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Hrabal V, Stenckova M, Zavadil Kokas F, Muller P, Nenutil R, Vojtesek B, Coates PJ. TAp73 and ΔTAp73 isoforms show cell-type specific distributions and alterations in cancer. Sci Rep 2024; 14:29949. [PMID: 39622910 PMCID: PMC11612387 DOI: 10.1038/s41598-024-80927-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.
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Affiliation(s)
- Vaclav Hrabal
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic.
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
| | - Michaela Stenckova
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic
| | - Filip Zavadil Kokas
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic
| | - Petr Muller
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic
| | - Rudolf Nenutil
- Department of Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Borivoj Vojtesek
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic
| | - Philip J Coates
- Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic.
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López I, Valdivia IL, Vojtesek B, Fåhraeus R, Coates P. Re-appraising the evidence for the source, regulation and function of p53-family isoforms. Nucleic Acids Res 2024; 52:12112-12129. [PMID: 39404067 PMCID: PMC11551734 DOI: 10.1093/nar/gkae855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 11/12/2024] Open
Abstract
The p53 family of proteins evolved from a common ancestor into three separate genes encoding proteins that act as transcription factors with distinct cellular roles. Isoforms of each member that lack specific regions or domains are suggested to result from alternative transcription start sites, alternative splicing or alternative translation initiation, and have the potential to exponentially increase the functional repertoire of each gene. However, evidence supporting the presence of individual protein variants at functional levels is often limited and is inferred by mRNA detection using highly sensitive amplification techniques. We provide a critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms. We conclude that despite the wealth of publications, several putative isoforms remain poorly established. Future research with improved technical approaches and the generation of isoform-specific protein detection reagents is required to establish the physiological relevance of p53-family isoforms in health and disease. In addition, our analyses suggest that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.
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Affiliation(s)
- Ignacio López
- Biochemistry, Faculty of Science, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
- Cell Biology Unit, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay
| | - Irene Larghero Valdivia
- Biochemistry, Faculty of Science, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
| | - Borivoj Vojtesek
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
| | - Robin Fåhraeus
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
- Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris Cité, 27 rue Juliette Dodu, Hôpital St. Louis, Paris F-75010, France
- Department of Medical Biosciences, Building 6M, Umeå University, Umeå 90185, Sweden
| | - Philip J Coates
- RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 65653, Czech Republic
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Low-Calle AM, Ghoneima H, Ortega N, Cuibus AM, Katz C, Prives C, Prywes R. A Non-Canonical Hippo Pathway Represses the Expression of ΔNp63. Mol Cell Biol 2024; 44:27-42. [PMID: 38270135 PMCID: PMC10829837 DOI: 10.1080/10985549.2023.2292037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/28/2023] [Indexed: 01/26/2024] Open
Abstract
The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cell carcinomas, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in MCF10A mammary epithelial cells as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for p63 repression. This suggests that regulation of p63 expression occurs by a noncanonical version of the Hippo pathway. We identified similarly regulated genes, suggesting the broader importance of this pathway. Interestingly, lowering p63 expression lead to increased YAP protein levels, indicating crosstalk of the YAP/TAZ-independent and -dependent branches of the Hippo pathway. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.
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Affiliation(s)
- Ana Maria Low-Calle
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Hana Ghoneima
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Nicholas Ortega
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Adriana M. Cuibus
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Chen Katz
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Carol Prives
- Department of Biological Sciences, Columbia University, New York, New York, USA
| | - Ron Prywes
- Department of Biological Sciences, Columbia University, New York, New York, USA
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Li Y, Giovannini S, Wang T, Fang J, Li P, Shao C, Wang Y, Shi Y, Candi E, Melino G, Bernassola F. p63: a crucial player in epithelial stemness regulation. Oncogene 2023; 42:3371-3384. [PMID: 37848625 PMCID: PMC10638092 DOI: 10.1038/s41388-023-02859-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/26/2023] [Accepted: 10/02/2023] [Indexed: 10/19/2023]
Abstract
Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, is an indispensable factor for their biological activities during epithelial development. The diversity of p63 isoforms expressed in distinct tissues allows this transcription factor to have a wide array of effects. p63 coordinates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. Through the regulation of these biological processes, p63 contributes to, not only normal epithelial development, but also epithelium-derived cancer pathogenesis. In this review, we provide an overview of the role of p63 in epithelial stemness regulation, including self-renewal, differentiation, proliferation, and senescence. We describe the differential expression of TAp63 and ΔNp63 isoforms and their distinct functional activities in normal epithelial tissues and in epithelium-derived tumors. Furthermore, we summarize the signaling cascades modulating the TAp63 and ΔNp63 isoforms as well as their downstream pathways in stemness regulation.
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Affiliation(s)
- Yanan Li
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China
| | - Sara Giovannini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Tingting Wang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China
| | - Jiankai Fang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China
| | - Peishan Li
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Shanghai, 200031, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, 215000, China.
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
- Biochemistry Laboratory, Istituto Dermopatico Immacolata (IDI-IRCCS), 00100, Rome, Italy.
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Francesca Bernassola
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
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Low-Calle AM, Ghoneima H, Ortega N, Cuibus AM, Katz C, Tong D, Prives C, Prywes R. A non-canonical Hippo pathway represses the expression of ΔNp63. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.13.528336. [PMID: 36824867 PMCID: PMC9949004 DOI: 10.1101/2023.02.13.528336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while in breast cancers its expression is often repressed. In the canonical conserved Hippo pathway, known to play a complex role in regulating growth of cancer cells, the protein kinases MST1/2 and LATS1/2 act sequentially to phosphorylate and inhibit the YAP/TAZ transcription factors. We found that in the MCF10A mammary epithelial cell line as well as in squamous and breast cancer cell lines, expression of ΔNp63 RNA and protein is strongly repressed by inhibition of the Hippo pathway protein kinases in a manner that is independent of p53. While MST1/2 and LATS1 are required for p63 expression, the next step of the pathway, namely phosphorylation and degradation of the YAP/TAZ transcriptional activators is not required for repression of p63. This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. We additionally identified additional genes that were similarly regulated suggesting the broader importance of this pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased YAP protein levels, thereby constituting a feedback loop. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells. One Sentence Summary Regulation of p63 expression occurs by a non-canonical version of the Hippo pathway in mammary epithelial, breast carcinoma and head and neck squamous carcinoma cells.
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Rodriguez Calleja L, Lavaud M, Tesfaye R, Brounais-Le-Royer B, Baud’huin M, Georges S, Lamoureux F, Verrecchia F, Ory B. The p53 Family Members p63 and p73 Roles in the Metastatic Dissemination: Interactions with microRNAs and TGFβ Pathway. Cancers (Basel) 2022; 14:cancers14235948. [PMID: 36497429 PMCID: PMC9741383 DOI: 10.3390/cancers14235948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 11/29/2022] [Indexed: 12/02/2022] Open
Abstract
TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73's pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy.
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Zhou P, Zhang C, Song X, Zhang D, Zhu M, Zheng H. ΔNp63α promotes Bortezomib resistance via the CYGB-ROS axis in head and neck squamous cell carcinoma. Cell Death Dis 2022; 13:327. [PMID: 35397613 PMCID: PMC8994767 DOI: 10.1038/s41419-022-04790-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 03/01/2022] [Accepted: 03/21/2022] [Indexed: 01/07/2023]
Abstract
Bortezomib, a proteasome inhibitor, proved potent in the treatment of recurrent multiple myeloma or mantle cell lymphoma. However, slow progress was made when it was applied to treat solid tumors. We discovered that different head and neck squamous cell carcinoma (HNSCC) cell lines had significantly different sensitivities to bortezomib, and also demonstrated that individual relatively sensitive HNSCC cell lines had fewer ΔNp63α expressions. Based on these findings, we speculated that ΔNp63α may be a key factor in the resistance of HNSCC cells to bortezomib. ΔNp63α knockdown made HNSCC more sensitive to bortezomib, while ΔNp63α overexpression made it more resistant. RNA sequencing (RNA-seq) analysis of ΔNp63α-knockdown cells revealed clear alterations in the subset of genes that were associated with oxidative stress and antioxidant defense. The gene CYGB was downregulated significantly. CHIP-seq detection showed that CYGB was the transcriptional regulatory site of ΔNp63α. CHIP-PCR showed evidence of ΔNp63α binding. The detection of the dual-luciferase reporter gene demonstrated that ΔNp63α significantly enhanced the CYGB promoter activity. Furthermore, we confirmed that CYGB plays a role in clearing excess ROS induced by bortezomib to inhibit HNSCC apoptosis. Consequently, ΔNp63α regulated the expression of CYGB in HNSCC. CYGB was the target of transcription regulation of ΔNp63α. It reduced apoptosis by clearing excess ROS produced by bortezomib, and thus exerted drug resistance.
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Affiliation(s)
- Peng Zhou
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.,Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221003, China
| | - Caiyun Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Xianmin Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Dadong Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.,3D Medicines Inc., Shanghai, 201114, China
| | - Minhui Zhu
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
| | - Hongliang Zheng
- Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
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Characterization of Desmoglein 3 (DSG3) as a Sensitive and Specific Marker for Esophageal Squamous Cell Carcinoma. Gastroenterol Res Pract 2022; 2022:2220940. [PMID: 35251162 PMCID: PMC8894070 DOI: 10.1155/2022/2220940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Although P40 and P63 are both sensitive and specific for routine esophageal squamous cell carcinoma (SCC) diagnosis, we recently showed that P40 and P63 immunoreactivities were significantly lower in well-differentiated SCC than those in higher grade tumors. Therefore, a novel esophageal SCC marker, ideally performing better in well-differentiated SCC, is still needed. We characterized desmoglein 3 (DSG3) immunohistochemistry in esophageal SCC, esophageal adenocarcinoma, small-cell lung carcinoma, and large B-cell lymphoma, alongside P40 and CK5/6. The World Health Organization classification was used to grade tumors as well-differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD). There were 20 WD, 26 MD, and 17 PD components among 39 esophageal SCC cases. All esophageal SCC components showed significant DSG3 immunoreactivity (mean, 80%; range, 30%–100%), and the proportions of DSG3 immunoreactive cells were higher in the WD and MD components than in the PD components. No esophageal adenocarcinoma cases showed more than 10% DSG3 immunoreactivity with only weak cytoplasmic staining. With a 5% immunoreactivity cutoff, DSG3 positivity was 100% in all 63 SCC components, 18% in adenocarcinoma cases, and 0% in small-cell lung carcinoma or large B-cell lymphoma cases. The overall DSG3 specificity was 94%. To the best of our knowledge, this is the first study to characterize DSG3 as a sensitive and specific marker for esophageal SCC.
