factor Networks Unveils Different Pathways in Human Papillomavirus 16-Positive Squamous Cell Carcinoma and Adenocarcinoma of the Uterine Cervix. Front Oncol 2021; 11:626187. [PMID: 34094909 PMCID: PMC8170088 DOI: 10.3389/fonc.2021.626187] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed by miR-96-5p or miR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381 might act by decreasing the levels of miR-96-5p and miR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.
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Affiliation(s)
- Saloe Bispo
- Instituto Carlos Chagas, FIOCRUZ, Curitiba, Brazil
| | | | - Patricia Savio de Araujo-Souza
- Department of Immunobiology, Biology Institute, Universidade Federal Fluminense (UFF), Niterói, Brazil.,Laboratory of Immunogenetics and Histocompatibility, Department of Genetics, Universidade Federal do Paraná, Curitiba, Brazil
| | - Ricardo Cintra
- Department of Biochemistry, Instituto de Quimica, Universidade de São Paulo, São Paulo, Brazil
| | | | - Natasha Andressa Nogueira Jorge
- Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.,Bioinformatics Group, Department of Computer Science, Interdisciplinary Center for Bioinformatics, Leipzig University, Leipzig, Germany
| | | | - Gabriel Wajnberg
- Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.,Atlantic Cancer Research Institute, Moncton, NB, Canada
| | - Nicole de Miranda Scherer
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Maria Luiza Nogueira Dias Genta
- Discipline of Gynecology, Department of Obstetrics and Gynecology, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Jesus Paula Carvalho
- Discipline of Gynecology, Department of Obstetrics and Gynecology, Instituto do Cancer do Estado de São Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Luisa Lina Villa
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.,Center for Translational Research in Oncology, Instituto do Cancer do Estado de São Paulo ICESP, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo FMUSP HC, São Paulo, Brazil
| | - Laura Sichero
- Center for Translational Research in Oncology, Instituto do Cancer do Estado de São Paulo ICESP, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo FMUSP HC, São Paulo, Brazil
| | - Fabio Passetti
- Instituto Carlos Chagas, FIOCRUZ, Curitiba, Brazil.,Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil
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Sun Y, Chen Y, Zhang X, Chen H, Zhou F. Primary ovarian serous carcinomas with extensive squamous differentiation: a case report and literature review. BMC WOMENS HEALTH 2021; 21:193. [PMID: 33964926 PMCID: PMC8106833 DOI: 10.1186/s12905-021-01336-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/28/2021] [Indexed: 11/18/2022]
Abstract
Background Primary ovarian serous carcinomas (OSC) with extensive squamous differentiation is a rare, and histological diagnostic criteria and biological behavior have not been fully established. We present an extremely rare case of primary OSC of the ovary with squamous differentiation. Case presentation A 58-year-old (gravidity 3, parity 2) female was admitted complaining of abdominal distention for 6 months. No apparent tumor in the cervix was found by a physical examination. Serum levels of cancer antigen 125 (CA125) was elevated (2723.0 IU/L). Macroscopically, a 7 cm tumor of the left uterine adnexa, a 5 cm tumor of the right adnexa, and a 3 cm tumor of the omentum were found. Histological and immunochemical tests confirmed a diagnosis of OSC with squamous differentiation. Debulking surgery with tumor resection was performed. The patient was subsequently received postoperative chemotherapy. Conclusions In summary, OSC with extensive squamous differentiation is a rare, and the inter- and intratumor heterogeneity may be the reason for this phenomenon. Histological diagnostic criteria and biological behavior have not been fully established because of the limited data.
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Affiliation(s)
- Yao Sun
- Department of Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yuezhou Chen
- Department of Reproductive and Genetic Medicine Center, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Xiaofei Zhang
- Department of Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Feng Zhou
- Department of Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China. .,Departments of Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China.
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Qin K, Jian D, Xue Y, Cheng Y, Zhang P, Wei Y, Zhang J, Xiong H, Zhang Y, Yuan X. DDX41 regulates the expression and alternative splicing of genes involved in tumorigenesis and immune response. Oncol Rep 2021; 45:1213-1225. [PMID: 33650667 PMCID: PMC7859996 DOI: 10.3892/or.2021.7951] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 11/30/2020] [Indexed: 12/19/2022] Open
Abstract
DEAD‑box helicase 41 (DDX41) is an RNA helicase and accumulating evidence has suggested that DDX41 is involved in pre‑mRNA splicing during tumor development. However, the role of DDX41 in tumorigenesis remains unclear. In order to determine the function of DDX41, the human DDX41 gene was cloned and overexpressed in HeLa cells. The present study demonstrated that DDX41 overexpression inhibited proliferation and promoted apoptosis in HeLa cells. RNA‑sequencing analysis of the transcriptomes in overexpressed and normal control samples. DDX41 regulated 959 differentially expressed genes compared with control cells. Expression levels of certain oncogenes were also regulated by DDX41. DDX41 selectively regulated the alternative splicing of genes in cancer‑associated pathways including the EGFR and FGFR signaling pathways. DDX41 selectively upregulated the expression levels of five antigen processing and presentation genes (HSPA1A, HSPA1B, HSPA6, HLA‑DMB and HLA‑G) and downregulated other immune‑response genes in HeLa cells. Additionally, DDX41‑regulated oncogenes and antigen processing and presentation genes were associated with patient survival rates. Moreover, DDX41 expression was associated with immune infiltration in cervical and endocervical squamous cancer. The present findings showed that DDX41 regulated the cancer cell transcriptome at both the transcriptional and alternative splicing levels. The DDX41 regulatory network predicted the biological function of DDX41 in suppressing tumor cell growth and regulating cancer immunity, which may be important for developing anticancer therapeutics.
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Affiliation(s)
- Kai Qin
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Danni Jian
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yaqiang Xue
- Laboratory for Genome Regulation and Human Health, ABLife Inc., Optics Valley International Biomedical Park, Wuhan, Hubei 430075, P.R. China
| | - Yi Cheng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yaxun Wei
- Center for Genome Analysis, ABLife Inc., Optics Valley International Biomedical Park, Wuhan, Hubei 430075, P.R. China
| | - Jing Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Huihua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yi Zhang
- Laboratory for Genome Regulation and Human Health, ABLife Inc., Optics Valley International Biomedical Park, Wuhan, Hubei 430075, P.R. China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Griesinger LM, Szczepanski JM, McMullen ER, Skala SL. Uncommon Cervical Lesions: A Review and Discussion of the Differential Diagnosis. Arch Pathol Lab Med 2020; 145:891-902. [PMID: 33091926 DOI: 10.5858/arpa.2020-0327-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— While the vast majority of cervical tumors consist of human papillomavirus (HPV)-related squamous cell carcinoma or adenocarcinoma, a subset of rare tumor types, frequently unrelated to HPV, does occur in this location. These tumors vary widely in prognostic and therapeutic implications, and accurate recognition is crucial to providing appropriate treatment. Some are benign or portend a favorable prognosis (adenoid basal carcinoma, ectopic prostate tissue), while others are frankly malignant lesions with a less favorable prognosis (adenoid cystic carcinoma, HPV-negative endocervical adenocarcinoma, mesonephric adenocarcinoma, clear cell carcinoma, small cell carcinoma, and adenosquamous carcinoma). OBJECTIVE.— To review the morphologic features of uncommon cervical lesions, the utility of immunohistochemistry for distinction between these entities, and the clinical and prognostic implications of accurate diagnosis. DATA SOURCES.— University of Michigan cases and review of the pertinent literature regarding the entities described. CONCLUSIONS.— Key morphologic and immunohistochemical features detailed herein will allow for the accurate distinction between these uncommon cervical lesions. Morphology is most useful in discriminating between the entities, as there is frequent immunohistochemical overlap between them; however, in rare instances immunohistochemistry can be useful in resolving the diagnosis.
