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Shantha Kumara HMC, Addison P, Yan XH, Sharma AR, Mitra N, Angammana HN, Hedjar Y, Chen YR, Cekic V, Richard WL. Plasma extracellular cold inducible RNA-binding protein levels are elevated for 1 month post-colectomy which may promote metastases. World J Gastrointest Oncol 2025; 17:100678. [PMID: 40235912 PMCID: PMC11995324 DOI: 10.4251/wjgo.v17.i4.100678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/10/2025] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Cold-inducible RNA-binding protein (CIRP) is related to a family of stress-induced RNA-binding proteins. It is primarily found in the nucleus, where it regulates transcription. Under stress, CIRP translocates to the cytoplasm where it modulates translation; a subset is secreted as extracellular CIRP (eCIRP) which is a damage-associated molecular pattern (DAMP) molecule that stimulates the production of inflammatory mediators. Elevated blood eCIRP levels may foster immune tolerance and facilitate tumor growth. Increased CIRP levels have been noted in various malignancies including colorectal cancer (CRC). This study's objective was to determine plasma eCIRP levels before and after minimally invasive colorectal resection (MICR) for CRC. AIM To assess plasma eCIRP levels prior to and following minimally invasive colorectal resection in the context of cancer pathology. METHODS MICR patients from an IRB-approved data/tissue bank for whom plasma samples were available were eligible. Plasma specimens were obtained preoperatively (preop) and at least 3 time's postop [between postoperative day (POD) 1-41]; late samples were grouped into 7-day blocks and were considered separate time points. eCIRP levels were assessed via enzyme-linked immunosorbent assay (pg/mL) and results presented as mean ± SD, analysis with Wilcoxon paired t-test). RESULTS A total of 83 CRC patients who underwent MICR [colon 66%, rectal 34%; laparoscopic-assisted (LA), 70%; hand-assisted laparoscopic (HAL), 30%] were studied. The mean preop eCIRP level was 896.8 ± 757.0 pg/mL. Elevations in mean plasma levels (P = < 0.001) were noted on POD1 (2549 ± 2632 pg/mL, n = 83), POD3 (1871 ± 1362 pg/mL, n = 77), POD7-13 (1788 ± 1403 pg/mL, n = 57), POD14-20 (1473 ± 738.8 pg/mL, n = 30), and POD21-27 (1681 ± 1375 pg/mL, n = 21). No significant differences were noted at POD 28-41. Higher values were noted in the HAL's (vs LA) group, however, there were more rectal cancers in the former. CONCLUSION Elevated plasma eCIRP levels persist for a month post MICR for CRC (change from baseline, 77%-184%); highest values seen on POD1. The initial surge may be due to the acute inflammatory response while later elevations may be related to wound healing and remodeling. The higher levels noted in the HAL's group (with greater IL and more rectal cases) suggest the extent of surgical trauma impacts eCIRP levels. Further investigations are needed.
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Affiliation(s)
- H M C Shantha Kumara
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Poppy Addison
- Division of Colon and Rectal Surgery, Department of Surgery, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, United States
| | - Xiao-Hong Yan
- Department of Pathology and Cell Biology, Columbia University Medical Center, Vanderbilt Clinic, New York, NY 10032, United States
| | - Anuj Raj Sharma
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Neil Mitra
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Hansani N Angammana
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Yanni Hedjar
- Department of Surgery, Brookdale Hospital and Medical Center, Brooklyn, NY 11212, United States
| | - Yi-Ru Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Vesna Cekic
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Whelan L Richard
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
- Donald and Barbara Zucker School of Medicine, Hofstra/Northwell 500 Hofstra Blvd, Hempstead, NY 11549, United States
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Go RE, Seong SM, Choi Y, Choi KC. A Fungicide, Fludioxonil, Formed the Polyploid Giant Cancer Cells and Induced Metastasis and Stemness in MDA-MB-231 Triple-Negative Breast Cancer Cells. Int J Mol Sci 2024; 25:9024. [PMID: 39201710 PMCID: PMC11354328 DOI: 10.3390/ijms25169024] [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: 06/29/2024] [Revised: 08/04/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.
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Affiliation(s)
| | | | | | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, Republic of Korea; (R.-E.G.); (S.-M.S.); (Y.C.)
