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Zheng W, Zou M, Hu X, Gao H, Song W, Hou Q, Liu Y, Cheng Z. Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis. Commun Biol 2025; 8:93. [PMID: 39833358 PMCID: PMC11756390 DOI: 10.1038/s42003-025-07529-7] [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: 05/10/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025] Open
Abstract
Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF.
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Affiliation(s)
- Weishuai Zheng
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Respiratory and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Menglin Zou
- Fourth Ward of Medical Care Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xingxing Hu
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Han Gao
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Weiwei Song
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qinhui Hou
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuan Liu
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
| | - Zhenshun Cheng
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
- Hubei Engineering Center for Infectious Disease Prevention, Control and Treatment, Wuhan, China.
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2
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Anastasi E, Farina A, Granato T, Colaiacovo F, Pucci B, Tartaglione S, Angeloni A. Recent Insight about HE4 Role in Ovarian Cancer Oncogenesis. Int J Mol Sci 2023; 24:10479. [PMID: 37445657 DOI: 10.3390/ijms241310479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in OC as it has been implicated not only in OC diagnosis but also in the prognosis and recurrence of this lethal neoplasm, actually acting as a clinical biomarker. There are several evidence about the predictive power of HE4 clinically, conversely less has been described concerning its role in OC oncogenesis. Based on these considerations, the main goal of this review is to clarify the role of HE4 in OC proliferation, angiogenesis, metastatization, immune response and also in the development of targeted therapy. Through a deeper understanding of its functions as a key molecule in the oncogenetic processes underlying OC, HE4 could be possibly considered as an essential resource not only for diagnosis but also for prognosis and therapy choice.
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Affiliation(s)
- Emanuela Anastasi
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonella Farina
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Teresa Granato
- CNR-IBPM, Institute of Molecular Biology and Pathology, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Flavia Colaiacovo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Beatrice Pucci
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Sara Tartaglione
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonio Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
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Cancer Biomarkers: Status and Its Future Direction. Indian J Surg 2023. [DOI: 10.1007/s12262-023-03723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
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Nisar N, Mir SA, Kareem O, Pottoo FH. Proteomics approaches in the identification of cancer biomarkers and drug discovery. Proteomics 2023. [DOI: 10.1016/b978-0-323-95072-5.00001-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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Mais V, Fais ML, Peiretti M, Fanni D, Massa E, Carboni G, Fais G, Deo G, Angioni S. HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review. Curr Oncol 2022; 29:8540-8555. [PMID: 36354733 PMCID: PMC9689414 DOI: 10.3390/curroncol29110673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/04/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Low-grade stage I endometrioid endometrial carcinomas should have an excellent prognosis, but a small subset of these cancers can relapse. The search for putative immunohistochemical prognostic markers for relapse in low-risk/low-grade endometrioid endometrial cancers remains open. Among the candidate molecules that may implicate the roles of immunohistochemical risk markers, we focused our attention on human epididymis protein 4 (HE4) after a review of the literature. Few authors have devoted themselves to this topic, and none have found a correlation between the tissue expression of HE4 and the molecular classification of endometrial cancer. Five different variants of HE4 mRNA and multiple protein isoforms of HE4 were identified many years ago, but current HE4 assays only measure the total HE4 expression and do not distinguish the different proteins encoded by different mRNA variants. It is important to have an approach to distinguish specific variants in the future.
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Affiliation(s)
- Valerio Mais
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
| | - Maria Luisa Fais
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
| | - Michele Peiretti
- Division of Gynecology and Obstetrics (AOU di Cagliari), Department of Surgical Sciences, University of Cagliari, 09042 Cagliari, Italy
| | - Daniela Fanni
- Division of Pathology (AOU di Cagliari), Department of Medical Sciences and Public Health, University of Cagliari, 09042 Cagliari, Italy
| | - Elena Massa
- Division of Oncology (AOU di Cagliari), Department of Medical Sciences and Public Health, University of Cagliari, 09042 Cagliari, Italy
| | - Giulia Carboni
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
| | - Giuseppina Fais
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
| | - Giuseppe Deo
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
| | - Stefano Angioni
- Department of Surgical Sciences, University of Cagliari Medical School, 09042 Cagliari, Italy
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Abdelrazek MA, Nageb A, Barakat LA, Abouzid A, Elbaz R. BC-DETECT: combined detection of serum HE4 and TFF3 improves breast cancer diagnostic efficacy. Breast Cancer 2022; 29:507-515. [PMID: 34994942 DOI: 10.1007/s12282-021-01328-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/28/2021] [Indexed: 11/02/2022]
Abstract
BACKGROUND Early accurate breast cancer (BC) diagnosis is critical in disease management. Mammography has been widely used. However, its radiation, and high false-negative and -positive results have always been a concern. We evaluated combined detection of human epididymal protein 4 (HE4) and trefoil factor 3 (TFF3) as substitute method to enhance BC diagnosis. METHODS HE4 and TFF3 blood levels were determined by ELISA in sera of 120 BC patients and 80 women (40 healthy and 40 benign breast disease) as controls. Receiver-operating characteristic curve was applied for evaluation diagnostic power of each biomarker and their combination. RESULTS In BC patients, serum HE4 [5 (2-11.9) vs. 3.1 (1.8-5.4) and 1 (1-3.5); P = 0.022] and TFF3 [5.3 (4.5-6.7) vs. 4.7 (4-4.8) and 3.9 (3-4.4); P = 0.027] were significantly higher than that in benign and healthy groups, respectively. Both HE4 (AUC = 0.783; P < 0.0001) and TFF3 (AUC = 0.759; P < 0.0001) had superior BC diagnostic ability compared to CEA and CA-15.3. Logistic regression analysis revealed simplified index BC-DETECT = HE4 + TFF3, and its values were significantly (P = 0.0132) elevated in BC (10.9 (8.4-17.2) compared to benign (7.2 (5.4-10.1)) and healthy (5.1 (4-6.3)) controls. AUC of BC-DETECT for BC prediction was (AUC = 0.850; P < 0.0001) with sensitivity, specificity, and positive and negative predictive values and accuracy of 84.2%, 70%, 80.8%, 74.7%, and 78.5%, respectively. High BC-DETECT levels were associated with tumor non-luminal subtypes, late stage, high grade, large size, lymph-node invasion, and multiple lesions. CONCLUSIONS BC-DETECT is inexpensive, rapid, and easy to perform and reliably guides BC early detection. Moreover, the association between elevated BC-DETECT values and disease severity may propose its potential role as prognostic marker.
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Affiliation(s)
- Mohamed A Abdelrazek
- Research and Development Department, Biotechnology Research Center, New Damietta, Egypt.
- Biochemistry Labs, Sherbin Central Hospital, Ministry of Health, Ad Daqahliyah, Egypt.
| | - Ahmed Nageb
- Department of Chemistry, Faculty of Science, Port Said University, Port Fuad, Egypt
| | - Lamiaa A Barakat
- Department of Chemistry, Faculty of Science, Port Said University, Port Fuad, Egypt
| | - Amr Abouzid
- Department of Surgical Oncology, Mansoura Oncology Centre, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rizk Elbaz
- Genetics Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Watrowski R, Obermayr E, Wallisch C, Aust S, Concin N, Braicu EI, Van Gorp T, Hasenburg A, Sehouli J, Vergote I, Zeillinger R. Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study. Cancers (Basel) 2022; 14:cancers14071780. [PMID: 35406551 PMCID: PMC8997061 DOI: 10.3390/cancers14071780] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/23/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer (OC) is the most lethal genital malignancy in women. We aimed to develop and validate new proteomic-based models for non-invasive diagnosis of OC. We also compared them to the modified Risk of Ovarian Malignancy Algorithm (ROMA-50), the Copenhagen Index (CPH-I) and our earlier Proteomic Model 2017. Biomarkers were assessed using bead-based multiplex technology (Luminex®) in 356 women (250 with malignant and 106 with benign ovarian tumors) from five European centers. The training cohort included 279 women from three centers, and the validation cohort 77 women from two other centers. Of six previously studied serum proteins (CA125, HE4, osteopontin [OPN], prolactin, leptin, and macrophage migration inhibitory factor [MIF]), four contributed significantly to the Proteomic Model 2021 (CA125, OPN, prolactin, MIF), while leptin and HE4 were omitted by the algorithm. The Proteomic Model 2021 revealed a c-index of 0.98 (95% CI 0.96, 0.99) in the training cohort; however, in the validation cohort it only achieved a c-index of 0.82 (95% CI 0.72, 0.91). Adding patient age to the Proteomic Model 2021 constituted the Combined Model 2021, with a c-index of 0.99 (95% CI 0.97, 1) in the training cohort and a c-index of 0.86 (95% CI 0.78, 0.95) in the validation cohort. The Full Combined Model 2021 (all six proteins with age) yielded a c-index of 0.98 (95% CI 0.97, 0.99) in the training cohort and a c-index of 0.89 (95% CI 0.81, 0.97) in the validation cohort. The validation of our previous Proteomic Model 2017, as well as the ROMA-50 and CPH-I revealed a c-index of 0.9 (95% CI 0.82, 0.97), 0.54 (95% CI 0.38, 0.69) and 0.92 (95% CI 0.85, 0.98), respectively. In postmenopausal women, the three newly developed models all achieved a specificity of 1.00, a positive predictive value (PPV) of 1.00, and a sensitivity of >0.9. Performance in women under 50 years of age (c-index below 0.6) or with normal CA125 (c-index close to 0.5) was poor. CA125 and OPN had the best discriminating power as single markers. In summary, the CPH-I, the two combined 2021 Models, and the Proteomic Model 2017 showed satisfactory diagnostic accuracies, with no clear superiority of either model. Notably, although combining values of only four proteins with age, the Combined Model 2021 performed comparably to the Full Combined Model 2021. The models confirmed their exceptional diagnostic performance in women aged ≥50. All models outperformed the ROMA-50.