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Pokorna Z, Vyslouzil J, Vojtesek B, Coates PJ. Identifying pathways regulating the oncogenic p53 family member ΔNp63 provides therapeutic avenues for squamous cell carcinoma. Cell Mol Biol Lett 2022; 27:18. [PMID: 35196980 PMCID: PMC8903560 DOI: 10.1186/s11658-022-00323-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/15/2022] [Indexed: 12/17/2022] Open
Abstract
Background ΔNp63 overexpression is a common event in squamous cell carcinoma (SCC) that contributes to tumorigenesis, making ΔNp63 a potential target for therapy. Methods We created inducible TP63-shRNA cells to study the effects of p63-depletion in SCC cell lines and non-malignant HaCaT keratinocytes. DNA damaging agents, growth factors, signaling pathway inhibitors, histone deacetylase inhibitors, and metabolism-modifying drugs were also investigated for their ability to influence ΔNp63 protein and mRNA levels. Results HaCaT keratinocytes, FaDu and SCC-25 cells express high levels of ΔNp63. HaCaT and FaDu inducible TP63-shRNA cells showed reduced proliferation after p63 depletion, with greater effects on FaDu than HaCaT cells, compatible with oncogene addiction in SCC. Genotoxic insults and histone deacetylase inhibitors variably reduced ΔNp63 levels in keratinocytes and SCC cells. Growth factors that regulate proliferation/survival of squamous cells (IGF-1, EGF, amphiregulin, KGF, and HGF) and PI3K, mTOR, MAPK/ERK or EGFR inhibitors showed lesser and inconsistent effects, with dual inhibition of PI3K and mTOR or EGFR inhibition selectively reducing ΔNp63 levels in HaCaT cells. In contrast, the antihyperlipidemic drug lovastatin selectively increased ΔNp63 in HaCaT cells. Conclusions These data confirm that ΔNp63-positive SCC cells require p63 for continued growth and provide proof of concept that p63 reduction is a therapeutic option for these tumors. Investigations of ΔNp63 regulation identified agent-specific and cell-specific pathways. In particular, dual inhibition of the PI3K and mTOR pathways reduced ΔNp63 more effectively than single pathway inhibition, and broad-spectrum histone deacetylase inhibitors showed a time-dependent biphasic response, with high level downregulation at the transcriptional level within 24 h. In addition to furthering our understanding of ΔNp63 regulation in squamous cells, these data identify novel drug combinations that may be useful for p63-based therapy of SCC. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-022-00323-x.
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Affiliation(s)
- Zuzana Pokorna
- Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Jan Vyslouzil
- Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Borivoj Vojtesek
- Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic
| | - Philip J Coates
- Research Center of Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
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Nishimori T, Hanazono K, Matsuda K, Kawamura Y, Kadosawa T, Endo Y, Uchide T. Prognostic role of ΔNp63 expression in canine transitional cell carcinoma of the urinary bladder. Open Vet J 2022; 11:700-706. [PMID: 35070867 PMCID: PMC8770170 DOI: 10.5455/ovj.2021.v11.i4.22] [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: 06/06/2021] [Accepted: 11/19/2021] [Indexed: 01/23/2023] Open
Abstract
Background Decreased p63 protein expression in canine transitional cell carcinoma (TCC) of the urinary bladder is associated with vascular invasion of the tumor, metastasis, and shortened survival. ΔNp63, an isoform of p63, is downregulated in high-grade invasive urothelial carcinoma in humans. However, the clinical significance of ΔNp63 expression in canine urinary bladder tumors is unknown. Therefore, it is essential to investigate ΔNp63 expression patterns in TCC, the most common urinary bladder tumor in dogs. Aim This study aimed to evaluate the expression and role of ΔNp63 in canine TCC of the urinary bladder. Methods ΔNp63 expression was compared between the normal canine urinary bladder, polypoid cystitis, and TCC. The correlation of ΔNp63 expression with histopathological and clinical findings were further evaluated, and its usefulness as a prognostic factor was examined. Results We observed that ΔNp63 was highly expressed in dogs' normal urinary bladder and polypoid cystitis, and its expression levels were low in TCC. Furthermore, low levels of ΔNp63 expression were associated with vascular invasion, metastasis, and shortened survival in dogs with TCC. Conclusion These results indicate that ΔNp63 expression could serve as a valuable biomarker for invasion, metastasis, and prognosis of canine TCC of the urinary bladder.
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Affiliation(s)
| | - Kiwamu Hanazono
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Kazuya Matsuda
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Yoshio Kawamura
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Tsuyoshi Kadosawa
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Yoshifumi Endo
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Tsuyoshi Uchide
- Laboratory of Veterinary Molecular Pathology and Therapeutics, Tokyo University of Agriculture and Technology, Fuchu, Japan
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Chi Z, Balani J, Gopal P, Peng L, Hammer S. Variations of P40 and P63 Immunostains in Different Grades of Esophageal Squamous Cell Carcinoma: A Potential Diagnostic Pitfall. Appl Immunohistochem Mol Morphol 2021; 29:674-679. [PMID: 34061488 DOI: 10.1097/pai.0000000000000943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/01/2021] [Indexed: 11/26/2022]
Abstract
The distinction of esophageal squamous cell carcinoma (SCC) from adenocarcinoma (adenoCA) using targeted therapies has become critical for small biopsies. In the United States, esophageal SCC is relatively uncommon compared with AdenoCA, with only few detailed immunohistochemical (IHC) studies on esophageal SCC. We characterized p40 and p63 IHC across various grades of squamous differentiation in esophageal SCC and compared their sensitivities between esophageal SCC and adenoCA. Twenty-eight esophageal SCC and 26 esophageal adenoCA (control group) samples were stained for p40, p63, and CK5/6. All hematoxylin-and-eosin-stained SCC slides were reviewed. Tumors were graded according to the World Health Organization classification: well, moderately, or poorly differentiated (WD, MD, and PD, respectively). Considering morphological heterogeneity, individual differentiation components within the same tumor were scored separately (0% to 100%) according to the proportion of immunoreactive cells and marked as positive (≥5%) or negative (<5%). Among 28 esophageal SCC, 15 had mixed intratumoral differentiation. There were 16 WD, 19 MD, and 14 PD components. P40 immunoreactivity was significantly lower in WD than in MD or PD components (P<0.001), P63 immunoreactivity patterns were similar (P<0.001), while CK5/6 showed no differences (P>0.05). The sensitivities for SCC components were 98% (P40), 100% (P63), and 100% (CK5/6), while those for esophageal AdenoCA were significantly lower: 4% (P40), 4% (P63), and 8% (CK5/6). P40 and P63 were sensitive and specific for routine esophageal SCC diagnosis. However, their immunostaining was significantly lower in WD SCC than in higher grade tumors. IHC results for small biopsy specimens should be interpreted carefully, particularly in WD components.
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Affiliation(s)
- Zhikai Chi
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX
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Mancini M, Cappello A, Pecorari R, Lena AM, Montanaro M, Fania L, Ricci F, Di Lella G, Piro MC, Abeni D, Dellambra E, Mauriello A, Melino G, Candi E. Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma. Discov Oncol 2021; 12:14. [PMID: 35201472 PMCID: PMC8777507 DOI: 10.1007/s12672-021-00409-6] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022] Open
Abstract
While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.
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Affiliation(s)
- M. Mancini
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - A. Cappello
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - R. Pecorari
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - A. M. Lena
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - M. Montanaro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - L. Fania
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - F. Ricci
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - G. Di Lella
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - M. C. Piro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - D. Abeni
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - E. Dellambra
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
| | - A. Mauriello
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - G. Melino
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
| | - E. Candi
- Istituto Dermopatico Dell’Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy
- Department of Experimental Medicine, University of Rome “Tor Vergata”, via Montpellier 1, 00133 Rome, Italy
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13
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Choe JH, Mazambani S, Kim TH, Kim JW. Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas. Cells 2021; 10:606. [PMID: 33803326 PMCID: PMC8000417 DOI: 10.3390/cells10030606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/25/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Squamous cell carcinomas (SCCs) arise from both stratified squamous and non-squamous epithelium of diverse anatomical sites and collectively represent one of the most frequent solid tumors, accounting for more than one million cancer deaths annually. Despite this prevalence, SCC patients have not fully benefited from recent advances in molecularly targeted therapy or immunotherapy. Rather, decades old platinum-based or radiation regimens retaining limited specificity to the unique characteristics of SCC remain first-line treatment options. Historically, a lack of a consolidated perspective on genetic aberrations driving oncogenic transformation and other such factors essential for SCC pathogenesis and intrinsic confounding cellular heterogeneity in SCC have contributed to a critical dearth in effective and specific therapies. However, emerging evidence characterizing the distinct genomic, epigenetic, and metabolic landscapes of SCC may be elucidating unifying features in a seemingly heterogeneous disease. In this review, by describing distinct metabolic alterations and genetic drivers of SCC revealed by recent studies, we aim to establish a conceptual framework for a previously unappreciated network of oncogenic signaling, redox perturbation, and metabolic reprogramming that may reveal targetable vulnerabilities at their intersection.
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Affiliation(s)
- Joshua H. Choe
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Simbarashe Mazambani
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
| | - Tae Hoon Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
| | - Jung-whan Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
- Research and Development, VeraVerse Inc., 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
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14
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Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of Notch, Hedgehog, Wnt, and ErbB signalling. Sci Rep 2020; 10:21128. [PMID: 33273537 PMCID: PMC7713208 DOI: 10.1038/s41598-020-77284-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022] Open
Abstract
Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo- and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identified through weighted gene co-expression network analysis (WGCNA), which significantly differentiated downstream signaling of Notch, ErbB, Hedgehog, and Wnt in LUSC and LUAD. Among co-expressed genes essential regulators of the cell cycle, DNA damage response, apoptosis, and proliferation have been found. Most of them were upregulated in LUSC compared to LUAD. In conclusion, identified downstream networks revealed distinct biological mechanisms underlying cancer development and progression in LUSC and LUAD that may diversify the clinical outcome of the disease.