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Papadimitriou MC, Pazaiti A, Iliakopoulos K, Markouli M, Michalaki V, Papadimitriou CA. Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119346. [PMID: 36030016 DOI: 10.1016/j.bbamcr.2022.119346] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/09/2022] [Accepted: 08/19/2022] [Indexed: 06/15/2023]
Abstract
Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.
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Affiliation(s)
- Marios C Papadimitriou
- Oncology Unit, Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 76, 115 28 Athens, Greece
| | - Anastasia Pazaiti
- Breast Clinic of Oncologic and Reconstructive Surgery, Metropolitan General Hospital, Leoforos Mesogeion 264, 155 62 Cholargos, Greece.
| | - Konstantinos Iliakopoulos
- Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 76, 115 28 Athens, Greece
| | - Mariam Markouli
- Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 76, 115 28 Athens, Greece
| | - Vasiliki Michalaki
- Oncology Unit, Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 76, 115 28 Athens, Greece
| | - Christos A Papadimitriou
- Oncology Unit, Second Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Vasilissis Sofias 76, 115 28 Athens, Greece.
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Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer. Cancers (Basel) 2020; 12:cancers12082268. [PMID: 32823571 PMCID: PMC7463708 DOI: 10.3390/cancers12082268] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/02/2020] [Accepted: 08/04/2020] [Indexed: 11/21/2022] Open
Abstract
Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.
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Palmer N, Kaldis P. Less-well known functions of cyclin/CDK complexes. Semin Cell Dev Biol 2020; 107:54-62. [PMID: 32386818 DOI: 10.1016/j.semcdb.2020.04.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/31/2022]
Abstract
Cyclin-dependent kinases (CDKs) are activated by cyclins, which play important roles in dictating the actions of CDK/cyclin complexes. Cyclin binding influences the substrate specificity of these complexes in addition to their susceptibility to inhibition or degradation. CDK/cyclin complexes are best known to promote cell cycle progression in the mitotic cell cycle but are also crucial for important cellular processes not strictly associated with cellular division. This chapter primarily explores the understudied topic of CDK/cyclin complex functionality during the DNA damage response. We detail how CDK/cyclin complexes perform dual roles both as targets of DNA damage checkpoint signaling as well as effectors of DNA repair. Additionally, we discuss the potential CDK-independent roles of cyclins in these processes and the impact of such roles in human diseases such as cancer. Our goal is to place the spotlight on these important functions of cyclins either acting as independent entities or within CDK/cyclin complexes which have attracted less attention in the past. We consider that this will be important for a more complete understanding of the intricate functions of cell cycle proteins in the DNA damage response.
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Affiliation(s)
- Nathan Palmer
- Institute of Molecular and Cell Biology (IMCB), A⁎STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore; National University of Singapore (NUS), Department of Biochemistry, Singapore, 117597, Republic of Singapore
| | - Philipp Kaldis
- Institute of Molecular and Cell Biology (IMCB), A⁎STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore; National University of Singapore (NUS), Department of Biochemistry, Singapore, 117597, Republic of Singapore; Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), Box 50332, SE-202 13, Malmö, Sweden.
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Organophosphate ester tri-o-cresyl phosphate interacts with estrogen receptor α in MCF-7 breast cancer cells promoting cancer growth. Toxicol Appl Pharmacol 2020; 395:114977. [PMID: 32234386 DOI: 10.1016/j.taap.2020.114977] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/12/2020] [Accepted: 03/24/2020] [Indexed: 12/16/2022]
Abstract
Plastic in the ocean degrades to microplastic, thereby enhancing the leaching of incorporated plasticizers due to the increased particle surface. The uptake of microplastic-derived plasticizers by marine animals and the subsequent entry in the food chain raises concerns for adverse health effects in human beings. Frequently used plasticizers as the organophosphate ester tri-o-cresyl phosphate (TOCP) are known to affect the male reproductive system. However, the overall endocrine potential of TOCP and the underlying molecular mechanisms remain elusive as yet. In this study, we investigated the molecular effects of TOCP on estrogen receptor α (ERα)-transfected HEK-ESR1 cells and the human breast cancer cell line MCF-7. Applying virtual screening and molecular docking, we identified TOCP as potent ligand of ERα in silico. Microscale thermophoresis confirmed the binding in vitro with similar intensity as the natural ligand 17-β-estradiol. To identify the molecular mechanisms of TOCP-mediated effects, we used next-generation sequencing to analyze the gene expression pattern of TOCP-treated MCF-7 cells. RNA-sequencing revealed 22 differently expressed genes associated with ESR1 as upstream regulator: CYP1A1, SLC7A11, RUNX2, DDIT4, STC2, KLHL24, CCNG2, CEACAM5, SLC7A2, MAP1B, SLC7A5, IGF1R, CD55, FOSL2, VEGFA, and HSPA13 were upregulated and PRKCD, CCNE1, CEBPA, SFPQ, TNFAIP2, KRT19 were downregulated. The affected genes promote tumor growth by increasing angiogenesis and nutritional supply, favor invasion and metastasis, and interfere with the cell cycle. Based on the gene expression pattern, we conclude TOCP to mediate endocrine effects on MCF-7 cells by interacting with ERα.