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Affiliation(s)
- Rafał Watrowski
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
- Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.A.)
| | - Eva Obermayr
- Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.A.)
| | - Christine Wallisch
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, 1090 Vienna, Austria;
| | - Stefanie Aust
- Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.A.)
| | - Nicole Concin
- Department of Obstetrics and Gynecology, Innsbruck Medical University, 6020 Innsbruck, Austria;
| | - Elena Ioana Braicu
- Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Toon Van Gorp
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (T.V.G.); (I.V.)
| | - Annette Hasenburg
- Department of Obstetrics and Gynecology, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
- Department of Obstetrics and Gynecology, University Medical Center, 55131 Mainz, Germany
| | - Jalid Sehouli
- Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (T.V.G.); (I.V.)
| | - Robert Zeillinger
- Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna, 1090 Vienna, Austria; (E.O.); (S.A.)
- Correspondence:
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Sethi A, Kumar L, Mathur S, Mahey R, Kachhawa G, Bhatla N. Prognostic Significance of HE4 Tissue Expression in Serous Epithelial Ovarian Carcinoma. South Asian J Cancer 2022; 11:125-132. [DOI: 10.1055/s-0042-1742711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Background Human Epididymis protein 4 (HE4) is expressed in ovarian cancer. Preoperative serum testing is still not widely available. This pilot study aimed to investigate the magnitude of expression of HE4 in tissue sections of serous epithelial ovarian carcinoma, its correlation with clinical outcome, and the feasibility of HE4 immunohistochemistry as a prognostic marker.
Materials and Method In this ambispective study, immunohistochemistry (IHC) was used to evaluate tissue sections of ovarian serous epithelial carcinoma at primary cytoreductive surgery. On HE4 immunohistochemistry (IHC), the magnitude of HE4 expression was assessed categorically as high or low HE4 expression and semiquantitatively by the H-score, and correlated with clinical outcome in terms of survival status, progression-free survival, and overall survival.
Results Of 32 cases, most (n = 31, 96.8%) were positive for HE4 IHC. The mean age was 49 ± 8.2 years; 29 (90.6%) patients were in FIGO stage IIIC; 25 (78.9%) had ≥1cm residual disease after surgery; 31 (96.8%) received adjuvant chemotherapy, either 3-weekly (n = 25, 81.2%) or dose-dense weekly (n = 6, 18.8%) regimen. The majority (n = 31, 96.8%) had a high-grade tumor, of whom 19 (59.4%) had high HE4 expression and 13(40.6%) patients had H-score in the range of 5 to 8. The mean H-score was 6.97 ± 3.61 (range 0 to 12). The overall survival of the study population at 64 months was 36.65% (95% CI: 8.59–66.34), with median overall survival of 59 months. A new scoring system was developed combining categorical HE4 expression and serum CA-125 levels; the combination of HE4 expression with postoperative CA-125 levels was found to be the best prognostic marker for overall survival (p = 0.05). A composite score of 2 identified patients with poor progression-free survival (HR 4.64, p = 0.039) and overall survival (HR 5.45, p = 0.05).
Conclusion The new composite scoring system using HE4 IHC with postoperative serum CA-125 levels offers an extremely useful option for prognosticating patients with serous epithelial ovarian carcinoma than serum CA-125 alone. This is useful where preoperative records are not available to the treating clinician.
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Affiliation(s)
- Ankita Sethi
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Lalit Kumar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Mathur
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Reeta Mahey
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Garima Kachhawa
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
| | - Neerja Bhatla
- Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India
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Janjua KA, Shahzad R, Shehzad A. Development of Novel Cancer Biomarkers for Diagnosis and Prognosis. CANCER BIOMARKERS IN DIAGNOSIS AND THERAPEUTICS 2022:277-343. [DOI: 10.1007/978-981-16-5759-7_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Blackman A, Mitchell J, Rowswell-Turner R, Singh R, Kim KK, Eklund E, Skates S, Bast RC, Messerlian G, Miller MC, Moore RG. Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors. Tumour Biol 2021; 43:355-365. [DOI: 10.3233/tub-211546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.
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Affiliation(s)
- Alexandra Blackman
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Jessica Mitchell
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Rachael Rowswell-Turner
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Rakesh Singh
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Kyu Kwang Kim
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Elizabeth Eklund
- Department of Pathology, Women and Infants Hospital, Brown University, RI, USA
| | - Steven Skates
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - Robert C. Bast
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Geralyn Messerlian
- Department of Pathology, Women and Infants Hospital, Brown University, RI, USA
| | - M. Craig Miller
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Richard G. Moore
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
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Salamonsen LA. Menstrual Fluid Factors Mediate Endometrial Repair. FRONTIERS IN REPRODUCTIVE HEALTH 2021; 3:779979. [PMID: 36304016 PMCID: PMC9580638 DOI: 10.3389/frph.2021.779979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Menstruation is a process whereby the outer functionalis layer of the endometrium is shed each month in response to falling progesterone and estrogen levels in a non-conception cycle. Simultaneously with the tissue breakdown, the surface is re-epithelialized, protecting the wound from infection. Once menstruation is complete and estrogen levels start to rise, regeneration progresses throughout the proliferative phase of the cycle, to fully restore endometrial thickness. Endometrial repair is unique compared to tissue repair elsewhere in the adult, in that it is rapid, scar-free and occurs around 400 times during each modern woman's reproductive life. The shedding tissue and that undergoing repair is bathed in menstrual fluid, which contains live cells, cellular debris, fragments of extracellular matrix, activated leukocytes and their products, soluble cellular components and extracellular vesicles. Proteomic and other analyses have revealed some detail of these components. Menstrual fluid, along with a number of individual proteins enhances epithelial cell migration to cover the wound. This is shown in endometrial epithelial and keratinocyte cell culture models, in an ex vivo decellularized skin model and in pig wounds in vivo. Thus, the microenvironment provided by menstrual fluid, is likely responsible for the unique rapid and scar-free repair of this remarkable tissue. Insight gained from analysis of this fluid is likely to be of value not only for treating endometrial bleeding problems but also in providing potential new therapies for poorly repairing wounds such as those seen in the aged and in diabetics.
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El-Hamed ATA, Mahmoud SAA, Soliman AA, El-Yasergy DF. Immunohistochemical Expression of “HE4” in Endometrial Hyperplasia versus Endometrial Endometrioid Carcinoma. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Aim
Endometrial cancer is the most common cancer of the female genital tract. No effective biomarkers currently exist to allow for an efficient risk classification of endometrial carcinoma. Human epididymis protein 4 (HE4) overexpression is first observed in ovarian cancer tissue and subsequent research has shown that the HE4 overexpression has also been observed in patients with endometrial carcinoma. To our knowledge, this marker was evaluated in small number of research studies in cases of endometrial carcinoma versus hyperplasia. This has inspired us to test for immunohistochemical expression of HE4 in endometrial endometrioid carcinoma and hyperplastic endometria and to correlate HE4 expression with various prognostic pathological parameters including International Federation of Gynecology and Obstetrics (FIGO) grading and staging.
Methods
Immunohistochemical staining for HE4 was performed on paraffin-embedded sections of forty cases of endometrial endometrioid carcinoma and thirty cases of endometrial hyperplasia: including 15 cases of non-atypical hyperplasia and 15 cases of atypical hyperplasia. A histochemical score was used to evaluate HE4 expression by the tumor cells.
Results
In this study, HE4 overexpression level was significantly higher in endometrial endometrioid carcinoma than endometrial hyperplasia and significantly higher than non-atypical endometrial hyperplasia (P<0.05). HE4 strong expression was detected in 20% of atypical endometrial hyperplasia, but no statistical significance was detected between atypical hyperplasia and endometrial carcinoma. HE4 overexpression showed statistically significant positive correlation with FIGO grading, FIGO staging, and depth of myometrial invasion.
Conclusion:
During interpretation of endometrial biopsies of atypical hyperplasia, HE4 strong expression might raise the possibility of the presence of coexisting adenocarcinoma not biopsied or even warning of a near future malignant transformation. Also, strong expression of HE4 by tissue biopsy of adenocarcinoma should be reported as this might predict higher grade and stage of the tumor, a point that should be considered by surgeons while performing hysterectomy. These results should be further confirmed by extending the study on a large scale, correlation of HE4 expression with the molecular classification of Tumor Cancer Genome Atlas and long term follow up are required to establish the prognostic significance of HE4 expression in endometrial carcinoma and atypical hyperplasia.
Keywords: Endometrial carcinoma, Endometrial hyperplasia, HE4, Immunohistochemistry.