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15
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Zhu ZJ, Teng M, Li HZ, Zheng LP, Liu JL, Chai SJ, Yao YX, Nair V, Zhang GP, Luo J. Marek's Disease Virus ( Gallid alphaherpesvirus 2)-Encoded miR-M2-5p Simultaneously Promotes Cell Proliferation and Suppresses Apoptosis Through RBM24 and MYOD1-Mediated Signaling Pathways. Front Microbiol 2020; 11:596422. [PMID: 33224130 PMCID: PMC7669912 DOI: 10.3389/fmicb.2020.596422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/08/2020] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) have been demonstrated for their involvement in virus biology and pathogenesis, including functioning as key determinants of virally-induced cancers. As an important oncogenic α-herpesvirus affecting poultry health, Marek’s disease virus serotype 1 [Gallid alphaherpesvirus 2 (GaHV-2)] induces rapid-onset T-cell lymphomatous disease commonly referred to as Marek’s disease (MD), an excellent biological model for the study of virally-induced cancer in the natural hosts. Previously, we have demonstrated that GaHV-2-encoded miRNAs (especially those within the Meq-cluster) have the potential to act as critical regulators of multiple processes such as virus replication, latency, pathogenesis, and/or oncogenesis. In addition to miR-M4-5p (miR-155 homolog) and miR-M3-5p, we have recently found that miR-M2-5p possibly participate in inducing MD lymphomagenesis. Here, we report the identification of two tumor suppressors, the RNA-binding protein 24 (RBM24) and myogenic differentiation 1 (MYOD1), being two biological targets for miR-M2-5p. Our experiments revealed that as a critical miRNA, miR-M2-5p promotes cell proliferation via regulating the RBM24-mediated p63 overexpression and MYOD1-mediated IGF2 signaling and suppresses apoptosis by targeting the MYOD1-mediated Caspase-3 signaling pathway. Our data present a new strategy of a single viral miRNA exerting dual role to potentially participate in the virally-induced T-cell lymphomagenesis by simultaneously promoting the cell proliferation and suppressing apoptosis.
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Affiliation(s)
- Zhi-Jian Zhu
- Research Center of Avian Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China
| | - Man Teng
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China
| | - Hui-Zhen Li
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China.,College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Lu-Ping Zheng
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China
| | - Jin-Ling Liu
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China
| | - Shu-Jun Chai
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China
| | - Yong-Xiu Yao
- The Pirbright Institute and UK-China Centre of Excellence for Research on Avian Diseases, Guildford, United Kingdom
| | - Venugopal Nair
- The Pirbright Institute and UK-China Centre of Excellence for Research on Avian Diseases, Guildford, United Kingdom
| | - Gai-Ping Zhang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, China
| | - Jun Luo
- Key Laboratory of Animal Immunology, Ministry of Agriculture and Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou, China.,UK-China Centre of Excellence for Research on Avian Diseases, Henan Academy of Agricultural Sciences, Zhengzhou, China.,Key Laboratory of Animal Disease and Public Safety, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
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16
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Patel A, Garcia LF, Mannella V, Gammon L, Borg TM, Maffucci T, Scatolini M, Chiorino G, Vergani E, Rodolfo M, Maurichi A, Posch C, Matin RN, Harwood CA, Bergamaschi D. Targeting p63 Upregulation Abrogates Resistance to MAPK Inhibitors in Melanoma. Cancer Res 2020; 80:2676-2688. [PMID: 32291316 DOI: 10.1158/0008-5472.can-19-3230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/04/2020] [Accepted: 04/09/2020] [Indexed: 11/16/2022]
Abstract
Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here, we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7-inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor-resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of Nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy. SIGNIFICANCE: Upregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.
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Affiliation(s)
- Ankit Patel
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Lucia Fraile Garcia
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Viviana Mannella
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Luke Gammon
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Tiffanie-Marie Borg
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Tania Maffucci
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Maria Scatolini
- Molecular Oncology Lab, Fondazione Edo ed Elvo Tempia, Biella, Italy
| | | | - Elisabetta Vergani
- Department of Experimental Oncology and Molecular Medicine, Immunotherapy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Monica Rodolfo
- Department of Experimental Oncology and Molecular Medicine, Immunotherapy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Andrea Maurichi
- Department of Surgery, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Christian Posch
- Department of Dermatology, The Rudolfstiftung Hospital, Vienna, Austria.,Faculty of Medicine, Sigmund Freud University, Vienna, Austria.,Department of Dermatology, Technical University of Munich, Munich, Germany
| | - Rubeta N Matin
- Department of Dermatology, Oxford University Hospitals NHS Foundation Trust, Headington, Oxford, United Kingdom
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Daniele Bergamaschi
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
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17
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Prieto‐Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Schülein‐Völk C, Eilers U, Ade CP, Calzado MA, Orian A, Maric HM, Münch C, Rosenfeldt M, Eilers M, Diefenbacher ME. Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells. EMBO Mol Med 2020; 12:e11101. [PMID: 32128997 PMCID: PMC7136964 DOI: 10.15252/emmm.201911101] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 12/27/2022] Open
Abstract
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
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Affiliation(s)
- Cristian Prieto‐Garcia
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
| | - Oliver Hartmann
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
| | - Michaela Reissland
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
| | - Fabian Braun
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
| | - Thomas Fischer
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Department for RadiotherapyUniversity Hospital WürzburgWürzburgGermany
| | - Susanne Walz
- Core Unit BioinformaticsComprehensive Cancer Centre MainfrankenUniversity of WürzburgWürzburgGermany
| | | | - Ursula Eilers
- Core Unit High‐Content MicroscopyBiocenterUniversity of WürzburgWürzburgGermany
| | - Carsten P Ade
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
- Department of Biochemistry and Molecular BiologyUniversity of WürzburgWürzburgGermany
| | - Marco A Calzado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)CórdobaSpain
- Departamento de Biología Celular, Fisiología e InmunologíaUniversidad de CórdobaCórdobaSpain
- Hospital Universitario Reina SofíaCórdobaSpain
| | - Amir Orian
- Faculty of MedicineTICCTechnion HaifaIsrael
| | - Hans M Maric
- Rudolf‐Virchow‐Center for Experimental BiomedicineWürzburgGermany
| | - Christian Münch
- Institute of Biochemistry IIGoethe UniversityFrankfurtGermany
| | - Mathias Rosenfeldt
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
- Institute for PathologyUniversity of WürzburgWürzburgGermany
| | - Martin Eilers
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
- Department of Biochemistry and Molecular BiologyUniversity of WürzburgWürzburgGermany
| | - Markus E Diefenbacher
- Department of Biochemistry and Molecular BiologyProtein Stability and Cancer GroupUniversity of WürzburgWürzburgGermany
- Comprehensive Cancer Centre MainfrankenWürzburgGermany
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18
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Guan Y, Wang G, Fails D, Nagarajan P, Ge Y. Unraveling cancer lineage drivers in squamous cell carcinomas. Pharmacol Ther 2020; 206:107448. [PMID: 31836455 PMCID: PMC6995404 DOI: 10.1016/j.pharmthera.2019.107448] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Guan Wang
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Danielle Fails
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Yejing Ge
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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19
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Moussa RA, Khalil EZI, Ali AI. Prognostic Role of Epithelial-Mesenchymal Transition Markers "E-Cadherin, β-Catenin, ZEB1, ZEB2 and p63" in Bladder Carcinoma. World J Oncol 2019; 10:199-217. [PMID: 31921376 PMCID: PMC6940035 DOI: 10.14740/wjon1234] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 10/29/2019] [Indexed: 12/20/2022] Open
Abstract
Background This study aimed to investigate the expression of epithelial-mesenchymal markers’ E-cadherin, β-catenin, zinc-finger E-box-binding homeobox 1 (ZEB1), zinc-finger E-box-binding homeobox 2 (ZEB2) and p63 in transitional cell carcinoma (TCC) and squamous cell carcinoma (SCC) variants of bladder carcinoma (BC) and their correlation with clinicopathological parameters of prognostic importance. Methods In this retrospective study, 91 patients were enrolled (66 with TCC and 25 with SCC). All patients had full clinical and follow-up data and available paraffin blocks. Immunohistochemical analysis was performed and correlated with clinicopathological factors. Results In TCC cases, reduced E-cadherin, β-catenin positivity and p63 expression rate were evident in the sitting of increased expression of ZEB1 and ZEB2. Patients with ZEB2 positive tumors were more likely to die compared to those with negative ZEB2 (P = 0.024). Moreover, in patients with muscle-invasive BCs, an intense p63 expression was associated with poor overall survival (OS) (P < 0.001). For patients with SCC, there was a reduction in E-cadherin and β-catenin positivity with elevated p63 expression and concomitant increased ZEB1 and ZEB2 expression. Poor prognosis was evident in association with reduced E-cadherin, positive nuclear β-catenin/reduced membranous β-catenin, ZEB1 and ZEB2 positive cases as well patients with elevated p63 expression (P < 0.001). TCC and SCC cases showed similar poor prognosis in association with elevated p63 expression (P < 0.001). Conclusions In both TCC and SCC variants, epithelial-mesenchymal transition (EMT) process is evident; however, its molecular mechanism shows some variations, specifically this notably different p63 expression pattern among two carcinoma variants with the similar impact of elevated p63 expression pattern on prognosis.