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Pereira BJA, Santana Júnior PAD, de Almeida AN, Cavalcante SG, de Melo KCM, de Aguiar PHP, Paiva WDS, Oba-Shinjo SM, Marie SKN. Cyclin E1 expression and malignancy in meningiomas. Clin Neurol Neurosurg 2020; 190:105647. [PMID: 31945623 DOI: 10.1016/j.clineuro.2019.105647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/12/2019] [Accepted: 12/19/2019] [Indexed: 10/25/2022]
Abstract
OBJECTIVE The aim of the present study was to analyze if the pathway Skp2-p27-cyclin E1 could also be a tumor progression marker for meningiomas. PATIENTS AND METHODS We used quantitative real-time PCR to assess the relative expression levels of the genes coding for cyclin E1 (CCNE1), Skp2 (SKP2), and p27 (P27). The expression levels were compared in grades I to III meningiomas and among different histological subtypes of grade I meningiomas. RESULTS Anaplastic meningiomas accounted for 4.9%, atypical meningiomas for 23.5% and grade I meningiomas for 71.6%.CCNE1 expression level was significantly higher in grade II compared to grade I meningiomas (p = 0.0027), and its expression level reliably predicts grade II meningiomas (ROC AUC = 0.731, p = 0.003). CCNE1 expression also correlated with SKP2 and P27 expression levels in grade I meningiomas (r = 0.539, p < 0.0001 and r = 0.687, p = <0.0001, respectively for CCNE1/SKP2 and CCNE1/P27, Spearman's test). Fibrous subtype among grade I meningiomas presented the highest expression levels of CCNE1, SKP2 and P27. Higher expression of cyclin E1 protein was detected in the nuclei of atypical meningiomas compared to grade I meningiomas. CONCLUSIONS CCNE1 expression level predicts meningioma malignancy, and the fibrous subtype presents the highest gene expression levels among grade I meningiomas.
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Affiliation(s)
- Benedito Jamilson Araújo Pereira
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil.
| | - Pedro Augustto de Santana Júnior
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil
| | | | - Stella Gonçalves Cavalcante
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil
| | - Keyde Cristina Martins de Melo
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil
| | | | - Wellingson da Silva Paiva
- Divisão de Neurocirurgia Funcional IPQ, Hospital das Clínicas da Universidade de São Paulo, SP, Brazil
| | - Sueli Mieko Oba-Shinjo
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil
| | - Suely Kazue Nagahashi Marie
- Laboratório de Biologia Molecular e celular (LIM 15), Departmento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, SP, Brazil
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Bonacho T, Rodrigues F, Liberal J. Immunohistochemistry for diagnosis and prognosis of breast cancer: a review. Biotech Histochem 2019; 95:71-91. [PMID: 31502889 DOI: 10.1080/10520295.2019.1651901] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is the most prevalent malignant tumor and main oncologic cause of mortality in women. Although most diagnosis of breast pathology is accomplished using hematoxylin and eosin stained sections, some cases require immunohistochemistry for proper evaluation. We investigated the latter cases including distinctions between ductal and lobular carcinoma, in situ and invasive carcinoma, typical ductal hyperplasia and atypical ductal hyperplasia/ductal carcinoma in situ, papillary and spindle cell lesion assessment, metastasis evaluation, and assessment of prognostic and therapy markers. E-cadherin is used to differentiate ductal and lobular carcinoma; 34βE12, CK8, p120 catenin and β-catenin also produce consistent results. Myoepithelial cell (MEC) stains are used to evaluate in situ and invasive carcinoma; calponin, smooth muscle myosin heavy chain and p63 are sensitive/specific markers. 34βE12 and CK5/6 are positive in ductal hyperplasia, which enables its differentiation from atypical ductal hyperplasia and ductal carcinoma in situ. CK 5/6, ER and MEC markers are consistent options for evaluating papillary lesions. Spindle cell lesions can be assessed using β-catenin, SMA, CD34, p63, CKs and hormone receptors. It is important to differentiate primary carcinomas from metastases; the most commonly used markers to identify breast origin include mammaglobin, GCDFP-15, GATA3 and ER, although none of these is completely sensitive or specific. Immunohistochemistry can be used to evaluate central prognostic and predictive factors including molecular subtypes, HER2, hormone receptors, proliferation markers (Ki-67) and lymph-vascular invasion markers including ERG, CD31, CD34, factor VIII and podoplanin. Owing to the complexity of mammary lesions, diagnosis also depends on each particular situation, evaluation of cytological characteristics revealed by immunochemistry and correlation with histological findings.