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13
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Alegría-Baños JA, Jiménez-López JC, Vergara-Castañeda A, de León DFC, Mohar-Betancourt A, Pérez-Montiel D, Sánchez-Domínguez G, García-Villarejo M, Olivares-Pérez C, Hernández-Constantino Á, González-Santiago A, Clara-Altamirano M, Arela-Quispe L, Prada-Ortega D. Kinetics of HE4 and CA125 as prognosis biomarkers during neoadjuvant chemotherapy in advanced epithelial ovarian cancer. J Ovarian Res 2021; 14:96. [PMID: 34275472 PMCID: PMC8287739 DOI: 10.1186/s13048-021-00845-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/02/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Ovarian cancer (OC) is considered the most lethal gynecological cancer, of which more than 65% cases are diagnosed in advanced stages, requiring platinum-based neoadjuvant chemotherapy (NACT). METHODS A prospective-longitudinal study was conducted among women with advanced epithelial ovarian cancer (AEOC), III and IV stages, and treated with NACT, at the National Cancer Institute - Mexico, from July 2017 to July 2018. Serum samples were obtained for quantification of CA125 and HE4 using ELISA at the first and in each of the three NACT cycles. The therapeutic response was evaluated through standard tomography. We determined whether CA125 and HE4, alone or in combination, were associated with TR to NACT during follow up. RESULTS 53 patients aged 38 to 79 years were included, 92.4% presented papillary serous subtype OC. Higher serum HE4 levels were observed in patients with non-tomographic response (6.89 vs 5.19 pmol/mL; p = 0.031), specially during the second (p = 0.039) and third cycle of NACT (p = 0.031). Multivariate-adjusted models showed an association between HE4 levels and TR, from the second treatment cycle (p = 0.042) to the third cycle (p = 0.033). Changes from baseline HE4 levels during the first cycle was negative associated with TR. No associations were found between CA125 and TR. CONCLUSIONS Serum HE4 levels were independently associated with TR among patients with AOEC treated with NACT, also a reduction between baseline HE4 and first chemotherapy levels was also independently associated with the TR. These findings might be relevant for predicting a lack of response to treatment.
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Affiliation(s)
- Jorge A Alegría-Baños
- Oncology Center, Médica Sur, Mexico City, Mexico.
- Chemical Sciences Faculty, Universidad La Salle, Benjamín Franklin 45, 06140, Mexico City, Mexico.
| | - José C Jiménez-López
- Science Faculty, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Arely Vergara-Castañeda
- Chemical Sciences Faculty, Universidad La Salle, Benjamín Franklin 45, 06140, Mexico City, Mexico
| | - David F Cantú de León
- Instituto Nacional de Cancerología, Colonia Seccion XVI, San Fernando 22, 14080, Tlalpan, Mexico City, Mexico
| | - Alejandro Mohar-Betancourt
- Instituto Nacional de Cancerología, Colonia Seccion XVI, San Fernando 22, 14080, Tlalpan, Mexico City, Mexico
| | - Delia Pérez-Montiel
- Instituto Nacional de Cancerología, Colonia Seccion XVI, San Fernando 22, 14080, Tlalpan, Mexico City, Mexico
| | | | | | | | | | | | | | - Liz Arela-Quispe
- Department of Molecular Imaging, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Diddier Prada-Ortega
- Instituto Nacional de Cancerología, Colonia Seccion XVI, San Fernando 22, 14080, Tlalpan, Mexico City, Mexico.
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY, 10032, USA.
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14
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Zhang C, Hu H, Wang X, Zhu Y, Jiang M. WFDC Protein: A Promising Diagnosis Biomarker of Ovarian Cancer. J Cancer 2021; 12:5404-5412. [PMID: 34405003 PMCID: PMC8364637 DOI: 10.7150/jca.57880] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 05/23/2021] [Indexed: 02/06/2023] Open
Abstract
An initial diagnosis of cancer is usually based on symptoms, abnormal physical examination and imaging tests. Ovarian cancer is difficult to be diagnosed timely due to the nonspecific symptoms, thus resulting in the high-risk mortality. Despite of the various diagnostic methods, there is still no reliable diagnostic test. Clinically, carbohydrate antigen 125(CA125) is widely recognized as a diagnosis biomarker of ovary cancer. However, CA125 is not sensitive to detect the ovary cancer at the early stage. It is essential to explore other potential biomarkers. Human epididymis protein 4 (HE4) in the whey/four-disulfide core (WFDC) proteins family shows satisfactory sensitivity in the early diagnosis of ovary cancer. In this present review, we summarized the important effects of WFDC family proteins on the proliferation, apoptosis and migration of ovary cancer and intended to provide more evidence to explore the possibility of WFDC protein as a diagnosis biomarker.
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Affiliation(s)
- Chen Zhang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Haoyue Hu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiaoyan Wang
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yajuan Zhu
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ming Jiang
- West China Hospital, Sichuan University, Chengdu, People's Republic of China
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15
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Mirmohseni Namini N, Abdollahi A, Movahedi M, Emami Razavi A, Saghiri R. HE4, A New Potential Tumor Marker for Early Diagnosis and Predicting of Breast Cancer Progression. IRANIAN JOURNAL OF PATHOLOGY 2021; 16:284-296. [PMID: 34306124 PMCID: PMC8298057 DOI: 10.30699/ijp.2021.135323.2482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 06/12/2021] [Indexed: 12/25/2022]
Abstract
Background & Objective: This study examined the potential of human epididymis protein 4 (HE4) as a marker in early diagnosis or as a prognostic factor for breast cancer (BC) patients. Methods: A total of 31 patients diagnosed with BC were enrolled in the study between 2008 and 2018. The mRNA and protein expression levels of HE4 were analyzed by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR) in the BC tissue and the non-tumoral adjacent tissue. Using ELISA technique, HE4 plasma levels were also measured in 43 BC patients compared to 43 healthy individuals. The correlation between HE4 expression and clinicopathological features was then investigated. Results: An increase in HE4 expression was observed at mRNA and protein levels in the BC group compared to the control group (P<0.01, P<0.0001, respectively). In addition, the relative expression of HE4 mRNA in BC patients showed a significant correlation with the differentiation grade of cancer cells (P<0.001). Plasma levels of HE4 was also associated with grade (P<0.0001), stage, and tumor size in BC patients (for both P<0.01). Patients with metastatic BC (P<0.01), lymphatic invasion, and lymph node involvement (for both P<0.05) showed significantly higher plasma levels of HE4 expression than patients without metastasis. Conclusion: According to our findings, upregulation of HE4 may be related to invasive BC phenotype. Measuring plasma levels of HE4 could be useful as a screening test in early diagnosis of BC.
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Affiliation(s)
- Nazanin Mirmohseni Namini
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Alireza Abdollahi
- Department of Pathology, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Monireh Movahedi
- Department of Biochemistry, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Saghiri
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
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16
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Atallah GA, Abd. Aziz NH, Teik CK, Shafiee MN, Kampan NC. New Predictive Biomarkers for Ovarian Cancer. Diagnostics (Basel) 2021; 11:465. [PMID: 33800113 PMCID: PMC7998656 DOI: 10.3390/diagnostics11030465] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/29/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Ovarian cancer is the eighth-most common cause of death among women worldwide. In the absence of distinctive symptoms in the early stages, the majority of women are diagnosed in advanced stages of the disease. Surgical debulking and systemic adjuvant chemotherapy remain the mainstays of treatment, with the development of chemoresistance in up to 75% of patients with subsequent poor treatment response and reduced survival. Therefore, there is a critical need to revisit existing, and identify potential biomarkers that could lead to the development of novel and more effective predictors for ovarian cancer diagnosis and prognosis. The capacity of these biomarkers to predict the existence, stages, and associated therapeutic efficacy of ovarian cancer would enable improvements in the early diagnosis and survival of ovarian cancer patients. This review not only highlights current evidence-based ovarian-cancer-specific prognostic and diagnostic biomarkers but also provides an update on various technologies and methods currently used to identify novel biomarkers of ovarian cancer.
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Affiliation(s)
| | | | | | | | - Nirmala Chandralega Kampan
- Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Malaysia; (G.A.A.); (N.H.A.A.); (C.K.T.); (M.N.S.)
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17
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Zhang Y, Wang K, Zhao Y, Fan J, Han T, Si YA, Zhou B, Zhang J, Hu Z, Xie M. Dual-label time-resolved fluoroimmunoassay for simultaneous measurement of human epidermal growth factor receptor 2 and human epididymis protein 4 in serum. J Anal Sci Technol 2020. [DOI: 10.1186/s40543-019-0201-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
AbstractIn this study, a novel dual-label time-resolved fluoroimmunoassay (TRFIA) is described for simultaneous quantification of human epidermal growth factor receptor 2 (HER-2) and human epididymis protein 4 (HE4) in serum to screen gynecologic cancers. A double-antibody sandwich TRFIA was introduced with europium and samarium chelates to simultaneously detect the concentrations of HER-2 and HE4. Under optimal conditions, the proposed method exhibited wide linear ranges for HER-2 of 0.07–500 ng ml−1 and for HE4 of 0.32–1000 pmol l−1 with the average coefficient of variation below 10%. The specificity was satisfied through determining the other common tumor markers. The recovery rates were 94.5% and 96.6% on average for HER-2 and HE4, respectively. Good correlations were observed in clinical samples between developed method and commercial chemiluminescence immunoassay kits. The results demonstrated that dual-label TRFIA for HER-2 and HE4 was rapid and precise, and therefore could have a promising use in large sample detection for gynecological cancer screening.