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Affiliation(s)
- Rabab Ahmed Moussa
- Pathology Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
| | | | - Ahmed Issam Ali
- Urology Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
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20
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Papadimitriou MA, Avgeris M, Levis PK, Tokas T, Stravodimos K, Scorilas A. ΔNp63 transcript loss in bladder cancer constitutes an independent molecular predictor of TaT1 patients post-treatment relapse and progression. J Cancer Res Clin Oncol 2019; 145:3075-3087. [PMID: 31595333 DOI: 10.1007/s00432-019-03028-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/16/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE Bladder cancer represents a major cause of malignancy-related morbidity and the most expensive per-patient-to-treat cancer, due to the lifelong surveillance of the patients. Accurate disease prognosis is essential in establishing personalized treatment decisions; yet optimum tools for precise risk stratification remain a competing task. In the present study, we have performed the complete evaluation of TP63 clinical significance in improving disease prognosis. METHODS The levels of ΔNp63 and TAp63 transcripts of TP63 were quantified in 342 bladder tissue specimens of our screening cohort (n = 182). Hedegaard et al. (Cancer Cell 30:27-42. doi:10.1016/j.ccell.2016.05.004, 2016) (n = 476) and TCGA provisional (n = 413) were used as validation cohorts for NMIBC and MIBC, respectively. Survival analysis was performed using recurrence and progression for NMIBC or mortality for MIBC as endpoint events. Bootstrap analysis was performed for internal validation, while decision curve analysis was used for the evaluation of the clinical net benefit on disease prognosis. RESULTS ΔNp63 was significantly expressed in bladder tissues, and was found to be over-expressed in bladder tumors. Interestingly, reduced ΔNp63 levels were correlated with muscle-invasive disease, high-grade tumors and high-EORTC-risk NMIBC patients. Moreover, ΔNp63 loss was independently associated with higher risk for NMIBC relapse (HR = 2.730; p = 0.007) and progression (HR = 7.757; p = 0.016). Hedegaard et al. and TCGA validation cohorts confirmed our findings. Finally, multivariate models combining ΔΝp63 loss with established prognostic markers led to a superior clinical benefit for NMIBC prognosis and risk stratification. CONCLUSIONS ΔΝp63 loss is associated with adverse outcome of NMIBC resulting in superior prediction of NMIBC early relapse and progression.
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Affiliation(s)
- Maria-Alexandra Papadimitriou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodostrian University of Athens, Panepistimiopolis, 157 01, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodostrian University of Athens, Panepistimiopolis, 157 01, Athens, Greece
| | - Panagiotis K Levis
- First Department of Urology, "Laiko" General Hospital, Medical School, National and Kapodostrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece
| | - Theodoros Tokas
- First Department of Urology, "Laiko" General Hospital, Medical School, National and Kapodostrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece
| | - Konstantinos Stravodimos
- First Department of Urology, "Laiko" General Hospital, Medical School, National and Kapodostrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodostrian University of Athens, Panepistimiopolis, 157 01, Athens, Greece.
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21
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Hu WM, Jin JT, Wu CY, Lu JB, Zhang LH, Zeng J, Lin SX. Expression of P63 and its correlation with prognosis in diffuse large B-cell lymphoma: a single center experience. Diagn Pathol 2019; 14:128. [PMID: 31711519 PMCID: PMC6844053 DOI: 10.1186/s13000-019-0880-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 08/29/2019] [Indexed: 12/25/2022] Open
Abstract
Background Large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma among adults. In some cases, DLBCL may seem similar to carcinoma cells, presenting a round, oval, or polygonal shape and clear nuclei. We found that the expression of P63 accounted for a considerable proportion of DLBCL cases. Under the circumstances, P63 expression may lead to a misdiagnosis, especially with a small biopsy. We aim to investigate the expression status and prognostic significance of P63 in a cohort of Chinese DLBCL patients. Methods P63, ΔNP63(P40), P53 and Ki67 were detected by immunohistochemistry (IHC). A ROC curve was adopted to find the best cut-off value for positive P63/P53 expression and high Ki67 expression. We defined P53 as positive when ≥50% of the tumor cells showed staining. The relationship between P63 and P53/Ki67 expression was examined. Time-to-event endpoints were estimated according to the Kaplan-Meier method. Moreover, multivariate analyses were conducted to evaluate the prognostic factors in DLBCL. Results Out of all the 159 DLBCL cases, 76 (47.8%) expressed P63 in the nuclei, while 41 (25.8%) were determined to have high expression by using a ROC cut-off value “≥6”. Examination of the different P63 isoforms revealed that the ΔNP63(P40) was unclearly and weakly expressed in only 3 cases, showing a fuzzy yellow cytoplasm. P63 expression was not correlated with subtype (GCB or non-GCB) or P53 but was correlated with a high proliferative index (Ki67). Kaplan-Meier analyses revealed that P63 expression was correlated with overall survival, and P63 positive cases showed poor survival outcomes (P<0.05) in our cohort. Conclusions ΔNP63(P40) is a useful marker in the differential diagnosis of poorly differentiated squamous cell carcinoma versus DLBCL in small needle biopsy. P63 may be involved in DLBCL tumor progression, and it is an unfavorable prognostic marker in DLBCL. A subgroup of P63 and P53 coexpression DLBCL patients with an extremely poor prognosis should be noted.
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Affiliation(s)
- Wan-Ming Hu
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jie-Tian Jin
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Chen-Yan Wu
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jia-Bin Lu
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Li-Hong Zhang
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Jing Zeng
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China. .,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
| | - Su-Xia Lin
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China. .,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
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22
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Ooizumi Y, Kojima K, Igarashi K, Tanaka Y, Harada H, Yokota K, Kaida T, Ishii S, Tanaka T, Yokoi K, Nishizawa N, Washio M, Ushiku H, Katoh H, Kosaka Y, Mieno H, Hosoda K, Watanabe M, Katada C, Hiki N, Yamashita K. Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2019; 26:4814-4825. [PMID: 31529309 DOI: 10.1245/s10434-019-07795-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer. METHODS OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC). RESULTS OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance. CONCLUSION Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.
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Affiliation(s)
- Yosuke Ooizumi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keita Kojima
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuharu Igarashi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoko Tanaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroki Harada
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Kaida
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Satoru Ishii
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Marie Washio
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hideki Ushiku
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroshi Katoh
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshimasa Kosaka
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroaki Mieno
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kei Hosoda
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Chikatoshi Katada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naoki Hiki
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. .,Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
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23
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Hsieh MH, Choe JH, Gadhvi J, Kim YJ, Arguez MA, Palmer M, Gerold H, Nowak C, Do H, Mazambani S, Knighton JK, Cha M, Goodwin J, Kang MK, Jeong JY, Lee SY, Faubert B, Xuan Z, Abel ED, Scafoglio C, Shackelford DB, Minna JD, Singh PK, Shulaev V, Bleris L, Hoyt K, Kim J, Inoue M, DeBerardinis RJ, Kim TH, Kim JW. p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas. Cell Rep 2019; 28:1860-1878.e9. [PMID: 31412252 PMCID: PMC7048935 DOI: 10.1016/j.celrep.2019.07.027] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/17/2019] [Accepted: 07/11/2019] [Indexed: 12/21/2022] Open
Abstract
Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.
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Affiliation(s)
- Meng-Hsiung Hsieh
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Joshua H Choe
- Department of Biological Sciences, Columbia University, New York, NY, USA
| | - Jashkaran Gadhvi
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Yoon Jung Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Marcus A Arguez
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Madison Palmer
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Haleigh Gerold
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Chance Nowak
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Hung Do
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Simbarashe Mazambani
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Jordan K Knighton
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Matthew Cha
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Justin Goodwin
- Graduate School of Art and Sciences and School of Medicine, Yale University, New Haven, CT, USA
| | - Min Kyu Kang
- Department of Radiation Oncology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Ji Yun Jeong
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Shin Yup Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Brandon Faubert
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zhenyu Xuan
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA; Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA
| | - E Dale Abel
- Division of Endocrinology and Metabolism and the Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Claudio Scafoglio
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - David B Shackelford
- Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - John D Minna
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Pankaj K Singh
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vladimir Shulaev
- Department of Biological Sciences, College of Science, Advanced Environmental Research Institute, University of North Texas, Denton, TX, USA
| | - Leonidas Bleris
- Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA
| | - Kenneth Hoyt
- Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, USA
| | - James Kim
- Department of Internal Medicine, Hamon Center for Therapeutic Oncology Research, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Masahiro Inoue
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ralph J DeBerardinis
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tae Hoon Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
| | - Jung-Whan Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
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24
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Epigenetic Regulation of iASPP-p63 Feedback Loop in Cutaneous Squamous Cell Carcinoma. J Invest Dermatol 2019; 139:1658-1671.e8. [DOI: 10.1016/j.jid.2019.01.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 01/09/2019] [Accepted: 01/09/2019] [Indexed: 01/09/2023]
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25
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King KE, George AL, Sakakibara N, Mahmood K, Moses MA, Weinberg WC. Intersection of the p63 and NF-κB pathways in epithelial homeostasis and disease. Mol Carcinog 2019; 58:1571-1580. [PMID: 31286584 DOI: 10.1002/mc.23081] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 12/12/2022]
Abstract
Overexpression of ΔNp63α, a member of the p53/p63/p73 family of transcription factors, is a molecular attribute of human squamous cancers of the head and neck, lung and skin. The TP63 gene plays important roles in epidermal morphogenesis and homeostasis, regulating diverse biological processes including epidermal fate decisions and keratinocyte proliferation and survival. When overexpressed experimentally in primary mouse keratinocytes, ΔNp63α maintains a basal cell phenotype including the loss of normal calcium-mediated growth arrest, at least in part through the activation and enhanced nuclear accumulation of the c-rel subunit of NF-κB (Nuclear Factor-kappa B). Initially identified for its role in the immune system and hematopoietic cancers, c-Rel has increasingly been associated with solid tumors and other pathologies. ΔNp63α and c-Rel have been shown to be associated in the nuclei of ΔNp63α overexpressing human squamous carcinoma cells. Together, these transcription factors cooperate in the transcription of genes regulating intrinsic keratinocyte functions, as well as the elaboration of factors that influence the tumor microenvironment (TME). This review provides an overview of the roles of ΔNp63α and c-Rel in normal epidermal homeostasis and elaborates on how these pathways may intersect in pathological conditions such as cancer and the associated TME.
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Affiliation(s)
- Kathryn E King
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
| | - Andrea L George
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
| | - Nozomi Sakakibara
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
| | - Kanwal Mahmood
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
| | - Michael A Moses
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
| | - Wendy C Weinberg
- Laboratory of M olecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland
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26
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Hegde GV, de la Cruz C, Giltnane JM, Crocker L, Venkatanarayan A, Schaefer G, Dunlap D, Hoeck JD, Piskol R, Gnad F, Modrusan Z, de Sauvage FJ, Siebel CW, Jackson EL. NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma. eLife 2019; 8:46551. [PMID: 31144617 PMCID: PMC6606022 DOI: 10.7554/elife.46551] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 05/28/2019] [Indexed: 12/14/2022] Open
Abstract
Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it’s downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.