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Affiliation(s)
- Laurie M Griesinger
- From the Department of Pathology, University of Michigan Medical School, Ann Arbor
| | | | - Emily R McMullen
- From the Department of Pathology, University of Michigan Medical School, Ann Arbor
| | - Stephanie L Skala
- From the Department of Pathology, University of Michigan Medical School, Ann Arbor
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Inzani F, Santoro A, Angelico G, Feraco A, Spadola S, Arciuolo D, Valente M, Carlino A, Piermattei A, Scaglione G, Scambia G, Rindi G, Zannoni GF. Neuroendocrine Carcinoma of the Uterine Cervix: A Clinicopathologic and Immunohistochemical Study with Focus on Novel Markers (Sst2-Sst5). Cancers (Basel) 2020; 12:cancers12051211. [PMID: 32408525 PMCID: PMC7281076 DOI: 10.3390/cancers12051211] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/06/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2-2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. METHODS All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). RESULTS All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell-neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell-neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2-3, in 9 cases); SST2 in 8 (50%, score 2-3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. CONCLUSIONS P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs.
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Affiliation(s)
- Frediano Inzani
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
- ENETS Center of Excellence, Neuroendocrine Tumour (NET) Center, 00168 Rome, Italy
| | - Angela Santoro
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Giuseppe Angelico
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Angela Feraco
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Saveria Spadola
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Damiano Arciuolo
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Michele Valente
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Angela Carlino
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Alessia Piermattei
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
| | - Giulia Scaglione
- Department of Surgical and Diagnostic Sciences, IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy;
| | - Giovanni Scambia
- Oncological Gynaecology Unit, Department of Woman, Child and Public Health Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
- Obstetric and Gynecologic Clinic Institute, Catholic University of Sacred Hearth, 00168 Rome, Italy
| | - Guido Rindi
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
- ENETS Center of Excellence, Neuroendocrine Tumour (NET) Center, 00168 Rome, Italy
- Pathological Anatomy Institute, Catholic University of Sacred Hearth, 00168 Rome, Italy
| | - Gian Franco Zannoni
- Department of Woman, Child and Public Health Sciences, Gynecopathology and Breast Pathology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (F.I.); (A.S.); (G.A.); (A.F.); (S.S.); (D.A.); (M.V.); (A.C.); (A.P.); (G.R.)
- Pathological Anatomy Institute, Catholic University of Sacred Hearth, 00168 Rome, Italy
- Correspondence:
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10
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Niemira M, Collin F, Szalkowska A, Bielska A, Chwialkowska K, Reszec J, Niklinski J, Kwasniewski M, Kretowski A. Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA). Cancers (Basel) 2019; 12:E37. [PMID: 31877723 PMCID: PMC7017323 DOI: 10.3390/cancers12010037] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 12/11/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4, MZB1, NIP7, and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUVmax, and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets.
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Affiliation(s)
- Magdalena Niemira
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.S.); (A.B.); (A.K.)
| | - Francois Collin
- Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, 15-276 Bialystok, Poland; (F.C.); (K.C.); (M.K.)
| | - Anna Szalkowska
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.S.); (A.B.); (A.K.)
| | - Agnieszka Bielska
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.S.); (A.B.); (A.K.)
| | - Karolina Chwialkowska
- Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, 15-276 Bialystok, Poland; (F.C.); (K.C.); (M.K.)
| | - Joanna Reszec
- Department of Medical Pathomorphology, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Miroslaw Kwasniewski
- Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, 15-276 Bialystok, Poland; (F.C.); (K.C.); (M.K.)
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.S.); (A.B.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland
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11
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White EA. Manipulation of Epithelial Differentiation by HPV Oncoproteins. Viruses 2019; 11:v11040369. [PMID: 31013597 PMCID: PMC6549445 DOI: 10.3390/v11040369] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/18/2019] [Accepted: 04/20/2019] [Indexed: 02/06/2023] Open
Abstract
Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.
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Affiliation(s)
- Elizabeth A White
- Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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12
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Sudhalkar N, Rathod NP, Mathews A, Chopra S, Sriram H, Shrivastava SK, Goda JS. Potential role of cancer stem cells as biomarkers and therapeutic targets in cervical cancer. Cancer Rep (Hoboken) 2019; 2:e1144. [PMID: 32721115 PMCID: PMC7941515 DOI: 10.1002/cnr2.1144] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Eradicating cancer stem cells (CSCs) that are termed as the "beating heart" of various malignant tumors, including cervical cancer, holds great importance in cancer therapeutics. CSCs not only confer chemo-radio resistance but also play an important role in tumor metastasis and thereby pose a potential barrier for the cure of cervical cancer. Cervical cancer, a common malignancy among females, is associated with high morbidity and mortality rates, and the study on CSCs residing in the niche is promising. RECENT FINDINGS Biomarker approach to screen the cervical CSCs has gained impetus since the past decade. Progress in identification and characterization of the stem cell biomarkers has led to many insights. For the diagnostic purpose, several biomarkers like viral (HPV16), stem cell markers, transcription factors (viz, SOX2, OCT 4, and c-Myc), and CSC surface markers (viz, ALDH1 and CD44) have been identified. The research so far has been directed to study the CSC stemness and demonstrates various gene expression signatures in cervical CSCs. Such studies hold a potential to improve diagnostic accuracy and predict therapeutic response and clinical outcome in patients. CONCLUSIONS Stem cell biomarkers have been validated and their therapeutic targets are being developed as "strategies to improve therapeutic ratio in personalized medicine." This review gives a brief overview of the cervical CSC biomarkers, their current and future diagnostic, prognostic, and therapeutic potential.
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Affiliation(s)
- Niyati Sudhalkar
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Nidul P. Rathod
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Ashwathi Mathews
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Supriya Chopra
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Harshini Sriram
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Shyam K. Shrivastava
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
| | - Jayant S. Goda
- Department of Radiation Oncology, ACTREC, Tata Memorial CentreHomi Bhaba National InstituteKharghar, Navi MumbaiIndia
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13
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Park HR, Kim YW, Park JH, Maeng YH, Nojima T, Hashimoto H, Park YK. Low Expression of P63 and P73 in Osteosarcoma. TUMORI JOURNAL 2018; 90:239-43. [PMID: 15237589 DOI: 10.1177/030089160409000214] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background The recent discovery of two p53-related genes, p63 and p73, has revealed an additional level of complexity to the study of p53 function. Both genes encode multiple proteins arising from alternative promoter usage and splicing, with transactivation, DNA-binding, and tetramerization domains. Recent data support a role for p63 in squamous and transitional cell carcinomas, as well as in certain lymphomas and thymomas. Methods To characterize the involvement of p63 and p73 in the development of osteosarcoma, we analyzed the expression and mutation of TAp63 and TAp73 in six osteosarcoma cell lines and twelve osteosarcoma specimens. Results Semiquantitative DNA/PCR analysis revealed that eight (67%) and six (50%) out of twelve osteosarcoma specimens showed significantly reduced levels of p63 and p73 transcription, respectively. Direct sequencing of the entire coding region detected no mutations in cell lines or osteosarcoma specimens. Conclusions Our data suggest that low expression of p63 and p73 is relatively common in osteosarcomas and might contribute to their molecular pathogenesis.
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Affiliation(s)
- Hye-Rim Park
- Department of Pathology, College of Medicine, Hallym University, Anyang, Korea
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14
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Chen Y, Peng Y, Fan S, Li Y, Xiao ZX, Li C. A double dealing tale of p63: an oncogene or a tumor suppressor. Cell Mol Life Sci 2018; 75:965-973. [PMID: 28975366 PMCID: PMC11105324 DOI: 10.1007/s00018-017-2666-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/20/2017] [Accepted: 09/25/2017] [Indexed: 12/15/2022]
Abstract
As a member of tumor suppressor p53 family, p63, a gene encoding versatile protein variant, has been documented to correlate with cancer formation and progression, though it is rarely mutated in cancer patients. However, it has long been controversial on whether p63 is an oncogene or a tumor suppressor. Here, we comprehensively reviewed reports on roles of p63 in development, tumorigenesis and tumor progression. According to data from molecular cell biology, genetic models and clinic research, we conclude that p63 may act as either an oncogene or a tumor suppressor gene in different scenarios: TA isoforms of p63 gene are generally tumor-suppressive through repressing cell proliferation, survival and metastasis; ΔN isoforms, however, may initiate tumorigenesis via promoting cell proliferation and survival, but inhibit tumor metastasis and progression; effects of p63 on tumor formation and progression depend on the context of the whole p53 family, and either amplification or loss of p63 gene locus can break the balance to cause tumorigenesis.