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18
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Liu SY, Ahsan Bilal M, Zhu JH, Li SM. Diagnostic value of serum human epididymis protein 4 in esophageal squamous cell carcinoma. World J Gastrointest Oncol 2020; 12:1167-1176. [PMID: 33133384 PMCID: PMC7579729 DOI: 10.4251/wjgo.v12.i10.1167] [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: 04/13/2020] [Revised: 05/24/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Numerous studies have demonstrated that human epididymis protein 4 (HE4) is overexpressed in various malignant tissues including ovarian, endometrial, lung, breast, pancreatic, and gastric cancers. However, no study has examined the diagnostic impact of HE4 in patient with esophageal squamous cell carcinoma (ESCC) until now. AIM To analyze the value of four serum tumor markers for the diagnosis of ESCC, and examine the associations of serum levels of HE4 with ESCC patients' clinicopathological characteristics. METHODS The case group consisted of 80 ESCC patients, which were compared to a control group of 56 patients with benign esophageal disease. Serum levels of HE4, carcinoma embryonic antigen (CEA), alpha fetal protein, and carbohydrate antigen 19-9 (CA19-9) were detected by ELISA. The associations of serum HE4 levels with ESCC patients' clinicopathological characteristics such as gender, tumor location, and pathological stage were also examined after operation. RESULTS The result of ELISA showed that serum HE4 level was significantly higher in the patients with ESCC than in the controls, and the staining intensity was inversely correlated with the pathological T and N stages. Serum HE4 levels had a sensitivity of 66.2% and specificity of 78.6% when the cutoff value was set at 3.9 ng/mL. Moreover, the combined HE4 and CA19-9 increased the sensitivity to 83.33%, and interestingly, the combination of HE4 with CEA led to the most powerful sensitivity of 87.5%. Furthermore, A positive correlation was observed between HE4 serum levels and pathological T and N stages (P = 0.0002 and 0.0017, respectively), but there was no correlation between HE4 serum levels and ESCC patient gender (P = 0.4395) or tumor location (P = 0.6777). CONCLUSION The results of this study suggest that detection of serum HE4 levels may be useful in auxiliary diagnosis and evaluation of the progression of ESCC.
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Affiliation(s)
- Shi-Yuan Liu
- Department of Thoracic Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Muhammad Ahsan Bilal
- Department of Dermatology and Venereology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Jian-Hong Zhu
- Department of Clinical Laboratory, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shao-Min Li
- Department of Thoracic Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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19
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Winkler I, Woś J, Karczmarczyk A, Miotła P, Gogacz M, Skorupska K, Rechberger T, Tabarkiewicz J, Wolińska E, Skrzypczak M. An association of circulating Tregs and Th17 cells producing IL-21 and IL-22 with the ROMA in ovarian cancer patients. Cytokine 2020; 134:155194. [PMID: 32707423 DOI: 10.1016/j.cyto.2020.155194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 07/01/2020] [Accepted: 07/04/2020] [Indexed: 12/19/2022]
Abstract
The purpose of the present study was to assess the association of regulatory T cells (Tregs; CD4+ FOXP3+) and helper T lymphocytes (Th17) releasing interleukin (IL)-21 and IL-22, with the Risk of Ovarian Malignancy Algorithm (ROMA). Similar association was made with two additional tumour markers, human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) from patients serum. The presence of Tregs and Th17 was determined both in the peripheral blood and in the tissue of epithelial ovarian tumors. Mononuclear cells obtained from patient's peripheral blood (PBMCs) and from ovarian tissue were isolated by density gradient centrifugation. As a control group patients who had undergone surgery for infertility without ovarian pathology were selected. The percentage of Tregs and Th17 releasing IL-21 or IL-22 cells from both peripheral blood and tumor tissue was measured by flow cytometry. No differences in demographic parameters like body mass index, age, or gravidity were observed among the studied groups. However, an increased concentration of marker HE4 and value of ROMA was identified in individuals with ovarian cancer when compared with women with cystadenomas. Furthermore, a negative correlation between the ROMA value in the serum and Tregs from the peripheral blood of patients with cystadenoma ovarian tumors was detected. The presented work documents, for the first time, the negative association between peripheral blood Tregs and ROMA evaluation based on the tumour markers present in the serum of women with ovarian cystadenoma. Such an effect might result from the negative impact of Tregs on the inflammation process and on tumorigenesis caused by the persistent inflammation.
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Affiliation(s)
- Izabela Winkler
- IInd Department of Gynecology, St John's Center Oncology, 20-090 Lublin, Poland; IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland.
| | - Justyna Woś
- Department of Clinical Immunology, Lublin Medical University, 20-093 Lublin, Poland
| | - Agnieszka Karczmarczyk
- Department of Experimental Hematooncology, Lublin Medical University, 20-093 Lublin, Poland
| | - Paweł Miotła
- IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland
| | - Marek Gogacz
- IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland
| | - Katarzyna Skorupska
- IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland
| | - Tomasz Rechberger
- IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland
| | - Jacek Tabarkiewicz
- Centre for Innovative Research in Medical and Natural Sciences, Medical Faculty of University of Rzeszów, 35-959 Rzeszów, Poland
| | - Ewa Wolińska
- Departament of Pathology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Maciej Skrzypczak
- IInd Department of Gynecology, Lublin Medical University, 20-954 Lublin, Poland
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20
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Bignotti E, Zanotti L, Todeschini P, Zizioli V, Romani C, Capoferri D, Tognon G, Sartori E, Calza S, Odicino F, Ravaggi A. Pre-treatment Serum HE4 Level as a Novel Independent Prognostic Biomarker for Uterine Cervical Carcinoma Patients. Front Oncol 2020; 10:584022. [PMID: 33134179 PMCID: PMC7550621 DOI: 10.3389/fonc.2020.584022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/01/2020] [Indexed: 12/21/2022] Open
Abstract
In spite of the effective implementation of screening programs, uterine cervical carcinoma (UCC) remains one of the major causes of cancer death among women around the world. The aim of this study was to investigate the prognostic value of serum human epididymis protein 4 (HE4) in UCC. Pre-treatment serum samples from 109 UCC patients and 99 healthy women were analyzed for HE4 levels by a quantitative chemiluminescent microparticle immunoassay on the automated ARCHITECT instrument. HE4 serum (sHE4) levels were significantly higher in UCC patients, regardless of tumor stage, compared with healthy controls. Elevated sHE4 levels were significantly associated with advanced FIGO stage and absence of disease-free interval after treatment. In univariable analysis, higher sHE4 levels were significantly correlated with shorter overall survival and progression-free survival. In multivariable analysis, sHE4 retained its significance as independent adverse prognostic factor for both survival endpoints. This study indicates that sHE4 is associated with a more aggressive tumor phenotype and a worse patient's prognosis. These results suggest the potential role of sHE4 as a novel prognostic marker and as an indicator of high-risk UCC patients for a tailored surgical and adjuvant therapy.
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Affiliation(s)
- Eliana Bignotti
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy.,"Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
| | - Laura Zanotti
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy.,"Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
| | - Paola Todeschini
- "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
| | - Valentina Zizioli
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy
| | - Chiara Romani
- "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
| | - Davide Capoferri
- "Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy
| | - Germana Tognon
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy
| | - Enrico Sartori
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy.,Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology University of Brescia, Brescia, Italy
| | - Stefano Calza
- Unit of Medical Statistics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.,Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.,Big & Open Data Innovation Laboratory (BODAI) Lab, University of Brescia, Brescia, Italy
| | - Franco Odicino
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy.,"Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy.,Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology University of Brescia, Brescia, Italy
| | - Antonella Ravaggi
- Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy.,"Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy.,Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology University of Brescia, Brescia, Italy
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21
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Ferraro S, Panteghini M. Making new biomarkers a reality: the case of serum human epididymis protein 4. Clin Chem Lab Med 2020; 57:1284-1294. [PMID: 30511925 DOI: 10.1515/cclm-2018-1111] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/31/2018] [Indexed: 01/01/2023]
Abstract
Background Measurement of human epididymis protein 4 (HE4) in serum has recently been proposed for clinical use in the framework of ovarian cancer (OvCa). We sought to retrace the translational phase and the clinical implementation steps boosting HE4's clinical value and discuss the effects of its introduction on the diagnostic and management pathways. Methods Meta-analyses of running evidence have preliminarily suggested that HE4 may overcome carbohydrate antigen 125 (CA125) in identifying OvCa, showing however several gaps that need to be considered, i.e. definition of biomarker diagnostic performance in the early detection of OvCa, added diagnostic value, biological and lifestyle factors of variation, and optimal interpretative criteria. Investigation of the influencing factors has shown that renal impairment represents a major limitation for HE4's diagnostic power. On the other hand, the demonstration of the substantial equivalence of results obtained by commercially available assays allows recommending harmonized thresholds for diagnostic purpose, even if the study of HE4's biological variation has clarified that the longitudinal interpretation of the biomarker changes according to the reference change value could be more appropriate. Summary We used HE4 as an example for describing the long and bumpy road for making a new biomarker a reality, and the issues that should be checked and the information that should be provided in moving a novel biomarker from its discovery to an effective clinical adoption.