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Affiliation(s)
- Ganapati V Hegde
- Discovery Oncology, Genentech, South San Francisco, United States
| | - Cecile de la Cruz
- Translational Oncology, Genentech, South San Francisco, United States
| | | | - Lisa Crocker
- Translational Oncology, Genentech, South San Francisco, United States
| | | | - Gabriele Schaefer
- Translational Oncology, Genentech, South San Francisco, United States
| | - Debra Dunlap
- Pathology, Genentech, South San Francisco, United States
| | - Joerg D Hoeck
- Molecular Oncology, Genentech, South San Francisco, United States
| | - Robert Piskol
- Bioinformatics, Genentech, South San Francisco, United States
| | - Florian Gnad
- Bioinformatics, Genentech, South San Francisco, United States
| | - Zora Modrusan
- Molecular Biology, Genentech, South San Francisco, United States
| | | | | | - Erica L Jackson
- Discovery Oncology, Genentech, South San Francisco, United States
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27
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METTL3 mediated m 6A modification plays an oncogenic role in cutaneous squamous cell carcinoma by regulating ΔNp63. Biochem Biophys Res Commun 2019; 515:310-317. [PMID: 31153635 DOI: 10.1016/j.bbrc.2019.05.155] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 05/24/2019] [Indexed: 12/13/2022]
Abstract
The cutaneous squamous cell carcinoma (cSCC) originates from epithelial stem cells through the dysregulation of self-renewal and differentiation. Recent studies have identified methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification as key regulator of fate of stem cells. However, little is known about the functional importance of METTL3 in cSCC. Here, Western blot and immunohistochemistry were used to investigate the METTL3 levels in cSCC tissues. Functional experiments including surface marker detection, Brdu incorporation assay, colony forming assay, m6A dot blot and tumor xenograft assay were performed to investigate the properties in cSCC cell lines after METTL3 knock down. The expression of METTL3 was up-regulated in cSCC samples. METTL3 knock down impaired cSCC cell stem-like properties, including colony forming ability in vitro and tumorigenicity in vivo. Furthermore, METTL3 knock down and methylation inhibitor cycloleucine could decrease the m6A levels and the expression of ΔNp63 in cSCC. Exogenous expression of ΔNp63 partially restored the cell proliferation of METTL3-knockdown cSCC cells. Therefore, our data indicated the m6A methyltransferases METTL3 as a critical gene in regulating tumorigeneis of cSCC.
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28
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Katoh I, Maehata Y, Moriishi K, Hata RI, Kurata SI. C-terminal α Domain of p63 Binds to p300 to Coactivate β-Catenin. Neoplasia 2019; 21:494-503. [PMID: 30986748 PMCID: PMC6462804 DOI: 10.1016/j.neo.2019.03.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/26/2019] [Accepted: 03/26/2019] [Indexed: 11/16/2022] Open
Abstract
TP63 (p63), a member of the tumor suppressor TP53 (p53) gene family, is essential for ectodermal tissue development and suppresses malignant progression of carcinomas. The most abundant isoform, ΔNp63α (referred to as p63), lacks the N-terminal transactivation (TA) domain, and was originally characterized as a dominant-negative type suppressor against p53 family proteins. It also binds to TCF/LEF to inhibit β-catenin. Nevertheless, transcriptional activation by p63 has also been observed in varied systems. To understand the puzzling results, we analyzed the structure–function relationship of p63 in the control of β-catenin-dependent transcription. p63 acted as a suppressor of moderately induced β-catenin. However, when nuclear targeted S33Y β-catenin was applied to cause the maximum enhancer activation, p63 displayed a β-catenin-coactivating function. The DNA-binding domain of p63 and the target sequence facilitated it. Importantly, we newly found that, despite the absence of TA domain, p63 was associated with p300, a general adaptor protein and chromatin modifier causing transcriptional activation. C-terminal α domain of p63 was essential for p300-binding and for the coactivator function. These results were related to endogenous p63-p300 complex formation and Wnt/β-catenin-responsive gene regulation by p63 in squamous cell carcinoma lines. The novel p63-p300 interaction may be involved in positive regulation of gene expression in tissue development and carcinogenesis.
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Affiliation(s)
- Iyoko Katoh
- Center for Medical Education and Sciences, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 408-3898, Japan; Oral Health Science Research Center, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan.
| | - Yojiro Maehata
- Department of Oral Science, Graduate School of Dentistry, Kanagawa Dental University, Yokosuka, Kanagawa 238-8580, Japan
| | - Kohji Moriishi
- Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 408-3898, Japan
| | - Ryu-Ichiro Hata
- Oral Health Science Research Center, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan
| | - Shun-Ichi Kurata
- Oral Health Science Research Center, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan.
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29
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Lakshmanachetty S, Balaiya V, High WA, Koster MI. Loss of TP63 Promotes the Metastasis of Head and Neck Squamous Cell Carcinoma by Activating MAPK and STAT3 Signaling. Mol Cancer Res 2019; 17:1279-1293. [PMID: 30910837 DOI: 10.1158/1541-7786.mcr-18-1355] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/06/2019] [Accepted: 03/20/2019] [Indexed: 01/02/2023]
Abstract
TP63 is frequently amplified or overexpressed in primary head and neck squamous cell carcinomas (HNSCC). Nevertheless, the role of TP63 in the initiation and progression of HNSCCs is not known. Using archival HNSCC tissue sections, we found that TP63 expression is often downregulated in late-stage human HNSCCs. To establish a causal link between TP63 loss and HNSCC tumorigenesis, we developed a genetically engineered mouse model in which Trp63 (the mouse homolog of human TP63) was ablated from head and neck epithelia. Upon exposure of the mice to a chemical carcinogen, we found that Trp63 ablation accelerated HNSCC initiation and progression. To determine whether these findings are relevant for human HNSCCs, we generated TP63 knockdown HNSCC cell lines. These cells were implanted into the tongue of athymic nude mice to generate orthotopic xenografts. We found that loss of TP63 promoted HNSCC progression and metastasis. Furthermore, we determined that tumor metastasis is dependent on MAPK activation in TP63 knockdown HNSCCs. The significance of these findings is underscored by our finding that pharmacologic inhibition of MAPK activity by trametinib drastically impaired HNSCC metastasis mediated by TP63 loss. In conclusion, our data provide novel mechanistic insights into the role of TP63 loss in HNSCC initiation and progression, and provide a rationale for the development of new therapeutic approaches specifically targeting TP63-dependent tumor pathways. IMPLICATIONS: Our findings uncover a novel functional role for TP63 loss in HNSCC metastasis and identify MAPK signaling as a potential therapeutic target for treating HNSCCs with low TP63 expression.
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Affiliation(s)
- Senthilnath Lakshmanachetty
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado.,Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado
| | - Velmurugan Balaiya
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado.,Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado
| | - Whitney A High
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado.,Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado
| | - Maranke I Koster
- Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado. .,Gates Center for Regenerative Medicine, University of Colorado School of Medicine, Aurora, Colorado.,Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado
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30
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Terrinoni A, Palombo R, Pitolli C, Caporali S, De Berardinis R, Ciccarone S, Lanzillotta A, Mauramati S, Porta G, Minieri M, Melino G, Bernardini S, Bruno E. Role of the TAp63 Isoform in Recurrent Nasal Polyps. Folia Biol (Praha) 2019; 65:170-180. [PMID: 31903890 DOI: 10.14712/fb2019065040170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
The pathogenic molecular mechanisms underlying the insurgence of nasal polyps has not been completely defined. In some patients, these lesions can have a recurrence after surgery removal, and the difference between recurrent and not recurrent patients is still unclear. To molecularly characterize and distinguish between these two classes, a cohort of patients affected by nasal polyposis was analysed. In all patients we analysed the p63 isoform expression using fresh tissues taken after surgery. Moreover, confocal immunofluorescence analysis of fixed sections was performed. The results show high ΔNp63 expression in samples from the nasal polyps of patients compared to the normal epithelia. Analysis of the expression level of the TAp63 isoform shows differential expression between the patients with recurrence compared to those not recurring. The data, considered as the ΔN/TAp63 ratio, really discriminate the two groups. In fact, even though ΔNp63 is expressed in non-recurrent patients, the resulting ratio ΔN/TAp63 is significantly lower in these patients. This clearly indicates that the status of TAp63 expression, represented by the ΔN/TAp63 ratio, could be considered a prognostic marker of low recurrence probability. In these samples we also investigated the expression of OTX2 transcription factor, known to be a selective activator of TAp63, detecting a significant correlation. Database analysis of HNSCC patients showed increased survival for the patients presenting OTX2 amplification and/or overexpression. These results, together with the fact that TAp63 can be selectively upregulated by HDAC inhibitors, open the possibility to consider local treatment of recurrent nasal polyps with these molecules.
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Affiliation(s)
- A Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - R Palombo
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - C Pitolli
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - S Caporali
- Department of Industrial Engineering, University of Rome Tor Vergata, Rome, Italy
| | - R De Berardinis
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - S Ciccarone
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - A Lanzillotta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - S Mauramati
- University of Pavia, Italy and Department of Otorhinolaryngology, University of Pavia, Foundation IRCCS Policlinico "San Matteo", Pavia, Italy
| | - G Porta
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - M Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - G Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - S Bernardini
- Department of Industrial Engineering, University of Rome Tor Vergata, Rome, Italy
| | - E Bruno
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
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31
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Yoshida M, Yokota E, Sakuma T, Yamatsuji T, Takigawa N, Ushijima T, Yamamoto T, Fukazawa T, Naomoto Y. Development of an integrated CRISPRi targeting ΔNp63 for treatment of squamous cell carcinoma. Oncotarget 2018; 9:29220-29232. [PMID: 30018747 PMCID: PMC6044376 DOI: 10.18632/oncotarget.25678] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/23/2018] [Indexed: 12/11/2022] Open
Abstract
TP63 encodes TAp63, which is functionally similar to the tumor suppressor TP53, and ΔNp63, which lacks the transcription-activating domain of TAp63 and appears potently oncogenic in squamous cell carcinomas (SCCs). In this study, we developed an integrated CRISPR interference (CRISPRi) system to selectively suppress ΔNp63 (CRISPRiΔNp63). We engineered this CRISPRi using tandemized guide RNA expression cassettes that targeted the 50 to 100 bp downstream of the transcription start site of ΔNp63 in combination with inactivated Cas9 linked to the transcription repression module Krüppel-associated box repressor domain. The plasmid vector harboring CRISPRiΔNp63 repressed ΔNp63 transcription in lung and esophageal SCC cells. Likewise, Ad-CRISPRiΔNp63, an all-in-one adenoviral vector containing the tandemized gRNAs and dCas9/KRAB expression cassette suppressed ΔNp63 expression in SCC cells. Ad-CRISPRiΔNp63 also effectively decreased cell proliferation and colony formation and induced apoptosis in lung and esophageal SCC cells in vitro and significantly inhibited tumor growth in a mouse lung SCC xenograft model in vivo. These results indicate that ΔNp63 suppression using CRISPRiΔNp63 may be an effective strategy for treating lung and esophageal SCC.