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Affiliation(s)
- Yonglong Chen
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yougong Peng
- Department of General Surgery, The Second People's Hospital of Jingmen, Jingmen, 448000, China
| | - Shijie Fan
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yimin Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Zhi-Xiong Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Chenghua Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
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15
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Regina C, Compagnone M, Peschiaroli A, Lena A, Annicchiarico-Petruzzelli M, Piro MC, Melino G, Candi E. Setdb1, a novel interactor of ΔNp63, is involved in breast tumorigenesis. Oncotarget 2018; 7:28836-48. [PMID: 26840455 PMCID: PMC5045360 DOI: 10.18632/oncotarget.7089] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 01/13/2016] [Indexed: 01/05/2023] Open
Abstract
ΔNp63 has been recently involved in self-renewal potential of breast cancer stem cells. Although the p63 transcriptional profile has been extensively characterized, our knowledge of the p63-binding partners potentially involved in the regulation of breast tumour progression is limited. Here, we performed the yeast two hybrid approach to identify p63α interactors involved in breast tumorigenesis and we found that SETDB1, a histone lysine methyl transferases, interacts with ΔNp63α and that this interaction contributes to p63 protein stability. SETDB1 is often amplified in primary breast tumours, and its depletion confers to breast cancer cells growth disadvantage. We identified a list of thirty genes repressed by ΔNp63 in a SETDB1-dependent manner, whose expression is positively correlated to survival of breast cancer patients. These results suggest that p63 and SETDB1 expression, together with the repressed genes, may have diagnostic and prognostic potential.
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Affiliation(s)
- Carla Regina
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Mirco Compagnone
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | | | - AnnaMaria Lena
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | | | - Maria Cristina Piro
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Gerry Melino
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.,IDI-IRCCS, Rome, Italy
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16
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Cervical Squamous Carcinomas With Prominent Acantholysis and Areas Resembling Breast Lobular Carcinoma. Int J Gynecol Pathol 2018; 37:74-81. [DOI: 10.1097/pgp.0000000000000387] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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17
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A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix. Gynecol Oncol 2017; 148:422-429. [PMID: 29248196 DOI: 10.1016/j.ygyno.2017.12.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 11/29/2017] [Accepted: 12/02/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND There remains uncertainty about the role of human papillomavirus (HPV) infection in causing small-cell neuroendocrine carcinoma (SCNC) and large-cell neuroendocrine carcinoma (LCNC) of the cervix. To clarify the role of HPV in the development of SCNC and LCNC, we conducted a systematic review and meta-analyses. METHODS PubMed and Embase were searched to initially identify 143 articles published on or before June 1, 2017. Studies were limited to methods that tested for HPV in the cancer tissue directly to minimize misattribution. Thirty-two studies with 403 SCNC and 9 studies of 45 LCNC were included in the analysis. RESULTS For SCNC, 85% (95% confidence interval [95%CI]=71%-94%) were HPV positive, 78% (95%CI=64%-90%) were HPV16 and/or HPV18 positive, 51% (95%CI=39%-64%) were singly HPV18 positive, and 10% (95%CI=4%-19%) were singly HPV16 positive. In a subset of 5 SCNC studies (75 cases), 93% were positive for p16INK4a by immunohistochemistry and 100% were HPV positive. For LCNC, 88% (95%CI=72%-99%) were HPV positive, 86% (95%CI=70%-98%) were positive for HPV16 or HPV18, 30% were singly HPV18 positive (95%CI=4%-60%), and 29% (95%CI=2%-64%) were singly HPV16 positive. CONCLUSIONS In conclusion, most SCNC and LCNC are caused by HPV, primarily HPV18 and HPV16. Therefore, most if not all SCNC and LCNC will be prevented by currently available prophylactic HPV vaccines.
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18
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DasGupta T, Nweze EI, Yue H, Wang L, Jin J, Ghosh SK, Kawsar HI, Zender C, Androphy EJ, Weinberg A, McCormick TS, Jin G. Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53. Oncotarget 2017; 7:27430-44. [PMID: 27034006 PMCID: PMC5053661 DOI: 10.18632/oncotarget.8443] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 03/17/2016] [Indexed: 01/24/2023] Open
Abstract
Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.
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Affiliation(s)
- Twishasri DasGupta
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA
| | - Emeka I Nweze
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.,Present Address: University of Nigeria, Nsukka, Nigera
| | - Hong Yue
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA
| | - Liming Wang
- Center for Molecular Cancer Diagnosis Inc., Twinsburg, OH, USA
| | - Jessica Jin
- Human Developmental and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Santosh K Ghosh
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA
| | - Hameem I Kawsar
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.,Present Address: St. Luke's Hospital, Chesterfield, MO, USA
| | - Chad Zender
- Department of Otolaryngology-Head & Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Elliot J Androphy
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Aaron Weinberg
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA
| | - Thomas S McCormick
- Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Ge Jin
- Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA
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19
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Kranjec C, Holleywood C, Libert D, Griffin H, Mahmood R, Isaacson E, Doorbar J. Modulation of basal cell fate during productive and transforming HPV-16 infection is mediated by progressive E6-driven depletion of Notch. J Pathol 2017; 242:448-462. [PMID: 28497579 PMCID: PMC5601300 DOI: 10.1002/path.4917] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 04/13/2017] [Accepted: 04/24/2017] [Indexed: 11/10/2022]
Abstract
In stratified epithelia such as the epidermis, homeostasis is maintained by the proliferation of cells in the lower epithelial layers and the concomitant loss of differentiated cells from the epithelial surface. These differentiating keratinocytes progressively stratify and form a self‐regenerating multi‐layered barrier that protects the underlying dermis. In such tissue, the continual loss and replacement of differentiated cells also limits the accumulation of oncogenic mutations within the tissue. Inactivating mutations in key driver genes, such as TP53 and NOTCH1, reduce the proportion of differentiating cells allowing for the long‐term persistence of expanding mutant clones in the tissue. Here we show that through the expression of E6, HPV‐16 prevents the early fate commitment of human keratinocytes towards differentiation and confers a strong growth advantage to human keratinocytes. When E6 is expressed either alone or with E7, it promotes keratinocyte proliferation at high cell densities, through the combined inactivation of p53 and Notch1. In organotypic raft culture, the activity of E6 is restricted to the basal layer of the epithelium and is enhanced during the progression from productive to abortive or transforming HPV‐16 infection. Consistent with this, the expression of p53 and cleaved Notch1 becomes progressively more disrupted, and is associated with increased basal cell density and reduced commitment to differentiation. The expression of cleaved Notch1 is similarly disrupted also in HPV‐16‐positive cervical lesions, depending on neoplastic grade. When taken together, these data depict an important role of high‐risk E6 in promoting the persistence of infected keratinocytes in the basal and parabasal layers through the inactivation of gene products that are commonly mutated in non‐HPV‐associated neoplastic squamous epithelia. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Christian Kranjec
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.,The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
| | - Christina Holleywood
- The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
| | - Diane Libert
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Heather Griffin
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.,The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
| | - Radma Mahmood
- The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
| | - Erin Isaacson
- The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
| | - John Doorbar
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.,The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK
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20
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Candi E, Smirnov A, Panatta E, Lena AM, Novelli F, Mancini M, Viticchiè G, Piro MC, Di Daniele N, Annicchiarico-Petruzzelli M, Melino G. Metabolic pathways regulated by p63. Biochem Biophys Res Commun 2017; 482:440-444. [PMID: 28212728 DOI: 10.1016/j.bbrc.2016.10.094] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 10/24/2016] [Indexed: 01/18/2023]
Abstract
The transcription factor p63 belongs to the p53-family and is a master regulator of proliferative potential, lineage specification, and differentiation in epithelia during development and tissue homeostasis. In cancer, p63 contribution is isoform-specific, with both oncogenic and tumour suppressive roles attributed, for ΔNp63 and TAp63, respectively. Recently, p53 and TAp73, in line with other tumour suppressor genes, have emerged as important regulators of energy metabolism and metabolic reprogramming in cancer. To date, p63 contributions in controlling energy metabolism have been partially investigated; given the extensive interaction of the p53 family members, these studies have potential implications in tumour cells for metabolic reprogramming. Here, we review the role of p63 isoforms, TAp63 and ΔNp63, in controlling cell metabolism, focusing on their specific metabolic target genes and their physiological/functional context of action.