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Affiliation(s)
- Simona Ferraro
- UOC Patologia Clinica, Ospedale "Luigi Sacco", Via GB Grassi 74, 20157 Milano, Italy.,Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Mauro Panteghini
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
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22
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Giampaolino P, Foreste V, Della Corte L, Di Filippo C, Iorio G, Bifulco G. Role of biomarkers for early detection of ovarian cancer recurrence. Gland Surg 2020; 9:1102-1111. [PMID: 32953625 DOI: 10.21037/gs-20-544] [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] [Indexed: 12/11/2022]
Abstract
Ovarian cancer is frequently diagnosed at an advanced stage and a fraction of these patients fail to respond to primary therapy and relapses in 70% of cases. On account of the high recurrence probability and the poor outcomes after recurrence, there is an urgent need to predict progression as early as possible and thus found the strategies to detect and prevent a recurrence. Considering that biomarkers have contributed to the management of ovarian cancer by distinguishing benign and malignant pelvic masses and monitoring response to treatment, in this review, we aim to discuss the latest evidence reported in the literature about the use of biomarkers to detect OC recurrence. In detail, we summarized all the evidence of the most quoted biomarkers like HE4, osteopontin, mesothelin (MSLN), Folate receptor α (FOLR1), paraneoplastic antigens, miRNA, cancer stem cells (CSCs) and a combination of them to evaluate their role as prognostic biomarkers for ovarian cancer recurrence.
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Affiliation(s)
- Pierluigi Giampaolino
- Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Virginia Foreste
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Claudia Di Filippo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Iorio
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Bifulco
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
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23
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Wang X, Liu G, Sheng N, Zhang M, Pan X, Liu S, Huang K, Cong Y, Xu Q, Jia X, Xu J. Peptidome characterization of ovarian cancer serum and the identification of tumor suppressive peptide ZYX 36-58. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:925. [PMID: 32953725 PMCID: PMC7475411 DOI: 10.21037/atm-20-2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Several serum biomarkers, including miRNA, mRNA, protein and peptides in cancer patients are also important mediators of cancer progression. Methods The differentially expressed peptides between the serum of ovarian cancer patients and healthy controls were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The function of the peptides was analyzed by CCK8, transwell, wound healing, and flow cytometry analysis. And the mechanism of the peptides was analyzed by peptide pull down, and high-throughput RNA-sequencing. Results A total of 7 and 46 peptides were significantly up-regulated and down-regulated in the serum of ovarian cancer patients, respectively. The precursor proteins of the differentially expressed peptides mainly involved in the complement and coagulation cascades, platelet activation, phagosome and focal adhesion pathways. Interestingly, focal adhesion, platelet activation, platelet-cancer cell interaction, complement activation, coagulation cascades and phagosome formation are all critical factors for cancer initiation or progression, which indicated that the peptides may play a crucial role in cancer development. And we identified one peptide, ZYX36-58, which was down-regulated in the serum of ovarian cancer patients, significantly inhibited invasion and migration and promoted the apoptosis of ovarian cancer cells. Mechanistic study indicated that ZYX36-58 interacted with and increased the protein level of the antiangiogenic protein thrombospondin-1 (TSP1), which has a tumor suppressive effect on ovarian cancer. Conclusions ZYX36-58, which was significantly down-regulated in the serum of ovarian cancer patients can significantly inhibit cell invasion, migration and promote apoptosis of ovarian cancer cells by binding and up-regulating TSP1 protein expression.
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Affiliation(s)
- Xusu Wang
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Guangquan Liu
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Na Sheng
- Model Animal Research Center of Nanjing University, Nanjing, China
| | - Mi Zhang
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Xinxing Pan
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Siyu Liu
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Ke Huang
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Yu Cong
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Qing Xu
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Xuemei Jia
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Juan Xu
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
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James NE, Emerson JB, Borgstadt AD, Beffa L, Oliver MT, Hovanesian V, Urh A, Singh RK, Rowswell-Turner R, DiSilvestro PA, Ou J, Moore RG, Ribeiro JR. The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes. Sci Rep 2020; 10:8558. [PMID: 32444701 PMCID: PMC7244765 DOI: 10.1038/s41598-020-65353-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 05/01/2020] [Indexed: 12/13/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.
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Affiliation(s)
- Nicole E James
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA
| | - Jenna B Emerson
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.,Warren-Alpert Medical School of Brown University, Providence, RI, USA
| | - Ashley D Borgstadt
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.,Warren-Alpert Medical School of Brown University, Providence, RI, USA
| | - Lindsey Beffa
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.,Warren-Alpert Medical School of Brown University, Providence, RI, USA
| | - Matthew T Oliver
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.,Warren-Alpert Medical School of Brown University, Providence, RI, USA
| | - Virginia Hovanesian
- Rhode Island Hospital, Digital Imaging and Analysis Core Facility, Providence, RI, USA
| | - Anze Urh
- Northwell Health Physician Partners Gynecologic Oncology, Brightwaters, NY, USA
| | - Rakesh K Singh
- University of Rochester Medical Center, Rochester, NY, USA
| | | | - Paul A DiSilvestro
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA.,Warren-Alpert Medical School of Brown University, Providence, RI, USA
| | - Joyce Ou
- Warren-Alpert Medical School of Brown University, Providence, RI, USA.,Women and Infants Hospital, Department of Pathology, Providence, RI, USA
| | | | - Jennifer R Ribeiro
- Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Providence, RI, USA. .,Warren-Alpert Medical School of Brown University, Providence, RI, USA.
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Lee YJ, Kim YM, Kang JS, Nam SH, Kim DY, Kim YT. Comparison of Risk of Ovarian Malignancy Algorithm and cancer antigen 125 to discriminate between benign ovarian tumor and early-stage ovarian cancer according to imaging tumor subtypes. Oncol Lett 2020; 20:931-938. [PMID: 32566022 DOI: 10.3892/ol.2020.11629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 04/01/2020] [Indexed: 01/23/2023] Open
Abstract
The present study aimed to compare the accuracy of the Risk of Ovarian Malignancy Algorithm (ROMA) and cancer antigen (CA)125 to discriminate between benign ovarian tumors and early-stage ovarian cancer according to imaging tumor subtypes associated with post-operative histopathological findings. A total of 1,207 patients who were assessed using the ROMA test due to suspected early-stage ovarian cancer and underwent surgery at Asan Medical Center (Seoul, Korea) between September 2014 and March 2018 were identified. A total of 981 patients who met the inclusion criteria were included in the retrospective analysis. Among the 981 subjects, 816 had benign tumors, 90 had malignant tumors and 75 had borderline tumors. Of the patients diagnosed with ovarian cancer or borderline tumor, 47.3% were judged as high-risk by the ROMA test and 58.2% had CA125 levels of >35 U/ml. The specificity and accuracy of ROMA were higher compared with those of CA125 in pre-menopausal females. However, the superiority of the ROMA test in the identification of malignant ovarian tumors compared with CA125 was only observed in patients with endometriotic-type tumors but not in any of the other tumor subtypes. In the endometriotic type of ovarian tumor, the superiority of the ROMA test compared to CA125 was confirmed in triage of ovarian tumor. However, the sensitivity and specificity of ROMA and CA125 were similar for the other tumor types. Therefore, future development of better tumor-specific biomarkers for triage of ovarian tumor is required.
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Affiliation(s)
- Young-Jae Lee
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Yong-Man Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Ji-Sik Kang
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - So-Hyun Nam
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Dae-Yeon Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Young-Tak Kim
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea
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Celik B, Bulut T, Yalcin AD. Tissue HE4 Expression Discriminates the Ovarian Serous Carcinoma but Not the Uterine Serous Carcinoma Patients. A New Adjunct to the Origin of the Tumor Site. Pathol Oncol Res 2020; 26:1145-1151. [PMID: 31165997 DOI: 10.1007/s12253-019-00675-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023]
Abstract
Both uterine serous carcinoma (USC) and ovarian serous carcinoma (OSC) are presented at advanced stage at the first admittion and dissseminated disease makes the anatomical site of the tumor origin imposible. CA125 and p53 are reliable markers that are useful for differentiating both uterine serous and ovarian serous carcinoma from their most common subtypes (endometrioid type carcinoma of ovary and uterus) but so far there is no histopathologic marker that differentiates USC from OSC. On the other hand, Trastuzumab (Herceptin) increases progression-free survival among USC patients, but not OSC patients and makes the histopathologically assigning the origin of the tumor important. So, the aim of this study was to evaluate the immunohistopathological discriminative value of the human epididymis secretory protein 4 (HE4) between OSC and USC patients. Patients with a diagnosis of OSC and UTC were enrolled. HE4 expression was evaluated by immunohistochemistry. The results were compared between groups. Of the tumor tissues studied, HE4 immunostaining was seen in the majority of ovarian serous carcinoma cases (89.65%), while endomatrial serous carcinoma cases were devoid of HE4 immunostaining. HE4 immunostaining was seen in 39.1% uterin serous carcinoma cases and this difference was statistically significant (p = 0.001). Our study demonstrated for the first time the potential of HE4 expression to predict the anatomical site of tumor origin. HE4 is a novel tumor marker that differentiates USC from OSC.
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Affiliation(s)
- Betul Celik
- Pathology Department, Health Science University, Antalya Hospital, Antalya, Turkey.