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Affiliation(s)
- Masakazu Yoshida
- Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505 Japan
| | - Etsuko Yokota
- Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505 Japan
| | - Tetsushi Sakuma
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, 739-8526 Japan
| | - Tomoki Yamatsuji
- Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505 Japan
| | - Nagio Takigawa
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, 700-8505 Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan
| | - Takashi Yamamoto
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, 739-8526 Japan
| | - Takuya Fukazawa
- Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505 Japan
| | - Yoshio Naomoto
- Department of General Surgery, Kawasaki Medical School, Okayama, 700-8505 Japan
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32
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Ooft ML, van Ipenburg J, van de Loo RJM, de Jong R, Moelans CB, de Bree R, de Herdt MJ, Koljenović S, Baatenburg de Jong R, Hardillo J, Willems SM. Differences in cancer gene copy number alterations between Epstein-Barr virus-positive and Epstein-Barr virus-negative nasopharyngeal carcinoma. Head Neck 2018; 40:1986-1998. [PMID: 29927011 DOI: 10.1002/hed.25195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 01/21/2018] [Accepted: 03/02/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) treatment is mainly based on clinical staging. We hypothesize that better understanding of the molecular heterogeneity of NPC can aid in better treatment decisions. Therefore, the purpose of this study was to present our exploration of cancer gene copy-number alterations (CNAs) of Epstein-Barr virus (EBV)-positive and EBV-negative NPC. METHODS Multiplex ligation-dependent probe amplification was applied to detect CNAs of 36 cancer genes (n = 103). Correlation between CNAs, clinicopathological features, and survival were examined. RESULTS The CNAs occurred significantly more in EBV-negative NPC, with PIK3CA and MCCC1 (P < .001) gain/amplification occurring more frequently. Gain/amplification of cyclin-L1 (CCNL1) and PTK2 (P < .001) predict worse disease-free survival (DFS) in EBV-positive NPC. CONCLUSION The EBV-positive and EBV-negative NPC show some similarities in cancer gene CNAs suggesting a common pathogenic route but also important differences possibly indicating divergence in oncogenesis. Copy number gain/amplification of CCNL1 and PTK2 are possibly good predictors of survival in EBV-positive NPC.
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Affiliation(s)
- Marc Lucas Ooft
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jolique van Ipenburg
- Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Rob J M van de Loo
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rick de Jong
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Remco de Bree
- Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Martine J de Herdt
- Department of Otorhinolaryngology - Head and Neck Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Senada Koljenović
- Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - R Baatenburg de Jong
- Department of Otorhinolaryngology - Head and Neck Surgery, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - J Hardillo
- Department of Otorhinolaryngology - Head and Neck Surgery, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Stefan Martin Willems
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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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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34
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Chen QY, Costa M. Oncogenic and tumor suppressive roles of special AT-rich sequence-binding protein. J Carcinog 2018; 17:2. [PMID: 30123095 PMCID: PMC6071479 DOI: 10.4103/jcar.jcar_8_17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 12/28/2017] [Indexed: 12/28/2022] Open
Abstract
In recent years, research efforts have been centered on the functional roles of special AT-rich sequence-binding protein (SATB2) in cancer development. Existing studies differ in the types of tumor tissues and cell lines used, resulting in mixed results, which hinder the clear understanding of whether SATB2 acts as a tumor suppressor or promoter. Literature search for this review consisted of a basic search on PubMed using keywords "SATB2" and "special AT-rich sequence-binding protein 2." Each article was then selected for further examination based on relevance of the title. In consideration to possible missing data from a primary PubMed search, after coding for relevant information, articles listed in the references section were filtered for further review. The current literature suggests that SATB2 can act both as a tumor suppressor and as a promoter since it can be regulated by multiple factors and is able to target different downstream genes in various types of cancer cell lines as well as tissues. Future studies should focus on its contradictory roles in different types of tumors. This paper provides a comprehensive review of currently available research on the role of SATB2 in different cancer cells and tissues and may provide some insight into the contradictory roles of SATB2 in cancer development.
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Affiliation(s)
- Qiao Yi Chen
- Department of Environmental Medicine, New York University School of Medicine, NY, USA
| | - Max Costa
- Department of Environmental Medicine, New York University School of Medicine, NY, USA
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35
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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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36
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Kaneko N, Kawano S, Yasuda K, Hashiguchi Y, Sakamoto T, Matsubara R, Goto Y, Jinno T, Maruse Y, Morioka M, Hattori T, Tanaka S, Tanaka H, Kiyoshima T, Nakamura S. Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial-mesenchymal transition of oral squamous cell carcinoma. Oral Oncol 2017; 75:148-157. [DOI: 10.1016/j.oraloncology.2017.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 10/28/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022]
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37
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Nemajerova A, Amelio I, Gebel J, Dötsch V, Melino G, Moll UM. Non-oncogenic roles of TAp73: from multiciliogenesis to metabolism. Cell Death Differ 2017; 25:144-153. [PMID: 29077094 PMCID: PMC5729534 DOI: 10.1038/cdd.2017.178] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/12/2017] [Accepted: 09/18/2017] [Indexed: 01/24/2023] Open
Abstract
The p53 family of transcription factors (p53, p63 and p73) covers a wide range of functions critical for development, homeostasis and health of mammals across their lifespan. Beside the well-established tumor suppressor role, recent evidence has highlighted novel non-oncogenic functions exerted by p73. In particular, p73 is required for multiciliated cell (MCC) differentiation; MCCs have critical roles in brain and airways to move fluids across epithelial surfaces and to transport germ cells in the reproductive tract. This novel function of p73 provides a unifying cellular mechanism for the disparate inflammatory and immunological phenotypes of p73-deficient mice. Indeed, mice with Trp73 deficiency suffer from hydrocephalus, sterility and chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance since MCCs are essential for cleaning airways from inhaled pollutants, pathogens and allergens. Cross-species genomic analyses and functional rescue experiments identify TAp73 as the master transcriptional integrator of ciliogenesis, upstream of previously known central nodes. In addition, TAp73 shows a significant ability to regulate cellular metabolism and energy production through direct transcriptional regulation of several metabolic enzymes, such as glutaminase-2 and glucose-6 phosphate dehydrogenase. This recently uncovered role of TAp73 in the regulation of cellular metabolism strongly affects oxidative balance, thus potentially influencing all the biological aspects associated with p73 function, including development, homeostasis and cancer. Although through different mechanisms, p63 isoforms also contribute to regulation of cellular metabolism, thus indicating a common route used by all family members to control cell fate. At the structural level, the complexity of p73's function is further enhanced by its ability to form heterotetramers with some p63 isoforms, thus indicating the existence of an intrafamily crosstalk that determines the global outcome of p53 family function. In this review, we have tried to summarize all the recent evidence that have emerged on the novel non-oncogenic roles of p73, in an attempt to provide a unified view of the complex function of this gene within its family.
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Affiliation(s)
- Alice Nemajerova
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Ivano Amelio
- Medical Research Council, Toxicology Unit, Leicester University, Hodgkin Building, Lancaster Road, PO Box 138, Leicester LE1 9HN, UK
| | - Jakob Gebel
- Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany
| | - Volker Dötsch
- Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany
| | - Gerry Melino
- Medical Research Council, Toxicology Unit, Leicester University, Hodgkin Building, Lancaster Road, PO Box 138, Leicester LE1 9HN, UK.,Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome 00133, Italy
| | - Ute M Moll
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
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38
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Kumakura Y, Rokudai S, Iijima M, Altan B, Yoshida T, Bao H, Yokobori T, Sakai M, Sohda M, Miyazaki T, Nishiyama M, Kuwano H. Elevated expression of ΔNp63 in advanced esophageal squamous cell carcinoma. Cancer Sci 2017; 108:2149-2155. [PMID: 28892579 PMCID: PMC5666030 DOI: 10.1111/cas.13394] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 07/28/2017] [Accepted: 08/14/2017] [Indexed: 12/27/2022] Open
Abstract
This study aims to explore the expression level of ΔNp63 in esophageal squamous cell carcinoma (ESCC). To investigate the association between ΔNp63 (p40) expression and ESCC biology, we compared the levels of ΔNp63 expression in normal and tumor tissues, with a specific focus on the diagnostic value of ΔNp63 in ESCC. We analyzed 160 consecutive patients with ESCC who underwent surgical resection without neoadjuvant chemotherapy at Gunma University Hospital (Maebashi, Japan) between September 2000 and January 2010. The clinicopathological characteristics and survival of patients were subclassified based on the expression of ΔNp63 as determined by immunohistochemistry, indicating that ΔNp63 was highly expressed in 75.6% (121/160) of ESCC patients. Clinicopathological analysis of ΔNp63 expression showed that ΔNp63‐positive tumors significantly correlated with two important clinical parameters: T factor (P = 0.0316) and venous invasion (P = 0.0195). The 5‐year overall survival rates of advanced ESCC patients with positive and negative expression of ΔNp63 were 35.6% and 71.7%, respectively. Multivariate analysis revealed that the expression of ΔNp63 was identified as an independent prognostic factor (P = 0.0049) in advanced ESCC. In line with this, ΔNp63α‐transduced ESCC cell lines increased tumor growth in a soft agar colony formation assay. We report here for the first time that ΔNp63 expression increases the oncogenic potential of ESCC and is an independent marker for predicting poor outcome in advanced ESCC. Our findings suggest that ΔNp63 could serve as a new diagnostic marker for ESCC and might be a relevant therapeutic target for the treatment of patients with this disease.