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Affiliation(s)
- Eleonora Candi
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy; IDI-IRCCS "Istituto Dermopatico dell'Immacolata", Biochemistry Laboratory, Rome, Italy.
| | - Artem Smirnov
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Emanuele Panatta
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Anna Maria Lena
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Flavia Novelli
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Mara Mancini
- Medical Research Council, Toxicology Unit, Leicester LE1 9HN, UK
| | | | - Maria Cristina Piro
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Nicola Di Daniele
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | | | - Gerry Melino
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy; Medical Research Council, Toxicology Unit, Leicester LE1 9HN, UK.
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21
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Park GB, Chung YH, Gong JH, Jin DH, Kim D. GSK-3β-mediated fatty acid synthesis enhances epithelial to mesenchymal transition of TLR4-activated colorectal cancer cells through regulation of TAp63. Int J Oncol 2016; 49:2163-2172. [PMID: 27599658 DOI: 10.3892/ijo.2016.3679] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/23/2016] [Indexed: 11/05/2022] Open
Abstract
Glycogen synthase kinase-3β (GSK-3β) in cancer cells is a critical regulatory component of both cellular metabolism and epithelial-mesenchymal transition (EMT) processes via regulation of the β-catenin/E-cadherin and phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Lipogenesis of cancer cells also plays a critical role in survival and metastasis. We investigated the role of GSK-3β-mediated intracellular fatty acid synthesis to control EMT in TLR4-activated colorectal cancer cells and the underlying regulatory mechanism. Engagement of TLR4 with lipopolysaccharide (LPS) in colon cancer cells promoted the induction of phosphorylated GSK-3β and related lipogenic enzymes as well as the expression of CD74, CD44 and macrophage inhibitory factor (MIF), but decreased expression of transcriptionally active p63 (TAp63). In addition, targeted inhibition of GSK-3β using SB216763 was accompanied by decreased intracellular fatty acid synthesis and blockage of CD74 and CD44 expression, whereas it reversed the level of TAp63. Although TAp63 overexpression had no effect on the expression of CD74 and CD44 in LPS-treated colon cancer cells, GSK-3β-dependent fatty acid synthesis and invasive activity were significantly suppressed. Notably, inhibition of CD44 or CD74 by siRNA not only attenuated de novo lipogenesis and migratory activity but also restored the expression of TAp63 in LPS-activated colon cancer cells. These results suggest that TAp63-mediated GSK-3β activation induced by TLR4 stimulation triggers migration and invasion of colon cancer cells through the regulation of lipid synthesis and GSK-3β-mediated CD74/CD44 expression could be a target to control fatty acid-related EMT process through the modulation of TAp63 expression.
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Affiliation(s)
- Ga Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
| | - Yoon Hee Chung
- Department of Anatomy, Chung‑Ang University College of Medicine, Seoul 06974, Republic of Korea
| | - Ji Hee Gong
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Dong-Hoon Jin
- Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea
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Abstract
Human papillomaviruses (HPVs) represent a large collection of viral types associated with significant clinical disease of cutaneous and mucosal epithelium. HPV-associated cancers are found in anogenital and oral mucosa, and at various cutaneous sites. Papillomaviruses are highly species and tissue restricted, and these viruses display both mucosotropic, cutaneotropic or dual tropism for epithelial tissues. A subset of HPV types, predominantly mucosal, are also oncogenic and cancers with these HPV types account for more than 200,000 deaths world-wide. Host control of HPV infections requires both innate and adaptive immunity, but the viruses have developed strategies to escape immune detection. Viral proteins can disrupt both innate pathogen-sensing pathways and T-cell based recognition and subsequent destruction of infected tissues. Current treatments to manage HPV infections include mostly ablative strategies in which recurrences are common and only active disease is treated. Although much is known about the papillomavirus life cycle, viral protein functions, and immune responsiveness, we still lack knowledge in a number of key areas of PV biology including tissue tropism, site-specific cancer progression, codon usage profiles, and what are the best strategies to mount an effective immune response to the carcinogenic stages of PV disease. In this review, disease transmission, protection and control are discussed together with questions related to areas in PV biology that will continue to provide productive opportunities of discovery and to further our understanding of this diverse set of human viral pathogens.
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Affiliation(s)
- Neil D Christensen
- The Jake Gittlen Laboratories for Cancer Research, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
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23
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Ganesan R, Hirschowitz L, Dawson P, Askew S, Pearmain P, Jones PW, Singh K, Chan KK, Moss EL. Neuroendocrine Carcinoma of the Cervix: Review of a Series of Cases and Correlation With Outcome. Int J Surg Pathol 2016; 24:490-6. [PMID: 27098591 DOI: 10.1177/1066896916643385] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Introduction Neuroendocrine carcinoma (NEC) of the cervix is associated with a poor prognosis despite multimodal treatment. The correct diagnosis of this tumor type is imperative to provide clinicians and patients with prognostic information and ensure that appropriate treatment is provided. Methods A clinicopathological study was undertaken on all cervical tumors registered as NEC with the West Midlands Cancer Intelligence Unit between January 1, 1998 and December 31, 2009. Of the 45 cases diagnosed during the study period, the tumor samples of 41 cases were traced, anonymized, and then independently reviewed by 2 gynecological pathologists. Results The review confirmed 31/41 (78%) cases to be NEC, which overall, represented 1.3% of all the cervical cancers registered in the West Midlands over the period of the study. In the correct histological context, synaptophysin was the most sensitive and specific positive immunohistochemical marker of NEC differentiation. The cases that on review were confirmed as NEC had a significantly worse outcome than the non-NEC cases: median survival for NEC cases was 33.3 months versus 315.0 months for the non-NEC cases, P = .013. Conclusions Histological review of a series of NECs has shown significantly reduced survival in those patients with confirmed NEC in comparison with those patients where a diagnosis of NEC was not confirmed. We propose morphological and immunohistochemical criteria for the diagnosis of cervical NEC; and discourage unqualified use of the term "small cell carcinoma" as this does not accurately convey the diagnosis of SCNEC. We urge pathologists to use the 2014 World Health Organization classification when reporting these tumors.
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Affiliation(s)
- Raji Ganesan
- Birmingham Women's NHS Foundation Trust, Birmingham, UK
| | | | - Philip Dawson
- West Midlands Cervical Screening QA Reference Centre, Public Health England, Birmingham, UK
| | - Sarah Askew
- West Midlands Cervical Screening QA Reference Centre, Public Health England, Birmingham, UK
| | - Philippa Pearmain
- West Midlands Cervical Screening QA Reference Centre, Public Health England, Birmingham, UK
| | | | - Kavita Singh
- Pan-Birmingham Gynaecological Cancer Centre, Birmingham, UK
| | - Kiong K Chan
- Pan-Birmingham Gynaecological Cancer Centre, Birmingham, UK
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24
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Regulatory Role of miR-203 in Occurrence and Progression of Kazakh Esophageal squamous cell carcinoma. Sci Rep 2016; 6:23780. [PMID: 27029934 PMCID: PMC4815010 DOI: 10.1038/srep23780] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 03/15/2016] [Indexed: 12/13/2022] Open
Abstract
Esophageal carcinoma is one of the most common malignant tumors and the Kazakh national minority (ethnic) in Xinjiang (northwest of China) has been reported to be one of the highest incidence of Esophageal squamous cell carcinoma (ESCC) in the world. MicroRNA-203 (miR-203) was described as a tumor-suppressive miRNA in several cancers, but little study about the role of miR-203 in Kazakh ESCC. Therefore, we aimed to investigate the role of miR-203 in the occurrence and progression of Kazakh ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect miR-203 expression, and immunohistochemistry (IHC) was used to examine P63 expression. The expression level of miR-203 in ESCC was significantly lower than that of cancer adjacent normal (CAN) samples (P < 0.05). Whereas the expression level of P63 in ESCC was significantly higher than that of CAN samples (P < 0.05), an inverse association between the expression of P63 and miR-203 was found but was not statistically significant (P > 0.05). These findings suggest that miR-203 is a tumor suppressor gene that plays an important role in inhibiting the occurrence of Kazakh ESCC in Xinjiang, China.