- Department of Pathology, Training Hospital, Varlik Mah, 07100, Antalya, Turkey.
| | - Tangul Bulut
- Pathology Department, Health Science University, Antalya Hospital, Antalya, Turkey
| | - Arzu Didem Yalcin
- Immunology Unit, Health Science University, Antalya Hospital, Antalya, Turkey
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27
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Markedly Elevated HE4 in Hepatic Neuroendocrine Neoplasm: A Report of Two Cases and Literature Review. HEPATITIS MONTHLY 2020. [DOI: 10.5812/hepatmon.101016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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El Bairi K, Afqir S, Amrani M. Is HE4 Superior over CA-125 in the Follow-up of Patients with Epithelial Ovarian Cancer? Curr Drug Targets 2020; 21:1026-1033. [PMID: 32334501 DOI: 10.2174/1389450121666200425211732] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/19/2020] [Accepted: 03/30/2020] [Indexed: 02/08/2023]
Abstract
Notwithstanding important advances in the treatment of epithelial ovarian cancer (EOC), this disease is still a leading cause of global high mortality from gynecological malignancies. Recurrence in EOC is inevitable and it is responsible for poor survival rates. There is a critical need for novel effective biomarkers with improved accuracy compared to the standard carbohydrate antigen-125 (CA-125) for follow-up. The human epididymis protein 4 (HE4) is used for early detection of EOC (ROMA algorithm) as well as for predicting optimal cytoreduction after neoadjuvant chemotherapy and survival outcomes. Notably, the emerging HE4 is a promising prognostic biomarker that has displayed better accuracy in various recent studies for detecting recurrent disease. In this mini-review, we discussed the potential of HE4 as an accurate predictor of EOC recurrence.
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Affiliation(s)
- Khalid El Bairi
- Faculty of Medicine and Pharmacy, Mohamed Ist University, Oujda, Morocco
| | - Said Afqir
- Faculty of Medicine and Pharmacy, Mohamed Ist University, Oujda, Morocco
| | - Mariam Amrani
- Faculty of Medicine and Pharmacy, Mohamed V University, Rabat, Morocco
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Lou T, Zhuang H, Liu C, Zhang Z. HDAC3 positively regulates HE4 expression to promote ovarian carcinoma progression. Arch Biochem Biophys 2019; 675:108044. [DOI: 10.1016/j.abb.2019.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/12/2019] [Accepted: 07/11/2019] [Indexed: 12/11/2022]
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Wang J, Deng L, Zhuang H, Liu J, Liu D, Li X, Jin S, Zhu L, Wang H, Lin B. Interaction of HE4 and ANXA2 exists in various malignant cells-HE4-ANXA2-MMP2 protein complex promotes cell migration. Cancer Cell Int 2019; 19:161. [PMID: 31210752 PMCID: PMC6567406 DOI: 10.1186/s12935-019-0864-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 05/27/2019] [Indexed: 02/06/2023] Open
Abstract
Background The interaction between human epididymis protein 4 (HE4) and annexin A2 (Annexin A2) has been found in ovarian cancer. However, it is dimness whether
the interaction exists in other malignant tumors. Methods Real-time PCR, western blotting and immunocytochemistry were used to detect mRNA and proteins expression. Co-immunoprecipitation and double-labeling immunofluorescence were used to detect the interaction among HE4, ANXA2 and MMP2. MTS assay was used to test cell proliferation. Adhesion test was used to test cell adhesion. Flow cytometry was applied to examine cell cycle. The scratch test and Transwell assay was performed to detect the migration and invasion of various malignant cell lines. Results Here we show that the overexpression of HE4 and ANXA2 in various malignant cells is a common phenomenon. HE4 and ANXA2 are co-localized in the cytoplasm and membrane of various tumor cells. ES-2 cells which had both high expression of HE4 and ANXA2 were much stronger in proliferation, adhesion, invasion, and migration than other tumor cells. HE4–ANXA2–MMP2 could form a triple protein complex. HE4 could mediate the expression of MMP2 via ANXA2 to promote cell migration progress. Conclusions The interaction of HE4 and ANXA2 exists in various types of cancer cells. HE4 and ANXA2 can promote the proliferation, adhesion, invasion, and migration of cancer cells. HE4–ANXA2–MMP2 form a protein complex and ANXA2 plays the role of “bridge”. They performed together to promote cell migration.
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Affiliation(s)
- Jing Wang
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Lu Deng
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China.,3Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China
| | - Huiyu Zhuang
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China.,4Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chaoyang District, Beijing, 100020 China
| | - Juanjuan Liu
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Dawo Liu
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Xiao Li
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Shan Jin
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Liancheng Zhu
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
| | - Huimin Wang
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China.,5Department of Gynecology, Liaoning Cancer Hospital & Institute China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110000 Liaoning China
| | - Bei Lin
- 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated To China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, No. 7 Mulan Road, Xihu District, Benxi, 117000 Liaoning China
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Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes. Oncotarget 2019. [DOI: 10.18632/oncotarget.26915] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Giampaolino P, Della Corte L, Foreste V, Vitale SG, Chiofalo B, Cianci S, Zullo F, Bifulco G. Unraveling a difficult diagnosis: the tricks for early recognition of ovarian cancer. Minerva Med 2019; 110:279-291. [PMID: 31081307 DOI: 10.23736/s0026-4806.19.06086-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epithelial ovarian cancer (EOC) is the predominant type of ovarian cancer (OC). The 5-year survival of patients has improved over the last three decades, although the overall cure rate of OC if about 30%. Despite high response rates after initial chemotherapy, most patients with advanced ovarian cancer ultimately develop the recurrent disease because of resistance to chemotherapy. A proper early diagnosis and treatment of patients with ovarian cancer are urgently needed. Nowadays the diagnosis is performed by means of clinical symptoms and signs, often indicators of a disease already at an advanced stage, tumor markers (CA125 and HE4), transvaginal ultrasonography and imaging, very useful in distinguishing adnexal masses. Understand the nature of an adnexal mass is the primary point to begin the diagnosis of OC. Validated different model to approach and characterize adnexal pathology preoperatively are described, such as the International Ovarian Tumor Analysis (IOTA) and the Assessment of Different NEoplasias in the AdneXa (ADNEX) model. New tumor markers, such as PRSS8, FOLR1, KLK6/7, GSTT1, and miRNAs, are getting ahead and are worth noting for early detection of ovarian cancer. Despite the development of numerous ultrasound models for the diagnosis of adnexal masses and the analysis of different tumor markers, the early diagnosis of ovarian cancer is still difficult to practice. Moreover, identifying genetic risk alleles, such as germline BRCA1 and BRCA2 mutations, for ovarian cancer has had a significant impact on disease prevention strategies.
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Affiliation(s)
- Pierluigi Giampaolino
- Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Virginia Foreste
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Salvatore G Vitale
- Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy -
| | - Benito Chiofalo
- Unit of Gynecologic Oncology, Department of Experimental Clinical Oncology, "Regina Elena" National Cancer Institute, Rome, Italy
| | - Stefano Cianci
- Division of Gynecologic Oncology, Department of Women and Children's Health, A. Gemelli University Hospital and Institute for Research and Care, Rome, Italy
| | - Fulvio Zullo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Bifulco
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
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James NE, Oliver MT, Ribeiro JR, Cantillo E, Rowswell-Turner RB, Kim KK, Chichester CO, DiSilvestro PA, Moore RG, Singh RK, Yano N, Zhao TC. Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6. Front Pharmacol 2019; 10:216. [PMID: 30941033 PMCID: PMC6433991 DOI: 10.3389/fphar.2019.00216] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/20/2019] [Indexed: 01/07/2023] Open
Abstract
While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon in vitro exposure to HE4. DUSP6 was found to be upregulated in CD8+ cells and CD56+ cells. HE4 exposure reduced Erk1/2 phosphorylation specifically in these cell populations and the effect was erased by co-incubation with a DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI). In co-culture with PBMCs, HE4-silenced SKOV3 human ovarian cancer cells exhibited enhanced proliferation upon exposure to external HE4, while this effect was partially attenuated by adding BCI to the culture. Additionally, the reversal effects of BCI were erased in the co-culture with CD8+ / CD56+ cell deprived PBMCs. Taken together, these findings show that HE4 enhances tumorigenesis of ovarian cancer by compromising cytotoxic CD8+ and CD56+ cells through upregulation of self-produced DUSP6.