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Affiliation(s)
- T Bonacho
- Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal
| | - F Rodrigues
- Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal.,Qualidade de Vida no Mundo Rural (QRural), Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal.,Sport, Health & Exercise Unit (SHERU), Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal
| | - J Liberal
- Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal.,Qualidade de Vida no Mundo Rural (QRural), Instituto Politécnico de Castelo Branco, Castelo Branco, Portugal
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α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3. Biosci Rep 2019; 39:BSR20190696. [PMID: 31127027 PMCID: PMC6558724 DOI: 10.1042/bsr20190696] [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: 03/22/2019] [Revised: 05/05/2019] [Accepted: 05/17/2019] [Indexed: 12/18/2022] Open
Abstract
Endometrial cancer (EC) is one of the most common cancers in females. Although the diagnosis and treatment in early stages can greatly improve the survival rate of patients, the advanced EC still is lethal. Radiotherapy is widely used against EC, and it is a great challenge to find an effective way to overcome the resistance of EC during radiotherapy. α-bisabolol is a promising drug, which has already exhibited its anti-tumor effect in some malignancies. Here we reported that α-bisabolol could inhibit the proliferation of EC cells. It is also shown that their abilities of migration and invasion were effectively reduced by α-bisabolol. Furthermore, our results also demonstrated that α-bisabolol could improve sensitivity of EC cells in radiotherapy and further inhibited the growth of EC cells. By Western blot, we found the expression of matrix metalloproteinases-9 (MMP-9) and cyclin E were significantly decreased, which indicated that EC cells can be further suppressed by using α-bisabolol and radiotherapy. It is also demonstrated in our study that the rate of apoptotic cells is markedly increased in EC by using these two treatments. The significant decrease in X-linked inhibitor of apoptosis protein (XIAP) and increase in caspase-3 detected in our study suggested that the enhancement of apoptosis is mediated by XIAP/caspase-3 pathway, which was further confirmed by examining the downstream effectors of caspase-3, COX-2, PARP and cleaved PARP. In the present study, we demonstrated that α-bisabolol could enhance the sensitivity of EC cells to radiotherapy, which provide a novel alternative for overcoming radioresistance of EC cells and achieving a better outcome in radiotherapy.
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Cancer molecular markers: A guide to cancer detection and management. Semin Cancer Biol 2018; 52:39-55. [PMID: 29428478 DOI: 10.1016/j.semcancer.2018.02.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 11/04/2017] [Accepted: 02/05/2018] [Indexed: 02/07/2023]
Abstract
Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors. In this context, current review provides a detail outlook on various molecular markers for diagnosis, prognosis and management of therapeutic response in cancer patients.
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Abstract
E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.