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25
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Yang K, Wu WM, Chen YC, Lo SH, Liao YC. ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion. PLoS One 2016; 11:e0147542. [PMID: 26784942 PMCID: PMC4718700 DOI: 10.1371/journal.pone.0147542] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 01/04/2016] [Indexed: 01/02/2023] Open
Abstract
p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.
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Affiliation(s)
- Kuan Yang
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Wei-Ming Wu
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Ya-Chi Chen
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, California, United States of America
| | - Yi-Chun Liao
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
- * E-mail:
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26
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Bergner S, Halec G, Schmitt M, Aubin F, Alonso A, Auvinen E. Individual and Complementary Effects of Human Papillomavirus Oncogenes on Epithelial Cell Proliferation and Differentiation. Cells Tissues Organs 2015; 201:97-108. [PMID: 26636751 DOI: 10.1159/000441716] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2015] [Indexed: 11/19/2022] Open
Abstract
Previous studies on human papillomavirus (HPV) type 16 protein functions have established the oncogenic nature of three viral proteins: E5, E6 and E7. Here we have studied the functions of these proteins by functional deletion of the individual E5, E6 or E7, or both E6 and E7 oncogenes in the context of the whole viral genome. These mutants, or the intact wild-type genome, were expressed from the natural viral promoters along with differentiation of epithelial HaCaT cells in three-dimensional collagen raft cultures. High episomal viral copy numbers were obtained using a transfection-based loxp-HPV16-eGFP-N1 vector system. All epithelial equivalents carrying the different HPV type 16 genomes showed pronounced hyperplastic and dysplastic morphology. Particularly the E7 oncogene, with contribution of E6, was shown to enhance cell proliferation. Specifically, the crucial role of E7 in HPV-associated hyperproliferation was clearly manifested. Based on morphological characteristics, immunohistochemical staining for differentiation and proliferation markers, and low expression of E1^E4, we propose that our raft culture models produce cervical intraepithelial neoplasia (CIN)1 and CIN2-like tissue. Our experimental setting provides an alternative tool to study concerted functions of HPV proteins in the development of epithelial dysplasia.
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Affiliation(s)
- Sven Bergner
- Research Program in Infection and Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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27
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Koh LF, Ng BK, Bertrand J, Thierry F. Transcriptional control of late differentiation in human keratinocytes by TAp63 and Notch. Exp Dermatol 2015; 24:754-60. [PMID: 26013684 DOI: 10.1111/exd.12764] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2015] [Indexed: 12/13/2022]
Abstract
We previously showed that in cervical carcinoma cells, the TAp63β isoform of the p63 transcription factor is negatively interfering with the carcinogenic pathways promoting anchorage-independent growth. In this study, we have defined the mechanisms underlying the effects of TAp63β through a transcriptome analysis of human keratinocytes overexpressing this protein. TAp63β modulated expression of 1203 genes (944 activated and 259 repressed; P-value <0.05), notably genes involved in epithelial development and keratinocyte differentiation. In comparison, while TAp63γ acts similarly to TAp63β to transactivate a selected panel of target genes, other p63 isoforms, including ΔNp63α, which is highly expressed in keratinocytes, are inactive. Upon induction of differentiation of primary human keratinocytes, we observed endogenous expression of TAp63β and γ isoforms, along with transcriptional activation of selected target genes. Intriguingly, our data also indicated that TAp63β activates transcription of members of the Notch pathway, which is known to promote keratinocyte differentiation. By inhibiting and activating the Notch pathway, we revealed a subset of TAp63β-activated genes that were co-dependent on Notch for their expression. Our work demonstrates that the shorter TAp63 isoforms (TAp63β/γ) are specifically induced in human keratinocytes and cooperate with Notch signalling to activate transcription of late differentiation genes supporting their role as putative tumor suppressors in HPV-associated tumorigenesis.
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Affiliation(s)
- Li Fang Koh
- Papillomavirus Regulation and Cancer Laboratory, Institute of Medical Biology, Biopolis, Singapore City, Singapore
| | - Boon Kiat Ng
- Papillomavirus Regulation and Cancer Laboratory, Institute of Medical Biology, Biopolis, Singapore City, Singapore
| | - Juliette Bertrand
- Papillomavirus Regulation and Cancer Laboratory, Institute of Medical Biology, Biopolis, Singapore City, Singapore
| | - Françoise Thierry
- Papillomavirus Regulation and Cancer Laboratory, Institute of Medical Biology, Biopolis, Singapore City, Singapore
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Gynecologic Cancer InterGroup (GCIG) consensus review for small cell carcinoma of the cervix. Int J Gynecol Cancer 2015; 24:S102-8. [PMID: 25341572 DOI: 10.1097/igc.0000000000000262] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Small cell carcinoma of the cervix (SCCC) is a rare histological entity of uterine cervical cancer. Compared with other common histological types, squamous cell carcinoma or adenocarcinoma, the outcome of SCCC is poor because of the high incidence of nodal or distant metastasis even with early stage. In this review, current consensus of epidemiology, pathology, and initial treatment for SCCC will be discussed.
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Canham M, Charsou C, Stewart J, Moncur S, Hoodless L, Bhatia R, Cong D, Cubie H, Busby-Earle C, Williams A, McLoughlin V, Campbell JDM, Cuschieri K, Howie S. Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease. PLoS One 2014; 9:e115379. [PMID: 25531390 PMCID: PMC4274002 DOI: 10.1371/journal.pone.0115379] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/22/2014] [Indexed: 12/27/2022] Open
Abstract
High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.
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Affiliation(s)
- Maurice Canham
- Human Papillomavirus Group, University of Edinburgh, Edinburgh, United Kingdom
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Chara Charsou
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - June Stewart
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Sharon Moncur
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Laura Hoodless
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Ramya Bhatia
- Human Papillomavirus Group, University of Edinburgh, Edinburgh, United Kingdom
| | - Duanduan Cong
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Heather Cubie
- Human Papillomavirus Group, University of Edinburgh, Edinburgh, United Kingdom
| | - Camille Busby-Earle
- Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Alistair Williams
- Simpson Centre for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom
| | - Victoria McLoughlin
- Scottish National Blood Transfusion Service National Science Laboratory, Edinburgh, United Kingdom
| | - John D. M. Campbell
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
- Scottish National Blood Transfusion Service National Science Laboratory, Edinburgh, United Kingdom
| | - Kate Cuschieri
- Scottish Human Papillomavirus Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Sarah Howie
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
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30
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Romus I, Triningsih FE, Mangunsudirdjo S, Harijadi A. Clinicopathology significance of p53 and p63 expression in Indonesian cervical squamous cell carcinomas. Asian Pac J Cancer Prev 2014; 14:7737-41. [PMID: 24460361 DOI: 10.7314/apjcp.2013.14.12.7737] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human papilloma virus infection is associated with genesis and malignant potential of cervical cancer. E6 and E7 oncogens are known to bind to p53 and retinoblastoma gene products, abrogating their functions as tumor suppressors, leading to an abnormal cell cycle machinery. Roles of the p53 homolog p63 have also been postulated, E6 expression leading to TAp63b degradation allowing anchorage independent growth. Molecular studies correlated with clinicopathological factors are important to determine prognosis and treatment strategies, but results have been controversial and need to be clarified. AIM To investigate expression of p53 and p63 in cervical squamous cell carcinomas in correlation with age, FIGO staging, morphology, and cancer cell proliferation. MATERIALS AND METHODS Expression of p53 and p63 immunohistochemical staining in a total of 56 paraffin-embedded tissues of cervical squamous cell carcinomas from Dr. Sardjito General Hospital Indonesia, was evaluated for correlation with clinicopathological parameters. The Mann-Whitney test was used to compare the percentage of p53 and p63 expression with patient age, FIGO staging and morphology and to compare mean p53 and p63 expression. The Spearman correlation test was applied to correlate p53 and p63 expression with that of Ki-67. A p-value of <0.05 was considered statistically significant. RESULTS There were significant associations between p53 expression with age (p=0.019) and FIGO staging (p=0.026), but not with with morphology or Ki-67 expression. There were no links between p63 expression and age, morphology, FIGO staging or Ki-67. CONCLUSIONS This study indicated that p53 has a prognostic value in cervical squamous cell carcinomas given the relation with FIGO staging.