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Affiliation(s)
- Nicole E James
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States.,Department of Pharmacy, University of Rhode Island, Kingston, RI, United States
| | - Matthew T Oliver
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Jennifer R Ribeiro
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Evelyn Cantillo
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Rachael B Rowswell-Turner
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | - Kyu-Kwang Kim
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | | | - Paul A DiSilvestro
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Richard G Moore
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | - Rakesh K Singh
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States
| | - Naohiro Yano
- Program in Women's Oncology, Department of Obstetrics and Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States.,Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, RI, United States
| | - Ting C Zhao
- Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, RI, United States
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Evans J, Infusini G, Mcgovern J, Cuttle L, Webb A, Nebl T, Milla L, Kimble R, Kempf M, Andrews CJ, Leavesley D, Salamonsen LA. Menstrual fluid factors facilitate tissue repair: identification and functional action in endometrial and skin repair. FASEB J 2018; 33:584-605. [DOI: 10.1096/fj.201800086r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Jemma Evans
- The Hudson Institute of Medical Research Clayton Victoria Australia
- Department of Molecular and Translational MedicineMonash University Clayton Victoria Australia
| | | | - Jacqui Mcgovern
- Institute of Health and Biomedical Innovation Brisbane Queensland Australia
| | - Leila Cuttle
- Centre for Children's Burns and Trauma ResearchSchool of Biomedical SciencesInstitute of Health and Biomedical InnovationCentre for Children's Health ResearchQueensland University of Technology Brisbane Queensland Australia
| | - Andrew Webb
- Walter and Eliza Hall Institute Parkville Victoria Australia
| | - Thomas Nebl
- Walter and Eliza Hall Institute Parkville Victoria Australia
| | - Liz Milla
- Walter and Eliza Hall Institute Parkville Victoria Australia
| | - Roy Kimble
- Centre for Children's Burns and Trauma ResearchCentre for Children's Health ResearchThe University of Queensland South Brisbane Queensland Australia
| | - Margit Kempf
- Centre for Children's Burns and Trauma ResearchCentre for Children's Health ResearchThe University of Queensland South Brisbane Queensland Australia
| | - Christine J. Andrews
- Centre for Children's Burns and Trauma ResearchCentre for Children's Health ResearchThe University of Queensland South Brisbane Queensland Australia
| | - David Leavesley
- Institute of Health and Biomedical Innovation Brisbane Queensland Australia
- Skin Research Institute of Singapore Singapore
| | - Lois A. Salamonsen
- The Hudson Institute of Medical Research Clayton Victoria Australia
- Department of Molecular and Translational MedicineMonash University Clayton Victoria Australia
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James NE, Chichester C, Ribeiro JR. Beyond the Biomarker: Understanding the Diverse Roles of Human Epididymis Protein 4 in the Pathogenesis of Epithelial Ovarian Cancer. Front Oncol 2018; 8:124. [PMID: 29740539 PMCID: PMC5928211 DOI: 10.3389/fonc.2018.00124] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 04/05/2018] [Indexed: 12/12/2022] Open
Abstract
Human epididymis protein 4 (HE4) is an important clinical biomarker used for the detection of epithelial ovarian cancer (EOC). While much is known about the predictive power of HE4 clinically, less has been reported regarding its molecular role in the progression of EOC. A deeper understanding of HE4’s mechanistic functions may help contribute to the development of novel targeted therapies. Thus far, it has been difficult to recommend HE4 as a therapeutic target owing to the fact that its role in the progression of EOC has not been extensively evaluated. This review summarizes what is collectively known about HE4 signaling and how it functions to promote tumorigenesis, chemoresistance, and metastasis in EOC, with the goal of providing valuable insights that will have the potential to aide in the development of new HE4-targeted therapies.
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Affiliation(s)
- Nicole E James
- Division of Gynecologic Oncology, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, United States.,Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, United States
| | - Clinton Chichester
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, United States
| | - Jennifer R Ribeiro
- Division of Gynecologic Oncology, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, United States
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Li LM, Zhu YX, Zhong Y, Su T, Fan XM, Xi Q, Li MY, Fu J, Tan H, Liu S. Human epididymis protein 4 in endometrial cancer: A meta-analysis. Clin Chim Acta 2018; 482:215-223. [PMID: 29630870 DOI: 10.1016/j.cca.2018.03.040] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 03/28/2018] [Accepted: 03/30/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Serum human epididymis protein 4 (HE4) is a potential marker for endometrial cancer (EC), however, the diagnostic value of HE4 for EC remains controversial. In this study, we performed a meta-analysis to estimate the diagnostic accuracy of serum HE4 for EC. METHODS Literature reports of the diagnostic accuracy of serum HE4 for EC were systematically identified using online data-bases. The meta-analysis was performed using STATA 12.0, Meta-Disc 1.4, and Review Manager 5.2. RESULTS A total of 4182 participants and 23 studies were included in our meta-analysis. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.65 (95% CI: 0.56-0.73), 0.91 (95% CI: 0.84-0.95), (95% CI: 4.38-12.64), 0.38 (95% CI: 0.31-0.47), 19.46 (95% CI: 11.61-32.62) and 0.84 (95% CI: 0.81 to 0.87), respectively. Our overall analysis suggested that HE4 is a useful diagnostic marker for EC. Subgroup analysis indicated that studies with benign disease controls showed higher diagnostic accuracies than those with healthy controls. CONCLUSION Serum HE4 may serve as a potential biomarker for EC diagnosis. Due to certain limitations, this conclusion should to be cautiously interpreted.
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Affiliation(s)
- Li-Man Li
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, 169# Donghu Road, Wuhan 430071, China
| | - Yu-Xuan Zhu
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Yi Zhong
- Proteomics and Metabolomics Laboratory, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Su
- Proteomics and Metabolomics Laboratory, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiao-Ming Fan
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Qian Xi
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Ming-Yong Li
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Jun Fu
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China
| | - Hong Tan
- Department of General Surgery, Chengdu Integrated TCM & Western Medicine Hospital (Chengdu First People's Hospital), Chengdu 610041, China.
| | - Shan Liu
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China.
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Chudecka-Głaz A, Cymbaluk-Płoska A, Wężowska M, Menkiszak J. Could HE4 level measurements during first-line chemotherapy predict response to treatment among ovarian cancer patients? PLoS One 2018; 13:e0194270. [PMID: 29584739 PMCID: PMC5870956 DOI: 10.1371/journal.pone.0194270] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/28/2018] [Indexed: 12/31/2022] Open
Abstract
Background This study assessed the prognostic value of HE4 marker measurements at various stages of first-line chemotherapy for ovarian cancer. Methods The study consisted of 90 ovarian cancer patients, including 48 women undergoing primary surgical treatment and 42 patients qualified for neoadjuvant chemotherapy. Each patient underwent HE4 and CA 125 level measurements at the time of diagnosis and subsequently as follows: after surgical treatment, after the third course of adjuvant chemotherapy, before interval cytoreductive surgery and after chemotherapy. The HE4 value was assessed based on the PSF, OS, DFS, surgical outcome, two-year survival and platinum sensitivity. Results Preoperative HE4 levels were a predictor of platinum sensitivity (AUC– 0.644; p = 0.035) and DFS (AUC = 0.637; p = 0.0492). A univariate logistic regression analysis showed that serum HE4 significantly correlated with PFS (baseline results over median HR = 2.96, p = 0.0009; baseline over 75 percentile HR = 2.44, p = 0.0062; normalization after treatment HR = 0.46, p = 0.0125; 50% reduction before IDS HR = 0.64, p = 0.0017). In the multivariate analysis, normalization after treatment and 50% reduction before IDS significantly influenced the PFS (HR = 0.29, p = 0.00008; HR = 0.23, p = 0.0024). The HE4 levels also correlated with the OS as follows: values below the median (HR = 1.88, p = 0.0087), normalization after chemotherapy (HR = 0.08, p = 0.0003), and 50% reduction before IDS (HR = 0.39, p = 0.0496). Conclusions The significant effect of the normalization of the HE4 marker after therapy and 50% reduction of HE4 levels before interval cytoreductive surgery on PFS and OS confirmed that HE4 might be an independent prognostic factor of treatment response. HE4 measurements performed during first-line treatment of ovarian cancer may have prognostic significance.
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Affiliation(s)
- Anita Chudecka-Głaz
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
- * E-mail:
| | - Aneta Cymbaluk-Płoska
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | - Małgorzata Wężowska
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
| | - Janusz Menkiszak
- Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
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Gonzalez VD, Samusik N, Chen TJ, Savig ES, Aghaeepour N, Quigley DA, Huang YW, Giangarrà V, Borowsky AD, Hubbard NE, Chen SY, Han G, Ashworth A, Kipps TJ, Berek JS, Nolan GP, Fantl WJ. Commonly Occurring Cell Subsets in High-Grade Serous Ovarian Tumors Identified by Single-Cell Mass Cytometry. Cell Rep 2018; 22:1875-1888. [PMID: 29444438 PMCID: PMC8556706 DOI: 10.1016/j.celrep.2018.01.053] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 12/18/2017] [Accepted: 01/17/2018] [Indexed: 01/16/2023] Open
Abstract
We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses. Furthermore, tumors from patients with poorer outcome had an increased frequency of another rare cell type that co-expressed vimentin, HE4, and cMyc. These poorer-outcome tumors also populated more cell phenotypes, as quantified by Simpson's diversity index. Thus, despite the recognized genomic complexity of the disease, the specific cell phenotypes uncovered here offer a focus for therapeutic intervention and disease monitoring.