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Lujan DA, Ochoa JL, Hartley RS. Cold-inducible RNA binding protein in cancer and inflammation. WILEY INTERDISCIPLINARY REVIEWS-RNA 2018; 9. [PMID: 29322631 DOI: 10.1002/wrna.1462] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/17/2017] [Accepted: 11/29/2017] [Indexed: 12/17/2022]
Abstract
RNA binding proteins (RBPs) play key roles in RNA dynamics, including subcellular localization, translational efficiency and metabolism. Cold-inducible RNA binding protein (CIRP) is a stress-induced protein that was initially described as a DNA damage-induced transcript (A18 hnRNP), as well as a cold-shock domain containing cold-stress response protein (CIRBP) that alters the translational efficiency of its target messenger RNAs (mRNAs). This review summarizes recent work on the roles of CIRP in the context of inflammation and cancer. The function of CIRP in cancer appeared to be solely driven though its functions as an RBP that targeted cancer-associated mRNAs, but it is increasingly clear that CIRP also modulates inflammation. Several recent studies highlight roles for CIRP in immune responses, ranging from sepsis to wound healing and tumor-promoting inflammation. While modulating inflammation is an established role for RBPs that target cytokine mRNAs, CIRP appears to modulate inflammation by several different mechanisms. CIRP has been found in serum, where it binds the TLR4-MD2 complex, acting as a Damage-associated molecular pattern (DAMP). CIRP activates the NF-κB pathway, increasing phosphorylation of Iκκ and IκBα, and stabilizes mRNAs encoding pro-inflammatory cytokines. While CIRP promotes higher levels of pro-inflammatory cytokines in certain cancers, it also decreases inflammation to accelerate wound healing. This dichotomy suggests that the influence of CIRP on inflammation is context dependent and highlights the importance of detailing the mechanisms by which CIRP modulates inflammation. WIREs RNA 2018, 9:e1462. doi: 10.1002/wrna.1462 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Daniel A Lujan
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine and University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Joey L Ochoa
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine and University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Rebecca S Hartley
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine and University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
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13
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Rangel N, Villegas VE, Rondón-Lagos M. Profiling of gene expression regulated by 17β-estradiol and tamoxifen in estrogen receptor-positive and estrogen receptor-negative human breast cancer cell lines. BREAST CANCER-TARGETS AND THERAPY 2017; 9:537-550. [PMID: 29033607 PMCID: PMC5614746 DOI: 10.2147/bctt.s146247] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
One area of great importance in breast cancer (BC) research is the study of gene expression regulated by both estrogenic and antiestrogenic agents. Although many studies have been performed in this area, most of them have only addressed the effects of 17β-estradiol (E2) and tamoxifen (TAM) on MCF7 cells. This study aimed to determine the effect of low doses of E2 and TAM on the expression levels of 84 key genes, which are commonly involved in breast carcinogenesis, in four BC cell lines differentially expressing estrogen receptor (ER) α and HER2 (MCF7, T47D, BT474, and SKBR3). The results allowed us to determine the expression patterns modulated by E2 and TAM in ERα+ and ERα− cell lines, as well as to identify differences in expression patterns. Although the MCF7 cell line is the most frequently used model to determine gene expression profiles in response to E2 and TAM, the changes in gene expression patterns identified in ERα+ and ERα− cell lines could reflect distinctive properties of these cells. Our results could provide important markers to be validated in BC patient samples, and subsequently used for predicting the outcome in ERα+ and ERα− tumors after TAM or hormonal therapy. Considering that BC is a molecularly heterogeneous disease, it is important to understand how well, and which cell lines, best model that diversity.
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Affiliation(s)
- Nelson Rangel
- Department of Medical Sciences, University of Turin, Turin, Italy.,Faculty of Natural Sciences and Mathematics, Universidad del Rosario, Bogotá, Colombia
| | - Victoria E Villegas
- Faculty of Natural Sciences and Mathematics, Universidad del Rosario, Bogotá, Colombia
| | - Milena Rondón-Lagos
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
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14
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Fredholm H, Magnusson K, Lindström LS, Tobin NP, Lindman H, Bergh J, Holmberg L, Pontén F, Frisell J, Fredriksson I. Breast cancer in young women and prognosis: How important are proliferation markers? Eur J Cancer 2017; 84:278-289. [PMID: 28844016 DOI: 10.1016/j.ejca.2017.07.044] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 07/26/2017] [Accepted: 07/27/2017] [Indexed: 01/03/2023]
Abstract
AIM Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis. METHODS Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged ≥40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins. RESULTS Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age <40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A (HR 6.21 [2.17-17.6]). CONCLUSIONS The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR+ tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.