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Affiliation(s)
- Ilhami Romus
- Department of Anatomical Pathology, Faculty of Medicine, Gadjah Mada University, Yogjakarta, Indonesia * E-mail :
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31
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Xie H, Lee L, Scicluna P, Kavak E, Larsson C, Sandberg R, Lui WO. Novel functions and targets of miR-944 in human cervical cancer cells. Int J Cancer 2014; 136:E230-41. [PMID: 25156441 PMCID: PMC4277326 DOI: 10.1002/ijc.29160] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 08/14/2014] [Accepted: 08/19/2014] [Indexed: 11/16/2022]
Abstract
Altered expression of specific microRNAs (miRNAs) has been observed in human cervical cancer. However, the biological functions of many of these miRNAs are yet to be discovered. We previously showed that miR-944 is significantly more abundant in cervical cancer tissues than their normal counterparts. In this study, we investigated the functions and targets of miR-944 in human cervical cancer cells. MiR-944 is located in the intron of the tumor protein p63 (TP63) gene, which is frequently overexpressed in cervical carcinomas. Using gain- and loss-of-function experiments in vitro, we demonstrate that miR-944 promotes cell proliferation, migration and invasion, but has no effect on apoptosis, in human cervical cancer cells. To identify the targets of miR-944, we performed photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation followed by deep sequencing. Among the candidate targets, we validated HECW2 (HECT domain ligase W2) and S100PBP (S100P binding protein) as direct targets of miR-944 using luciferase reporter assays and western blot analysis. Our findings reveal novel functions and targets of miR-944 in human cervical cancer cells, which may provide new insights of its role in cervical carcinogenesis.
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Affiliation(s)
- Hong Xie
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden
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Longano A, Lenghaus D, Nizamovski J, Nelva P. p40 immunoperoxidase staining of anorectal carcinomas. Histopathology 2014; 66:464-6. [PMID: 24899414 DOI: 10.1111/his.12470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Affiliation(s)
- Anthony Longano
- Department of Anatomical Pathology, Monash Medical Centre, Clayton, Vic., Australia
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Abstract
p53 and its related genes, p63 and p73 constitute the p53 gene family. While p53 is the most frequently mutated gene in human tumors, p63 and p73 are rarely mutated or deleted in cancers. Many studies have reported p63/p73 overexpression in human cancers while others showed that a loss of p63/p73 is associated with tumor progression and metastasis. Thus, whether p63 or p73 is a tumor suppressor gene or an oncogene has been a matter of debate. This controversy has been attributed to the existence of multiple splicing isoforms with distinct functions; the full-length TA isoform of p63 has structural and functional similarity to wild-type p53, whereas the ΔNp63 acts primarily in dominant-negative fashion against all family members of p53. Differential activities of TA and ΔN isoforms have been shown in vivo by creating isform-specific gene knockout mice. All p53, p63, p73 proteins bind to and activate target genes with p53-response elements; p63 also binds to distinct p63-response elements and regulate expression of specific target genes involved in skin, limb, and craniofacial development. Interestingly, several studies have shown that both p63 and p73 are involved in cellular response to cancer therapy and others have indicated that both of these molecules are required for p53-induced apoptosis, suggesting functional interplay among p53 family proteins. Consistent with these findings, aberrant splicing that result in ΔNp63 or ΔNp73 overexpression are frequently found in human cancers, and is associated with poor clinical outcomes of patients in the latter. Thus immunohistochemical staining of tumor specimen with ΔNp73-specific antibody might have diagnostic values in cancer clinics.
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Affiliation(s)
- Kazushi Inoue
- The Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA,
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Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I. Caspase-1 is a novel target of p63 in tumor suppression. Cell Death Dis 2013; 4:e645. [PMID: 23703390 PMCID: PMC3674380 DOI: 10.1038/cddis.2013.175] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
p63 is a p53 family transcription factor, which besides unique roles in epithelial development, shares tumor suppressive activity with its homolog p53. The p63 gene has different transcriptional start sites, which generate two N-terminal isoforms (transactivation domain (TA)p63 and amino terminal truncated protein(ΔN)p63); in addition alternative splicing at the 5′-end give rise to at least five C-terminal isoforms. This complexity of gene structure has probably fostered the debate and controversy on p63 function in cancer, with TP63-harboring two distinctive promoters, codifying for the TAp63 and ΔNp63 isoforms, and having discrete functions. However, ΔNp63 also drives expression of target genes that have a relevant role in cancer and metastasis. In this study, we identified a novel p63 transcriptional target, caspase-1. Caspase-1 is proinflammatory caspase, which functions in tumor suppression. We show that both p63 isoforms promote caspase-1 expression by physical binding to its promoter. Consistent with our in vitro findings, we also identified a direct correlation between p63 and caspase-1 expression in human cancer data sets. In addition, survival estimation analysis demonstrated that functional interaction between p63 and caspase-1 represents a predictor of positive survival outcome in human cancers. Overall, our data report a novel p63 target gene involved in tumor suppression, and the clinical analysis underlines the biological relevance of this finding and suggests a further clinically predictive biomarker.
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Affiliation(s)
- I Celardo
- Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK
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Vaiphei K, Kochhar R, Bhardawaj S, Dutta U, Singh K. High prevalence of human papillomavirus in esophageal squamous cell carcinoma: a study in paired samples. Dis Esophagus 2013; 26:282-7. [PMID: 22676445 DOI: 10.1111/j.1442-2050.2012.01365.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the common cancers with a poor prognosis. Incidences of human papillomavirus (HPV) infection range from 0 to 67% in different parts of the world. It has been frequently associated with high-risk HPV genotypes 16 and 18. The present study analyzes the prevalence of HPV infection in ESCC tumor and adjoining mucosa. Fresh tissue samples were obtained from ESCC tumor (group I) and adjoining mucosa (group II). Aliquots of DNA extracts were used. There were 23 patients with paired samples, 19 (83%) were male. HPV was positive in 20/23 (87%). Mean age of HPV positive in group I was 56.63 ± 6.96 and in group II 54.31 ± 7.13 years (P > 0.05). Majority had more than one viral type. HPV52 was the most common observed in 14 (61%) males and two (9%) females. Other common viruses were HPV55, 39, and 59. Smoking had a significant association with viral positivity. p63 and p16 oncoproteins correlated with degree of tumor differentiation but not with viral status. We documented high prevalence of high-risk HPV in ESCC. Our observations support the concept of persistent infection by an oncogenic HPV in cancer development. Our study highlights importance of documenting viral genotype in a defined geographic area.
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Affiliation(s)
- K Vaiphei
- Departments of Histopathology Gastroenterology, PGIMER, Chandigarh, India.
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Ohta Y, Kunimura T, Omatsu M, Shiokawa A, Kushima M, Ota H. Mixed mucin-producing and squamous differentiated tumor of the uterine cervix: a report of a case as adenosquamous carcinoma in situ. J Obstet Gynaecol Res 2013; 39:420-3. [PMID: 23294292 DOI: 10.1111/j.1447-0756.2012.01904.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We report a non-invasive mixed mucin-producing and squamous differentiated tumor of the uterine cervix. This tumor was composed of two cell types: mucin-producing cells and non-mucin-producing cells. These cells were intimately mixed with each other, and showed intraepithelial spreading. The mucin-producing cells showed signet-ring or columnar shapes, and were localized to the lower-to-upper epithelial layer. The non-mucin-producing cells had eosinophilic cytoplasms with a monotonous appearance through the epithelium. Mitosis was sometimes observed in both cell types. Immunohistochemically, both cell types were positive for p16(INK4A) . The non-mucin-producing cells were positive for p63 and 34βE12, suggesting squamous differentiation. Although most mucin-producing cells were p63(-) , a few of them were p63(+) and many 34βE12 immunoreactive cells were found in the mucin-producing cells. This tumor was adenosquamous carcinoma in situ.
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Affiliation(s)
- Yoshiki Ohta
- Department of Pathology Second Department of Pathology, Showa University, Tokyo, Japan.