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Affiliation(s)
- Yuji Kumakura
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Susumu Rokudai
- Department of Molecular Pharmacology and Oncology, Gunma University, Maebashi, Japan
| | - Misaki Iijima
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Bolag Altan
- Department of Oncology Clinical Development, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Tomonori Yoshida
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Halin Bao
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Takehiko Yokobori
- Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Tatsuya Miyazaki
- Department of General Surgical Science, Gunma University, Maebashi, Japan
| | - Masahiko Nishiyama
- Department of Molecular Pharmacology and Oncology, Gunma University, Maebashi, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University, Maebashi, Japan
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Yan W, Zhang Y, Chen X. TAp63γ and ΔNp63γ are regulated by RBM38 via mRNA stability and have an opposing function in growth suppression. Oncotarget 2017; 8:78327-78339. [PMID: 29108232 PMCID: PMC5667965 DOI: 10.18632/oncotarget.18463] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 04/23/2017] [Indexed: 11/25/2022] Open
Abstract
The p63 gene is expressed as TAp63 from the P1 promoter and as ΔNp63 from the P2 promoter. Through alternative splicing, five TA and five ΔN isoforms (α-ε) are expressed. Isoforms α-β and δ share an identical 3’ untranslated region (3’UTR) whereas isoform γ has a unique 3’UTR. Recently, we found that RBM38 RNA-binding protein is a target of p63 and RBM38 in turn regulates p63α/β expression via mRNA stability. However, it is uncertain whether p63γ has a unique biological activity and whether p63γ is regulated by RBM38. Here, we found that the levels of ΔNp63γ transcript and protein are induced upon overexpression of RBM38 but decreased by RBM38 knockdown. Conversely, we found that the levels of ΔNp63β transcript and protein are decreased by ectopic expression of RBM38 but increased by RBM38 knockdown, consistent with our previous report. Interestingly, RBM38 increases the half-life of p63γ mRNA by binding to a GU-rich element in p63γ 3’UTR. In contrast, our previous studies showed that RBM38 decreases the half-life of p63α/β mRNAs by binding to AU-/U-rich elements in their 3’UTR. We also found that knockout of p63γ in ME180 and HaCaT cells, in which ΔNp63 isoforms are predominant, inhibits cell proliferation and migration, suggesting that ΔNp63γ has a pro-growth activity. In contrast, we found that knockout of TAp63γ in MIA PaCa-2 cells, in which TAp63 isoforms are predominant, promotes cell proliferation, migration, and inhibits cellular senescence. Taken together, we conclude that ΔNp63γ has an oncogenic potential whereas TAp63γ is a tumor suppressor.
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Affiliation(s)
- Wensheng Yan
- The Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California, USA
| | - Yanhong Zhang
- The Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California, USA
| | - Xinbin Chen
- The Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California, USA
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40
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P40 Immunostain Does Not Outperform p63 as a Myoepithelial Cell Marker in the Daily Practice of Breast Pathology. Appl Immunohistochem Mol Morphol 2017; 26:599-604. [PMID: 28549030 DOI: 10.1097/pai.0000000000000507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
P40 antibody has been shown to be a more specific squamous and basal cell marker compared with p63. As detection of myoepithelial cells (MECs) plays a critical role in breast pathology, and the fact that p40 targets an isoform of p63, this study was designed to compare these antibodies in a variety of lesions, especially those with an sclerotic stroma and carcinoma in situ. All studied lesions were selected from the daily cases of the 3 authors and stained with p63, p40, and calponin immunohistochemical stains. Thirty-four cases (and 19 internal controls) were included. Seventy percent constituted sclerotic lesions (12 cases) and ductal carcinoma in situ (12 cases). P40 and p63 stained all lesions and showed a similar patchy staining pattern in 50% of ductal carcinoma in situ and sclerotic lesions. Compared with internal controls, p40 and p63 demonstrated decreased staining intensity in up to 70% and 8% of all cases, respectively, with no cross-reactivity with mesenchymal cells and minor cross-reactivity with epithelial cells. In our study, p40 did not outperform p63 as a MEC marker. p40 showed a decreased intensity in a higher number of cases (P<0.0001). In our opinion, p63 continues to be the best nuclear marker for the detection of MECs in the daily practice of breast pathology.
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41
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Sakamoto T, Kawano S, Matsubara R, Goto Y, Jinno T, Maruse Y, Kaneko N, Hashiguchi Y, Hattori T, Tanaka S, Kitamura R, Kiyoshima T, Nakamura S. Critical roles of Wnt5a-Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and production of matrix metalloproteinase-2 via ΔNp63β-mediated epithelial-mesenchymal transition. Oral Oncol 2017; 69:15-25. [PMID: 28559016 DOI: 10.1016/j.oraloncology.2017.03.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/22/2017] [Accepted: 03/28/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVES We previously showed that ΔNp63β, a splicing variant of ΔNp63, mediated EMT and affected cell motility. DNA microarray was thus performed to elucidate the mechanism that ΔNp63β affects cell motility. As the results, Wnt5a was significantly down-regulated by ΔNp63β overexpression in tongue SCC cell line (SQUU-B) with EMT phenotype. MATERIALS AND METHODS Seven OSCC cell lines were used. Expression of ΔNp63, Wnt5a, its receptor Ror2, and matrix metalloproteinases (MMPs) were analyzed by RT-PCR, real-time PCR, and western blotting, and gelatin zymography. Furthermore, we examined the effects of siRNA for Wnt5a or Ror2 and recombinant human Wnt5a (rhWnt5a) on motility of tongue SCC cells. Biopsy specimens from tongue SCC patients were used for immunohistochemical staining of Wnt5a and Ror2. RESULTS Wnt5a and Ror2 were expressed only in SQUU-B cells without ΔNp63 expression, and negatively associated with ΔNp63 expression in other cells. ΔNp63β overexpression in SQUU-B cells decreased Wnt5a and Ror2 expression. By Wnt5a or Ror2 knockdown, cell motility was remarkably inhibited, but EMT markers expression was unaffected. MMP-2 expression and the activities inversely correlated with ΔNp63 expression, and were inhibited by Wnt5a or Ror2 knockdown. Cell motility and MMP-2 activities were recovered by adding rhWnt5a in the cells with Wnt5a knockdown, but not in those with Ror2 knockdown. Moreover, immunohistochemical analyses in tongue SCC specimens found that high expression of Wnt5a or Ror2 was associated with poorer prognosis. CONCLUSION Wnt5a-Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP-2 following ΔNp63β-mediated EMT.
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Affiliation(s)
- Taiki Sakamoto
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Shintaro Kawano
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Ryota Matsubara
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Yuichi Goto
- Maxillofacial Diagnostic and Surgical Sciences, Department of Oral and Maxillofacial Rehabilitation, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
| | - Teppei Jinno
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Yasuyuki Maruse
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Naoki Kaneko
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Yuma Hashiguchi
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Taichi Hattori
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Shoichi Tanaka
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Ryoji Kitamura
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Seiji Nakamura
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Di Giacomo V, Tian TV, Mas A, Pecoraro M, Batlle-Morera L, Noya L, Martín-Caballero J, Ruberte J, Keyes WM. ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82. Oncogene 2017; 36:4381-4392. [PMID: 28368419 PMCID: PMC5543260 DOI: 10.1038/onc.2017.42] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 01/01/2017] [Accepted: 01/19/2017] [Indexed: 12/12/2022]
Abstract
ΔNp63α is a critical mediator of epithelial development and stem cell function in a variety of tissues including the skin and breast, while overexpression of ΔNp63α acts as an oncogene to drive tumor formation and cancer stem cell properties in squamous cell carcinoma. However, with regards to the prostate, while ΔNp63α is expressed in the basal stem cells of the mature gland, during adenocarcinoma development, its expression is lost and its absence is used to clinically diagnose the malignant state. Surprisingly, here we identify a sub-population of bone metastatic prostate cancer cells in the PC3 cell line that express ΔNp63α. Interestingly, we discovered that ΔNp63α favors adhesion and stem-like growth of these cells in the bone microenvironment. In addition, we show that these properties require expression of the target gene CD82. Together, this work uncovers a population of bone metastatic prostate cancer cells that express ΔNp63α, and provides important information about the mechanisms of bone metastatic colonization. Finally, we identify metastasis-promoting properties for the tetraspanin family member CD82.
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Affiliation(s)
- V Di Giacomo
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - T V Tian
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - A Mas
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - M Pecoraro
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - L Batlle-Morera
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - L Noya
- Department of Animal Health and Anatomy and Center for Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - J Ruberte
- Department of Animal Health and Anatomy and Center for Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - W M Keyes
- Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,Development and Stem Cells program, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Université de Strasbourg, Illkirch, France
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43
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Feller L, Khammissa RAG, Lemmer J. Is chronic ulcerative stomatitis a variant of lichen planus, or a distinct disease? J Oral Pathol Med 2017; 46:859-863. [PMID: 28186659 DOI: 10.1111/jop.12561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2017] [Indexed: 12/31/2022]
Abstract
Chronic ulcerative stomatitis is an immune-mediated mucocutaneous disorder characterized clinically by erosions or ulcers. Most cases are limited to the mouth. The histopathological features are non-specific or mimic those of oral lichen planus, and studies by immunofluorescent microscopy are essential for definitive diagnosis. The defining immunopathogenic mechanism is the binding of IgG to the nuclear protein deltaNp63alpha of keratinocytes in the basal and parabasal cell layers of the oral stratified epithelium. DeltaNp63alpha functions as a regulator of epithelial stem cell activity and as an antiapoptotic agent and regulates the expression of cell-to-cell and cell-to-basement membrane adhesion molecules. The autoimmune IgG-deltaNp63alpha interaction is thought to result in damage to the structural attachment of keratinocytes to one another and to the epithelial basement membrane zone and in dysregulation of the cell cycle and apoptosis of basal keratinocytes with the development of erosions or ulcers. The aims of treatment are to suppress the pathogenic immunoinflammatory responses, to prevent local infection and to promote healing. The purpose of this article is to provide a succinct review of the diagnostic, clinical and etiopathogenic features of, and treatment guidelines for chronic ulcerative stomatitis, and to argue that this disease should be regarded as a variant of oral lichen planus, rather than as a distinct entity.