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Affiliation(s)
- Hanna Fredholm
- Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; Department of Breast- and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden.
| | - Kristina Magnusson
- Uppsala University, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden
| | - Linda S Lindström
- Karolinska Institutet, Department of Biosciences and Nutrition, Stockholm, Sweden
| | - Nicholas P Tobin
- Karolinska Institutet, Department of Oncology and Pathology, Cancer Center Karolinska, Stockholm, Sweden
| | - Henrik Lindman
- Uppsala University, Department of Radiology, Oncology and Radiation Science, Uppsala University Hospital, Uppsala, Sweden
| | - Jonas Bergh
- Karolinska Institutet, Department of Oncology and Pathology, Cancer Center Karolinska, Stockholm, Sweden; Karolinska Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden
| | - Lars Holmberg
- Uppsala University, Department of Surgical Sciences, Regional Cancer Center, Uppsala University Hospital, Uppsala, Sweden; King's College London, Faculty of Life Sciences and Medicine, Division of Cancer Studies, London, UK
| | - Fredrik Pontén
- Uppsala University, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden
| | - Jan Frisell
- Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; Department of Breast- and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Irma Fredriksson
- Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; Department of Breast- and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden
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15
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Cai Z, Liu Q. Cell Cycle Regulation in Treatment of Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1026:251-270. [PMID: 29282688 DOI: 10.1007/978-981-10-6020-5_12] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first-generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies. Here we will review the mechanisms of cell cycle regulation and targeting key cell cycle regulators (such as CDKs) in breast cancer treatment. Particularly, we will discuss the mechanism of CDK inhibitors in disrupting cell cycle progression, the use of selective CDK4/6 inhibitors in treatment of advanced, hormone receptor (HR)-positive postmenopausal breast cancer patients, and other clinical trials that aim to extend the utilization of these agents.
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Affiliation(s)
- Zijie Cai
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China
| | - Qiang Liu
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China.
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16
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Yan F, Wang X, Zhu M, Hu X. RNAi-mediated downregulation of cyclin Y to attenuate human breast cancer cell growth. Oncol Rep 2016; 36:2793-2799. [PMID: 27666310 DOI: 10.3892/or.2016.5126] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 11/26/2015] [Indexed: 11/06/2022] Open
Abstract
Cyclin Y (CCNY) is a newly identified PFTK1 interacting protein and has been found to be associated with the proliferation and tumorigenesis of human non-small cell lung cancer. In the present study, we analyzed the expression levels of CCNY in 65 cases of breast cancer (BC) tissues and in four BC cell lines, BT-474, MDA-MB-231, T-47D and MCF-7. Lentivirus-mediated short hairpin RNA (shRNA) was employed to knock down CCNY expression in MCF-7 and MDA-MB-231 cells. The effects of CCNY depletion on cell growth were examined by MTT, colony formation and flow cytometry assays. The results showed that immunohistochemical expression of CCNY in tumor tissues is stronger than that in normal tissues. CCNY was also expressed in all four BC cells. The knockdown of CCNY resulted in a significant reduction in cell proliferation and colony formation ability. Cell cycle analysis showed that CCNY knockdown arrested MDA-MB‑231 cells in the G0/G1 phase. Furthermore, depletion of CCNY inhibited BC cell growth via the activation of Bad and GSK3β, as well as cleavages of PARP and caspase-3 in a p53-dependent manner. Therefore, we believe that CCNY has biological effect in BC development, and its inhibition via an RNA interference lentiviral system may provide a therapeutic option for BC.