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Hayashi T, Yoshinaga A, Ohno R, Ishii N, Kamata S, Yamada T. Expression of thep63and Notch Signaling Systems in Rat Testes During Postnatal Development: Comparison With Their Expression Levels in the Epididymis and Vas Deferens. ACTA ACUST UNITED AC 2013; 25:692-8. [PMID: 15292098 DOI: 10.1002/j.1939-4640.2004.tb02843.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The role of tubular structures that contribute to the passage of spermatozoa is not solely passive; these structures actively contribute to their own functions, although these tubules and ducts are contiguous and collaborate in the development of the male gamete along their lengths. The testis has the specific function to generate spermatozoa and spermatozoa undergo numerous changes as they pass through the epididymis. A member of the p53 family of genes, p63, is highly expressed in the basal layers of epithelial tissues and plays a key role in maintaining their cell populations, whereas Notch 1 and its ligand Jagged 2 have an important role in the differentiation of germ cells and Jagged 2 is up-regulated by TAp63, one of the p63 isoforms, which transactivates p53 target genes and induces apoptosis. Although the presence of p63 in most epithelia is established, the role of p63 and its possible relationship with the Notch system in the seminiferous epithelium have not been examined. Therefore, we investigated the expression of p63, Jagged 2, and Notch 1 in the testis during postnatal development in comparison with their expression levels in the vaso-epididymal epithelium. In the testis, the expression of TAp63 mRNA increased at day 14 after birth and the expressions of Jagged 2 and Notch 1 mRNA increased at day 16 after birth, suggesting that TAp63-mediated Jagged 2 induction activates the Notch signaling system. On the other hand, the strong signal of DeltaNp63 mRNA was already recognized in the vas deferens at day 0 after birth and advanced chronologically along the duct to the caput epididymis and p63 protein was expressed in basal cells in their epithelium, whereas the mRNAs of Jagged 2 and Notch 1 were maintained at a low level. Consequently, examination of our data raises the probability that TAp63 has an important role for maintenance of germ cell numbers, triggering or balancing the development, differentiation, and apoptosis of germ cells in the testis, which is completely different from the role of DeltaNp63 in other epithelial tissues.
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Affiliation(s)
- Tetsuo Hayashi
- Department of Urology, Saitama Medical Center, Saitama Medical School, 1981 Tsujido, Kamoda, Kawagoe, Saitama 350-8550, Japan.
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López J, Ruíz G, Organista-Nava J, Gariglio P, García-Carrancá A. Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix. Open Virol J 2012; 6:232-40. [PMID: 23341858 PMCID: PMC3547319 DOI: 10.2174/1874357901206010232] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2012] [Revised: 08/16/2012] [Accepted: 08/27/2012] [Indexed: 12/18/2022] Open
Abstract
Different rate of development of productive infections (as low grade cervical intraepithelial neoplasias), or high grade lesions and cervical malignant tumors associated with infections of the Transformation zone (TZ) by High-Risk Human Papillomavirus (HR-HPV), could suggest that different epithelial host target cells could exist. If there is more than one target cell, their differential infection by HR-HPV may play a central role in the development of cervical cancer. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support in several solid tumors, including cervical cancer (CC). According to the cancer stem cell (CSC) hypothesis, CC can now be considered a disease in which stem cells of the TZ are converted to cervical cancer stem cells by the interplay between HR-HPV viral oncogenes and cellular alterations that are thought to be finally responsible for tumor initiation and maintenance. Current studies of CSC could provide novel insights regarding tumor initiation and progression, their relation with viral proteins and interplay with the tumor micro-environment. This review will focus on the biology of cervical cancer stem cells, which might contribute to our understanding of the mechanisms responsible for cervical tumor development.
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Affiliation(s)
- Jacqueline López
- Programa de Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México
(UNAM), Mexico City, Mexico
| | - Graciela Ruíz
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional (CINVESTAV del IPN), Mexico City, Mexico
| | - Jorge Organista-Nava
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Fisiología Celular (IFC), UNAM, Mexico City, Mexico
| | - Patricio Gariglio
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto
Politécnico Nacional (CINVESTAV del IPN), Mexico City, Mexico
| | - Alejandro García-Carrancá
- Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM & División de
Investigación Básica, Instituto Nacional de Cancerología (INCan), Secretaría de Salud (SSA), Mexico City, Mexico
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Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung. Am J Surg Pathol 2012; 36:1472-6. [PMID: 22982890 DOI: 10.1097/pas.0b013e318260cde7] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Distinguishing invasive high-grade urothelial carcinoma (UC) from other carcinomas occurring in the genitourinary tract may be difficult. The differential diagnosis includes high-grade prostatic adenocarcinoma, spread from an anal squamous cell carcinoma (SCC), or spread from a uterine cervical SCC. In terms of metastatic UC, the most common problem is differentiating spread of UC to the lung from a primary pulmonary SCC. Immunohistochemical analysis (IHC) for GATA binding protein 3 (GATA3), thrombomodulin (THROMBO), and uroplakin III was performed on a tissue microarray (TMA) containing 35 cases of invasive high-grade UC. GATA3 IHC was also performed on TMAs containing 38 high-grade (Gleason score ≥8) prostatic adenocarcinomas, representative tissue sections from 15 invasive anal SCCs, representative tissue sections from 19 invasive cervical SCCs, and TMAs with 12 invasive cervical carcinomas of the cervix [SCC (n=10), SCC with neuroendocrine features (n=1), and adenosquamous carcinoma (n=1)]. In addition, GATA3 IHC was performed on representative tissue sections from 15 pulmonary UC metastases and a TMA with 25 SCCs of the lung and 5 pulmonary non-small cell carcinomas with squamous features. GATA3, THROMBO, and uroplakin III were positive in 28 (80%), 22 (63%), and 21 (60%) cases of high-grade UC, respectively. All cases of GATA3-positive staining were nonfocal; 25 (89%) cases demonstrated moderate to strong staining, and 3 (11%) demonstrated weak staining. Of the 7 cases that failed to express GATA3, 5 were positive for THROMBO and/or uroplakin III, whereas 2 were negative for all 3 markers. None of the 38 high-grade prostatic adenocarcinomas was positive for GATA3. Weak GATA3 staining was present in occasional basal cells of benign prostate glands, in a few benign atrophic glands, and in urothelial metaplasia. Of the 15 cases of anal SCCs, 2 (7%) cases showed focal weak staining, and 1 (3%) showed focal moderate staining. Weak staining was also rarely observed in the benign anal squamous epithelium. Of the 31 uterine cervical carcinomas, 6 (19%) showed weak GATA3 staining (3 nonfocal and 3 focal), and 2 (6%) demonstrated focal moderate staining. Twelve (80%) of the metastatic UCs to the lung were positive for GATA3, with 11 cases showing diffuse moderate or strong staining and 1 case showing focal moderate staining. None of the pulmonary SCCs or non-small cell carcinomas with squamous features was GATA3 positive. GATA3 IHC is a sensitive marker for UC, and positive staining in UC is typically nonfocal and moderate or strong in intensity. GATA3 is also highly specific in excluding high-grade prostate adenocarcinoma. Although some cervical and anal SCCs can be GATA3 positive, unlike in UC, staining is more commonly focal and weak. GATA3 is also a useful maker when diagnosing metastatic UC to the lung.