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Affiliation(s)
- Liviu Feller
- Department of Periodontology and Oral Medicine, Sefako Makgatho Health Sciences University, Pretoria, South Africa
| | - Razia A G Khammissa
- Department of Periodontology and Oral Medicine, Sefako Makgatho Health Sciences University, Pretoria, South Africa
| | - Johan Lemmer
- Department of Periodontology and Oral Medicine, Sefako Makgatho Health Sciences University, Pretoria, South Africa
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Jeon YJ, Park JH, Chung CH. Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress. Mol Cells 2017; 40:83-89. [PMID: 28241406 PMCID: PMC5339507 DOI: 10.14348/molcells.2017.0027] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 02/23/2017] [Indexed: 12/15/2022] Open
Abstract
Error-free replication and repair of DNA are pivotal to organisms for faithful transmission of their genetic information. Cells orchestrate complex signaling networks that sense and resolve DNA damage. Post-translational protein modifications by ubiquitin and ubiquitin-like proteins, including SUMO and NEDD8, are critically involved in DNA damage response (DDR) and DNA damage tolerance (DDT). The expression of interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, has recently been shown to be induced under various DNA damage conditions, such as exposure to UV, camptothecin, and doxorubicin. Here we overview the recent findings on the role of ISG15 and its conjugation to target proteins (e.g., p53, ΔNp63α, and PCNA) in the control of cellular responses to genotoxic stress, such as the inhibition of cell growth and tumorigenesis.
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Affiliation(s)
- Young Joo Jeon
- Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 35015,
Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015,
Korea
| | - Jong Ho Park
- School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826,
Korea
| | - Chin Ha Chung
- School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826,
Korea
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45
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Guamán-Ortiz LM, Orellana MIR, Ratovitski EA. Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells. Curr Genomics 2017; 18:132-155. [PMID: 28367073 PMCID: PMC5345338 DOI: 10.2174/1389202917666160803150639] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 11/24/2015] [Accepted: 11/28/2015] [Indexed: 02/07/2023] Open
Abstract
Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.
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Affiliation(s)
- Luis Miguel Guamán-Ortiz
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Isabel Ramirez Orellana
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward A Ratovitski
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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46
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Katoh I, Fukunishi N, Fujimuro M, Kasai H, Moriishi K, Hata RI, Kurata SI. Repression of Wnt/β-catenin response elements by p63 (TP63). Cell Cycle 2016; 15:699-710. [PMID: 26890356 PMCID: PMC4845946 DOI: 10.1080/15384101.2016.1148837] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Submitted: TP63 (p63), a member of the tumor suppressor TP53 (p53) gene family, is expressed in keratinocyte stem cells and well-differentiated squamous cell carcinomas to maintain cellular potential for growth and differentiation. Controversially, activation of the Wnt/β-catenin signaling by p63 (Patturajan M. et al., 2002, Cancer Cells) and inhibition of the target gene expression (Drewelus I. et al., 2010, Cell Cycle) have been reported. Upon p63 RNA-silencing in squamous cell carcinoma (SCC) lines, a few Wnt target gene expression substantially increased, while several target genes moderately decreased. Although ΔNp63α, the most abundant isoform of p63, appeared to interact with protein phosphatase PP2A, neither GSK-3β phosphorylation nor β-catenin nuclear localization was altered by the loss of p63. As reported earlier, ΔNp63α enhanced β-catenin-dependent luc gene expression from pGL3-OT having 3 artificial Wnt response elements (WREs). However, this activation was detectable only in HEK293 cells examined so far, and involved a p53 family-related sequence 5' to the WREs. In Wnt3-expressing SAOS-2 cells, ΔNp63α rather strongly inhibited transcription of pGL3-OT. Importantly, ΔNp63α repressed WREs isolated from the regulatory regions of MMP7. ΔNp63α-TCF4 association occurred in their soluble forms in the nucleus. Furthermore, p63 and TCF4 coexisted at a WRE of MMP7 on the chromatin, where β-catenin recruitment was attenuated. The combined results indicate that ΔNp63α serves as a repressor that regulates β-catenin-mediated gene expression.
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Affiliation(s)
- Iyoko Katoh
- a Center for Medical Education and Sciences, Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan.,b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan
| | - Nahoko Fukunishi
- c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan
| | - Masahiro Fujimuro
- d Department of Cell Biology , Kyoto Pharmaceutical University , Yamashina , Kyoto , Japan
| | - Hirotake Kasai
- e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan
| | - Kohji Moriishi
- e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan
| | - Ryu-Ichiro Hata
- b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan
| | - Shun-Ichi Kurata
- b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan.,c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan
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47
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Armstrong SR, Wu H, Wang B, Abuetabh Y, Sergi C, Leng RP. The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System. Int J Mol Sci 2016; 17:2041. [PMID: 27929429 PMCID: PMC5187841 DOI: 10.3390/ijms17122041] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 11/23/2016] [Accepted: 11/30/2016] [Indexed: 12/18/2022] Open
Abstract
The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63. p63 is rarely mutated in human tumors and is predominately regulated at the post-translational level by phosphorylation and ubiquitination. This review focuses primarily on regulation of p63 by the ubiquitin E-3 ligase family of enzymes via ubiquitination and proteasome-mediated degradation, and introduces a new key regulator of the p63 protein.
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Affiliation(s)
- Stephen R Armstrong
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Hong Wu
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Benfan Wang
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Yasser Abuetabh
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Consolato Sergi
- Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada.
| | - Roger P Leng
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
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Nekulova M, Holcakova J, Gu X, Hrabal V, Galtsidis S, Orzol P, Liu Y, Logotheti S, Zoumpourlis V, Nylander K, Coates PJ, Vojtesek B. ΔNp63α expression induces loss of cell adhesion in triple-negative breast cancer cells. BMC Cancer 2016; 16:782. [PMID: 27724925 PMCID: PMC5057421 DOI: 10.1186/s12885-016-2808-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 09/23/2016] [Indexed: 12/31/2022] Open
Abstract
Background p63, a member of the p53 protein family, plays key roles in epithelial development and carcinogenesis. In breast cancer, p63 expression has been found predominantly in basal-A (epithelial-type) triple-negative breast carcinomas (TNBC). To investigate the functional role of p63 in basal-A TNBC, we created MDA-MB-468 cell lines with inducible expression of the two major N-terminal p63 isoforms, TAp63α and ∆Np63α. Results TAp63α did not have significant effect on gene expression profile and cell phenotype, whilst the main effect of ΔNp63α was reduction of cell adhesion. Gene expression profiling revealed genes involved in cell adhesion and migration whose expression relies on overexpression of ΔNp63α. Reduced cell adhesion also led to decreased cell proliferation in vitro and in vivo. Similar data were obtained in another basal-A cell line, BT-20, but not in BT-549 basal-B (mesenchymal-like) TNBC cells. Conclusions In basal-A TNBC cells, ∆Np63α has much stronger effects on gene expression than TAp63α. Although p63 is mentioned mostly in connection with breast cell differentiation and stem cell regulation, we showed that a major effect of p63 is regulation of cell adhesion, a process important in metastasis and invasion of tumour cells. That this effect is not seen in mesenchymal-type TNBC cells suggests lineage-dependent functions, mirroring the expression of ∆Np63α in primary human breast cancers. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2808-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marta Nekulova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
| | - Jitka Holcakova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
| | - Xiaolian Gu
- Department of Medical Biosciences, Umeå University, Umeå, 90185, Sweden
| | - Vaclav Hrabal
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
| | - Sotiris Galtsidis
- Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece
| | - Paulina Orzol
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
| | - Yajing Liu
- NCRC, 026-329S, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Stella Logotheti
- Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece
| | | | - Karin Nylander
- Department of Medical Biosciences, Umeå University, Umeå, 90185, Sweden
| | - Philip J Coates
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
| | - Borivoj Vojtesek
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic.
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Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells. Proc Natl Acad Sci U S A 2016; 113:E6107-E6116. [PMID: 27681615 DOI: 10.1073/pnas.1613417113] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ∆Np63α, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ∆Np63 promoter is sufficient for repression induced by H-RasV12. The suppression of ∆Np63α expression by these oncogenes concomitantly leads to an epithelial-to-mesenchymal transition (EMT). In addition, the depletion of ∆Np63α alone is sufficient to induce EMT. Both H-RasV12 expression and ∆Np63α depletion induce individual cell invasion in a 3D collagen gel in vitro system, thereby demonstrating how Ras can drive the mammary epithelial cell state toward greater invasive ability. Together, these results suggest a pathway by which RAS and PIK3CA oncogenes induce EMT through regulation of ∆Np63α.
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50
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Pelosi G, Scarpa A, Forest F, Sonzogni A. The impact of immunohistochemistry on the classification of lung tumors. Expert Rev Respir Med 2016; 10:1105-21. [PMID: 27617475 DOI: 10.1080/17476348.2017.1235975] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION To highlight the role of immunohistochemistry to lung cancer classification on the basis of existing guidelines and future perspectives. AREAS COVERED Four orienting key-issues were structured according to an extensive review on the English literature: a) cancer subtyping; b) best biomarkers and rules to follow; c) negative and positive profiling; d) suggestions towards an evidence-based proposal for lung cancer subtyping. A sparing material approach based on a limited number of specific markers is highly desirable. It includes p40 for squamous cell carcinoma ('no p40, no squamous'), TTF1 for adenocarcinoma, synaptophysin for neuroendocrine tumors and vimentin for sarcomatoid carcinoma. A close relationship between genotype and phenotype also supports a diagnostic role for negative profiles. Expert commentary: Highly specific and sensitive IHC markers according to positive and negative diagnostic algorithms seem appropriate for individual patients' lung cancer subtyping.
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Affiliation(s)
- Giuseppe Pelosi
- a Department of Oncology and Hemato-Oncology , Università degli Studi di Milano , Milan , Italy
| | - Aldo Scarpa
- b Department of Pathology and Diagnostics , University and Hospital Trust of Verona , Verona , Italy.,c ARC-Net Research Centre , University and Hospital Trust of Verona , Verona , Italy
| | - Fabien Forest
- d Department of Pathology , University Hospital Center (CHU), North Hospital , Saint Etienne , France
| | - Angelica Sonzogni
- e Department of Pathology and Laboratory Medicine , Fondazione IRCCS Istituto Nazionale Tumori , Milan , Italy
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