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Affiliation(s)
- Feng Yan
- College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, P.R. China
| | - Xiaoming Wang
- Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital and Jiangsu Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
| | - Mingchen Zhu
- Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital and Jiangsu Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaoya Hu
- College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, P.R. China
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17
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Inoue K, Fry EA. Novel Molecular Markers for Breast Cancer. BIOMARKERS IN CANCER 2016; 8:25-42. [PMID: 26997872 PMCID: PMC4790586 DOI: 10.4137/bic.s38394] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/16/2016] [Accepted: 02/14/2016] [Indexed: 01/15/2023]
Abstract
The use of molecular biomarkers assures that breast cancer (BC) patients receive optimal treatment. Established biomarkers, such as estrogen receptor, progesterone receptor, HER2, and Ki67, have been playing significant roles in the subcategorization of BC to predict the prognosis and decide the specific therapy to each patient. Antihormonal therapy using 4-hydroxytamoxifen or aromatase inhibitors have been employed in patients whose tumor cells express hormone receptors, while monoclonal antibody to HER2 has been administered to HER2-positive BCs. Although new therapeutic agents have been developed in the past few decades, many patients still die of the disease due to relapse; thus, novel molecular markers that predict therapeutic failure and those that can be targets for specific therapy are expected. We have chosen four of such molecules by reviewing recent publications, which are cyclin E, B-Myb, Twist, and DMP1β. The oncogenicity of these molecules has been demonstrated in vivo and/or in vitro through studies using transgenic mice or siRNAs, and their expressions have been shown to be associated with shortened overall or disease-free survival of BC patients. The former three molecules have been shown to accelerate epithelial-mesenchymal transition that is often associated with cancer stem cell-ness and metastasis; all these four can be novel therapeutic targets as well. Thus, large prospective studies employing immunohistochemistry will be needed to establish the predictive values of these molecules in patients with BC.
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Affiliation(s)
- Kazushi Inoue
- Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Elizabeth A. Fry
- Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA
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18
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Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer. Tumour Biol 2016; 37:9813-23. [PMID: 26810187 DOI: 10.1007/s13277-016-4870-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/14/2016] [Indexed: 12/25/2022] Open
Abstract
Cyclin E is a well-characterized cell cycle regulator and an amplified oncogene in breast cancer. Over-expression of cyclin E has generally been associated with poor survival. Recent studies have shown an interaction between HER-2 (ERBB2) and cyclin E, but the exact mechanism is unknown. Interestingly, cyclin E over-expression has been associated with trastuzumab resistance. We studied cyclin E over-expression, CCNE1 amplification, and relapse-free survival in HER-2-positive primary breast cancers treated with and without trastuzumab therapy. Formalin-fixed paraffin-embedded tissue samples from 202 HER-2-positive breast carcinomas were studied. Expression levels of cyclin E and proliferation marker Ki-67 were determined using immunohistochemistry. Chromogenic in situ hybridization (CISH) with a gene-specific bacterial artificial chromosome (BAC) probe was used to analyze presence of CCNE1 amplification. Majority of HER-2-positive breast carcinomas exhibited nuclear staining for cyclin E protein. Cyclin E was highly expressed (≥50 % cells) in 37 % of cases. Incidence of CCNE1 amplification (≥6 gene copies/cell or clusters) was 8 %. Cyclin E amplification and over-expression were strongly associated with each other, grade, hormone receptors, and Ki-67. Neither high cyclin E expression nor CCNE1 amplification was associated with relapse-free survival (RFS) irrespective of short-term (9-week regimen) adjuvant trastuzumab therapy. These results confirm cyclin E and HER-2 gene co-amplification in a fraction of HER-2-positive breast cancers. Cyclin E is frequently over-expressed but appears to have limited value as a prognostic or predictive factor in HER-2-positive breast cancer regardless of trastuzumab therapy.