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Abstract
McCluggage W G (2012) Histopathology New developments in endocervical glandular lesions There is evidence that the prevalence of premalignant and malignant endocervical glandular lesions is increasing in real as well as in apparent terms. In this review, new developments and selected controversial aspects of endocervical glandular lesions are covered, concentrating mainly on premalignant and malignant lesions. The terminology of premalignant endocervical glandular lesions is discussed with a comparison of the World Health Organization classification and the cervical glandular intraepithelial neoplasia (CGIN) system, which is in widespread use in the United Kingdom. Primary cervical adenocarcinomas comprise a heterogeneous group of different morphological types, and while it is known that the majority of these are associated with high-risk human papillomavirus (HPV), it has become clear in recent years that most of the more uncommon morphological types are unassociated with HPV, although they may sometimes be p16-positive. A spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation is now recognized; these include type A tunnel clusters, typical and atypical lobular endocervical glandular hyperplasia, adenoma malignum and gastric-type adenocarcinoma. The latter is a recently described variant of primary cervical adenocarcinoma which has a different morphological appearance to the usual endocervical type and which is probably associated with different patterns of spread and a worse prognosis. There is accumulating evidence that 'early invasive' cervical adenocarcinomas have an excellent prognosis and are suitable for conservative management. Immunohistochemical markers of value in the distinction between a primary cervical and endometrial adenocarcinoma are discussed. While it is well known that a panel of markers comprising oestrogen receptor (ER), vimentin, p16 and monoclonal carcinoembryonic antigen (CEA) is useful, several major pitfalls are pointed out and this panel of markers is predominantly of value in 'low-grade' adenocarcinomas. A related group of lesions, including cervical ectopic prostatic tissue and vaginal tubulosquamous polyp, are probably derived from para-urethral Skene's glands and may be positive with prostatic markers. Recent developments in cervical neuroendocrine neoplasms are discussed, as these are associated not uncommonly with a premalignant or malignant endocervical glandular lesion.
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Affiliation(s)
- W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.
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41
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Sidhu HK, Patel RV, Goldenberg G. Dermatology clinics: what's new in dermatopathology: news in nonmelanocytic neoplasia. Dermatol Clin 2012; 30:623-41, vi. [PMID: 23021050 DOI: 10.1016/j.det.2012.06.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This article reviews the recent dermatopathology literature involving nonmelanocytic neoplasia, with a focus on important work done over the last 5 years. The discussion includes advances in the understanding of Merkel cell carcinoma pathogenesis and prognosis; changes in the seventh edition of the American Joint Committee of Cancer staging manual in reference to staging of squamous cell carcinoma and Merkel cell carcinoma; newly described or rare histopathologic patterns and entities including squamoid eccrine ductal carcinoma, rippled-pattern adnexal neoplasms, onychomatricoma, spindle cell predominant trichodiscoma/neurofollicular hamartoma, and myoepithelioma; and microsatellite instability in sebaceous neoplasms of Muir-Torre syndrome and other tumors.
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Affiliation(s)
- Harleen K Sidhu
- Department of Pathology, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
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42
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Cheung TH, Man KNM, Yu MY, Yim SF, Siu NSS, Lo KWK, Doran G, Wong RRY, Wang VW, Smith DI, Worley MJ, Berkowitz RS, Chung TKH, Wong YF. Dysregulated microRNAs in the pathogenesis and progression of cervical neoplasm. Cell Cycle 2012; 11:2876-84. [PMID: 22801550 DOI: 10.4161/cc.21278] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) play an important role in a variety of physiological as well as pathophysiological processes, including carcinogenesis. The aim of this study is to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to unveil individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues and compared to normal cervical epithelium. Unsupervised hierarchical clustering of the miRNA expression pattern displayed a distinct separation between the CIN and normal cervical epithelium samples. Supervised analysis identified 12 highly differentially regulated miRNAs, including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203, which distinguished the high-grade CIN specimens from normal cervical epithelium. This miRNA signature was further validated by an independent set of high-grade CIN cases. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma from normal controls. Target prediction analysis revealed that these dysregulated miRNAs mainly control apoptosis signaling pathways and cell cycle regulation. These findings contribute to understanding the role of microRNAs in the pathogenesis and progression of cervical neoplasm at the molecular level.
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Affiliation(s)
- Tak-hong Cheung
- Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
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43
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Role of p63 in Development, Tumorigenesis and Cancer Progression. CANCER MICROENVIRONMENT 2012; 5:311-22. [PMID: 22847008 DOI: 10.1007/s12307-012-0116-9] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 07/10/2012] [Indexed: 12/23/2022]
Abstract
The p53-related protein p63 has pleiotropic functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. The p63 gene is expressed as multiple isoforms that either contain an N-terminal p53-homologous transactivation domain (TAp63) or that lack this domain (ΔNp63). Multiple studies have demonstrated that p63 plays a crucial role in stratified epithelial development, and have shown the importance of p63 for maintaining proliferation potential, inducing differentiation, and preventing senescence. Additionally, much research focuses on the role of p63 in cancer progression. Clinical evidence suggests that p63 may play a role in inhibiting metastasis. Similarly, genetic mice models together with cell culture data strongly indicate that p63 deficiency may be a causative factor for metastatic spread. Moreover, the role of p63 in cancer metastasis has been shown to be greatly related to the ability of mutant p53 to promote cancer malignancy. However, there is still much confusion as to what the role of each specific isoform is. In this review, we highlight some of the major findings in the current literature regarding the role of specific p63 isoforms in development, tumorigenesis, and particularly in cancer metastasis.
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44
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Detection of Human Papillomavirus in Small Cell Carcinomas of the Anus and Rectum. Am J Surg Pathol 2012; 36:1087-92. [DOI: 10.1097/pas.0b013e3182549b6d] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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45
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Cell density-dependent acetylation of ΔNp63α is associated with p53-dependent cell cycle arrest. FEBS Lett 2012; 586:1128-34. [DOI: 10.1016/j.febslet.2012.03.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 03/09/2012] [Accepted: 03/12/2012] [Indexed: 11/20/2022]
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46
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Induction the cornification of squamous cancerous cells to eliminate tumor cells by promotion cell differentiation and stratum. Med Hypotheses 2011; 77:763-4. [DOI: 10.1016/j.mehy.2011.07.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 07/18/2011] [Indexed: 01/05/2023]
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47
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p53 Family: Role of Protein Isoforms in Human Cancer. J Nucleic Acids 2011; 2012:687359. [PMID: 22007292 PMCID: PMC3191818 DOI: 10.1155/2012/687359] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 07/04/2011] [Indexed: 01/07/2023] Open
Abstract
TP53, TP63, and TP73 genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.
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Ben Khalifa Y, Teissier S, Tan MKM, Phan QT, Daynac M, Wong WQ, Thierry F. The human papillomavirus E6 oncogene represses a cell adhesion pathway and disrupts focal adhesion through degradation of TAp63β upon transformation. PLoS Pathog 2011; 7:e1002256. [PMID: 21980285 PMCID: PMC3182928 DOI: 10.1371/journal.ppat.1002256] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 07/21/2011] [Indexed: 11/19/2022] Open
Abstract
Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical pathway in human carcinogenesis.
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Affiliation(s)
| | | | | | | | | | - Wei Qi Wong
- Institute of Medical Biology, A*STAR, Singapore
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49
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Melino G. p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ 2011; 18:1487-99. [PMID: 21760596 DOI: 10.1038/cdd.2011.81] [Citation(s) in RCA: 189] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
p53 mutations, occurring in two-thirds of all human cancers, confer a gain of function phenotype, including the ability to form metastasis, the determining feature in the prognosis of most human cancer. This effect seems mediated at least partially by its ability to physically interact with p63, thus affecting a cell invasion pathway, and accordingly, p63 is deregulated in human cancers. In addition, p63, as an 'epithelial organizer', directly impinges on epidermal mesenchimal transition, stemness, senescence, cell death and cell cycle arrest, all determinant in cancer, and thus p63 affects chemosensitivity and chemoresistance. This demonstrates an important role for p63 in cancer development and its progression, and the aim of this review is to set this new evidence that links p63 to metastasis within the context of the long conserved other functions of p63.
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Affiliation(s)
- G Melino
- Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester, UK.
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50
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The role of p63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett 2011; 16:296-327. [PMID: 21442444 PMCID: PMC6275999 DOI: 10.2478/s11658-011-0009-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Accepted: 03/07/2011] [Indexed: 01/01/2023] Open
Abstract
The transcription factor p63 has important functions in tumorigenesis, epidermal differentiation and stem cell self-renewal. The TP63 gene encodes multiple protein isoforms that have different or even antagonistic roles in these processes. The balance of p63 isoforms, together with the presence or absence of the other p53 family members, p73 and p53, has a striking biological impact. There is increasing evidence that interactions between p53-family members, whether cooperative or antagonistic, are involved in various cell processes. This review summarizes the current understanding of the role of p63 in tumorigenesis, metastasis, cell migration and senescence. In particular, recent data indicate important roles in adult stem cell and cancer stem cell regulation and in the response of cancer cells to therapy.
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