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19
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Montazeri H, Bouzari S, Azadmanesh K, Ostad SN, Ghahremani MH. Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells. Asian Pac J Cancer Prev 2015; 16:7575-82. [DOI: 10.7314/apjcp.2015.16.17.7575] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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20
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Darzynkiewicz Z, Zhao H, Zhang S, Marietta YL, Ernest YL, Zhang Z. Initiation and termination of DNA replication during S phase in relation to cyclins D1, E and A, p21WAF1, Cdt1 and the p12 subunit of DNA polymerase δ revealed in individual cells by cytometry. Oncotarget 2015; 6:11735-50. [PMID: 26059433 PMCID: PMC4494901 DOI: 10.18632/oncotarget.4149] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 05/03/2015] [Indexed: 12/18/2022] Open
Abstract
During our recent studies on mechanism of the regulation of human DNA polymerase δ in preparation for DNA replication or repair, multiparameter imaging cytometry as exemplified by laser scanning cytometry (LSC) has been used to assess changes in expression of the following nuclear proteins associated with initiation of DNA replication: cyclin A, PCNA, Ki-67, p21(WAF1), DNA replication factor Cdt1 and the smallest subunit of DNA polymerase δ, p12. In the present review, rather than focusing on Pol δ, we emphasize the application of LSC in these studies and outline possibilities offered by the concurrent differential analysis of DNA replication in conjunction with expression of the nuclear proteins. A more extensive analysis of the data on a correlation between rates of EdU incorporation, likely reporting DNA replication, and expression of these proteins, is presently provided. New data, specifically on the expression of cyclin D1 and cyclin E with respect to EdU incorporation as well as on a relationship between expression of cyclin A vs. p21(WAF1) and Ki-67 vs. Cdt1, are also reported. Of particular interest is the observation that this approach makes it possible to assess the temporal sequence of degradation of cyclin D1, p21(WAF1), Cdt1 and p12, each with respect to initiation of DNA replication and with respect to each other. Also the sequence or reappearance of these proteins in G2 after termination of DNA replication is assessed. The reviewed data provide a more comprehensive presentation of potential markers, whose presence or absence marks the DNA replicating cells. Discussed is also usefulness of these markers as indicators of proliferative activity in cancer tissues that may bear information on tumor progression and have a prognostic value.
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Affiliation(s)
- Zbigniew Darzynkiewicz
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY
| | - Hong Zhao
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY
| | - Sufang Zhang
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY
| | - Y.W.T. Lee Marietta
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY
| | - Y.C. Lee Ernest
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY
| | - Zhongtao Zhang
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY
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21
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Huang L, Ren F, Tang R, Feng Z, Chen G. Prognostic Value of Expression of Cyclin E in Gastrointestinal Cancer: A Systematic Review and Meta-Analysis. Technol Cancer Res Treat 2015; 15:12-9. [PMID: 25627202 DOI: 10.1177/1533034614568098] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 12/21/2014] [Indexed: 01/08/2023] Open
Abstract
Cyclin E is a critical regulator in cell cycle and promotes the initiation of DNA replication and centrosome duplication in late G1. The overexpression of cyclin E is common in cancers of the digestive system. However, whether cyclin E represents a prognostic biomarker in gastrointestinal cancer remains controversial. We reviewed the published literatures to clarify the association between cyclin E determined by immunohistochemistry (IHC) and survival in gastrointestinal cancer. Literatures were searched in PubMed and Cochrane Library published up to December 1, 2014. A total of 282 articles were initially identified, and 14 articles were included in this study. Meta-analysis was performed for 10 studies with a total of 1300 patients. Combined hazard risk (HR) and corresponding 95% confidence interval (CI) were calculated by random-effect model due to the heterogeneity. The quality of included studies was assessed by the Newcastle-Ottawa Scale and the Methodological Index for Non-Randomized Studies (MINORS). We found that high level of cyclin E was a predicator of poor prognosis among patients with gastrointestinal cancer (HR = 1.67, 95% CI = 1.06-2.63, P = .028). In summary, overexpression of cyclin E is associated with poor prognosis in gastrointestinal cancer and expression of cyclin E determined by IHC might be a prognostic marker for gastrointestinal cancer in clinical practice.
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Affiliation(s)
- Lanshan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fanghui Ren
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ruixue Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhenbo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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22
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TRIM31 is downregulated in non-small cell lung cancer and serves as a potential tumor suppressor. Tumour Biol 2014; 35:5747-52. [PMID: 24566900 DOI: 10.1007/s13277-014-1763-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 02/13/2014] [Indexed: 02/06/2023] Open
Abstract
The present study aims to investigate expression pattern and biological roles of TRIM31 in human non-small cell lung cancer (NSCLC). We examined TRIM31 expression in 116 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We found TRIM31 downregulation in 47 out of 116 (40.5 %) cancer samples, which correlated with tumor status (p=0.0132), advanced p-TNM stage (p=0.001), and nodal metastasis (p=0.0382). TRIM31 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TRIM31 plasmid was performed in H157 and H1299 cells. TRIM31 overexpression inhibited cell growth rate and colony formation ability in both cell lines. In addition, expression of cell cycle regulator cyclin D1 and cyclin E were decreased after TRIM31 transfection. In conclusion, TRIM31 might serve as a tumor suppressor in non-small cell lung cancer.
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