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Affiliation(s)
- Veronica D Gonzalez
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nikolay Samusik
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tiffany J Chen
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Erica S Savig
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nima Aghaeepour
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - David A Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 Third Street, San Francisco, CA 94158, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, 1450 Third Street, San Francisco, CA 94158, USA
| | - Ying-Wen Huang
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Valeria Giangarrà
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Alexander D Borowsky
- Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Pathology and Laboratory Medicine, Comprehensive Cancer Center, University of California, Davis School of Medicine, Sacramento, CA 95817, USA
| | - Neil E Hubbard
- Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Pathology and Laboratory Medicine, Comprehensive Cancer Center, University of California, Davis School of Medicine, Sacramento, CA 95817, USA
| | - Shih-Yu Chen
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Guojun Han
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Alan Ashworth
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 Third Street, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, 1450 Third Street, San Francisco, CA 94158, USA
| | - Thomas J Kipps
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jonathan S Berek
- Stanford Comprehensive Cancer Institute and Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Garry P Nolan
- Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wendy J Fantl
- Stanford Comprehensive Cancer Institute and Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Ribeiro JR, Gaudet HM, Khan M, Schorl C, James NE, Oliver MT, DiSilvestro PA, Moore RG, Yano N. Human Epididymis Protein 4 Promotes Events Associated with Metastatic Ovarian Cancer via Regulation of the Extracelluar Matrix. Front Oncol 2018; 7:332. [PMID: 29404274 PMCID: PMC5786890 DOI: 10.3389/fonc.2017.00332] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 12/26/2017] [Indexed: 01/06/2023] Open
Abstract
Human epididymis protein 4 (HE4) has received much attention recently due to its diagnostic and prognostic abilities for epithelial ovarian cancer. Since its inclusion in the Risk of Ovarian Malignancy Algorithm (ROMA), studies have focused on its functional effects in ovarian cancer. Here, we aimed to investigate the role of HE4 in invasion, haptotaxis, and adhesion of ovarian cancer cells. Furthermore, we sought to gain an understanding of relevant transcriptional profiles and protein kinase signaling pathways mediated by this multifunctional protein. Exposure of OVCAR8 ovarian cancer cells to recombinant HE4 (rHE4) promoted invasion, haptotaxis toward a fibronectin substrate, and adhesion onto fibronectin. Overexpression of HE4 or treatment with rHE4 led to upregulation of several transcripts coding for extracellular matrix proteins, including SERPINB2, GREM1, LAMC2, and LAMB3. Gene ontology indicated an enrichment of terms related to extracellular matrix, cell migration, adhesion, growth, and kinase phosphorylation. LAMC2 and LAMB3 protein levels were constitutively elevated in cells overexpressing HE4 and were upregulated in a time-dependent manner in cells exposed to rHE4 in the media. Deposition of laminin-332, the heterotrimer comprising LAMC2 and LAMB3 proteins, was increased in OVCAR8 cells treated with rHE4 or conditioned media from HE4-overexpressing cells. Enzymatic activity of matriptase, a serine protease that cleaves laminin-332 and contributes to its pro-migratory functional activity, was enhanced by rHE4 treatment in vitro. Proteomic analysis revealed activation of focal adhesion kinase signaling in OVCAR8 cells treated with conditioned media from HE4-overexpressing cells. Focal adhesions were increased in cells treated with rHE4 in the presence of fibronectin. These results indicate a direct role for HE4 in mediating malignant properties of ovarian cancer cells and validate the need for HE4-targeted therapies that will suppress activation of oncogenic transcriptional activation and signaling cascades.
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Affiliation(s)
- Jennifer R. Ribeiro
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
| | - Hilary M. Gaudet
- Department of Chemistry, Wheaton College, Norton, MA, United States
| | - Mehreen Khan
- Department of Chemistry, Wheaton College, Norton, MA, United States
| | - Christoph Schorl
- Center for Genomics and Proteomics, Genomics Core Facility, Brown University, Providence, RI, United States
| | - Nicole E. James
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, United States
| | - Matthew T. Oliver
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
| | - Paul A. DiSilvestro
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
| | - Richard G. Moore
- Department of Obstetrics and Gynecology, Wilmot Cancer Institute, Division of Gynecologic Oncology, University of Rochester Medical Center, Rochester, NY, United States
| | - Naohiro Yano
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
- Roger Williams Medical Center, Department of Surgery, Boston University Medical School, Providence, RI, United States
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Diagnostic and Prognostic Biomarkers in ovarian cancer and the potential roles of cancer stem cells – An updated review. Exp Cell Res 2018; 362:1-10. [DOI: 10.1016/j.yexcr.2017.10.018] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/20/2017] [Indexed: 01/06/2023]
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Celik B, Bulut T. Human epididymis protein 4 may not be a reliable screening biomarker for detecting lung carcinoma patients. Biomed Rep 2017; 7:297-300. [PMID: 29085624 DOI: 10.3892/br.2017.971] [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: 07/27/2017] [Accepted: 08/08/2017] [Indexed: 11/05/2022] Open
Abstract
Human epididymis protein 4 (HE4) acts as a protease inhibitor. It has been detected in the serum of patients with lung cancer patients and its utility for lung cancer screening was found in different studies. Nevertheless, little is known regarding the expression of HE4 in lung carcinoma subtypes. The aim of the present study was to investigate whether HE4 expression is a reliable marker for detecting any lung carcinoma subtypes, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and adenocarcinoma (AC). In total, 141 lung carcinoma patients were enrolled in the study. Biopsy samples were obtained from bronchoscopic biopsy. The tumors were classified as SCLC (group 1, 54 cases) or NSCLC (group 2, 87 cases) based on histology and immunohistochemistry. The latter was sub-grouped as adenocarcinoma (group 2a, AC) and squamous cell carcinoma (group 2b, SCC). The immunohistochemical expression of HE4 was compared between the groups. The study revealed that the majority of the SCLC and SCC cases were devoid of HE4 (90.1 and 89.65%, respectively). Approximately 10% of cases had HE4 immune expression and the staining was focal and moderate throughout the tumor tissue. On the other hand, 78.8% of AC expressed HE4 and the staining was diffuse and strong. The overall HE4 expression in the lung cancer patients was 33.7%. In conclusion, the results of the present study have shown that HE4 is expressed in adenocarcinoma of the lung but it is not frequent in SCC and SCLC. The value of HE4 as a screening biomarker for lung cancer is limited but its presence exclusively in adenocarcinoma may provide new insight for targeted therapy.
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Affiliation(s)
- Betul Celik
- Department of Pathology, University of Health Sciences, Antalya Training and Research Hospital, Antalya 07050, Turkey
| | - Tangul Bulut
- Department of Pathology, University of Health Sciences, Antalya Training and Research Hospital, Antalya 07050, Turkey
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Shen Y, Wang Y, Jiang X, Lu L, Wang C, Luo W, Zhang Y, Li P, Du Z, Dai T, Wu C, Fang A, Yao Y, Peng Q, Yang J. Preparation and characterization of a high-affinity monoclonal antibody against human epididymis protein-4. Protein Expr Purif 2017; 141:44-51. [PMID: 28928083 DOI: 10.1016/j.pep.2017.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 09/12/2017] [Accepted: 09/13/2017] [Indexed: 02/08/2023]
Abstract
Human epididymis protein-4 (HE4) may serve as a putative biomarker for the early diagnosis, therapy and especially prognosis of ovarian, lung and breast cancer. Detection and targeting of HE4 using the anti-HE4 antibody could be one of the effective strategies for the cancer diagnosis and treatment in clinical practice. In this study, a high-efficiency expression system was established to purify recombinant HE4. We obtained high purity HE4 in 400 mg quantity from 1 L culture supernatant of HEK293F cells. CCK-8 and cell cycle assays indicated that the purified recombinant HE4 protein could promote SKOV3 cell cycle and proliferation at the concentration of 0.1 mg/L. Furthermore, an anti-HE4 high-affinity monoclonal antibody 9C3 (ka = 8.1 × 106 1/MS, kd = 4.4 × 10-5 1/S, KD = 5.5 × 10-12 M) was prepared using hybridoma technique and analyzed by surface plasmon resonance technology using this HE4 protein. Differential Scanning calorimeter (DSC) analysis showed that 9C3 had a commendable thermal stability with the Tm value of 73 °C. Analyses of western blot, immunohistochemistry and immunofluorescence showed that the 9C3 was highly specific to HE4 in human cancer cells and tissues. In conclusion, our study designed a method to prepare human recombinant HE4 with high yield and generated a high-affinity anti-HE4 monoclonal antibody that might have potential for basic research and clinical application.
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Affiliation(s)
- Yunlong Shen
- Research Center for Public Health and Preventive Medicine, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, Chengdu, 610041, PR China; Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China; R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Yuxi Wang
- Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Xiaohua Jiang
- Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Liang Lu
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Chengdi Wang
- Department of Respiratory Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China.
| | - Wenxin Luo
- Department of Respiratory Medicine, West China Hospital of Sichuan University, No. 37, Guo Xue Street, Chengdu, Sichuan, 610041, PR China.
| | - Yongxia Zhang
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Pei Li
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Zhengwei Du
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Tengfei Dai
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Congcong Wu
- R & D Department of AtaGenix Laboratories Co., Ltd. (Wuhan), Wuhan, PR China.
| | - Aiping Fang
- Research Center for Public Health and Preventive Medicine, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, Chengdu, 610041, PR China; Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Yuqin Yao
- Research Center for Public Health and Preventive Medicine, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, Chengdu, 610041, PR China; Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China.
| | - Qian Peng
- Cancer Center, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu 610072, Sichuan, PR China.
| | - Jinliang Yang
- Lab of Genetically Engineered Antibody, Cancer Center, West China Medical School, West China Hospital, Sichuan University, Chengdu, PR China.
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Chen P, Yang Q, Li X, Qin Y. Potential association between elevated serum human epididymis protein 4 and renal fibrosis: A systemic review and meta-analysis. Medicine (Baltimore) 2017; 96:e7824. [PMID: 28885334 PMCID: PMC6392936 DOI: 10.1097/md.0000000000007824] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human epididymis protein 4 (HE4), a matrix metalloprotease 2 (MMP2), and a matrix metalloprotease 9 (MMP9) inhibitor, promotes renal fibrosis by inhibiting the degradation of type I collagen. However, the predictive value of HE4 for renal fibrosis remains controversial, even though it has been identified as one of the most upregulated genes in cultured fibrosis-associated myofibroblasts. This systematic review and meta-analysis was conducted to investigate the potential association between circulating HE4 and renal fibrosis. METHODS Original and review articles published until January 2017 that analyzed the performance of serum HE4 in renal fibrosis were systematically searched for in PubMed (1966-2017.1), Cochrane Library, Web of Science, EMBASE (1980-2017.1), China National Knowledge Infrastructure, Wanfang Database, and VIP (Weipu Database). The meta-analysis was performed using RevMan 5.3 version. Pertinent studies were reviewed and the standardized mean difference (SMD) with 95% confidence interval was extracted. A total of 5 studies reporting 460 participants were included in the final analysis. Subgroup and sensitivity analyses were performed to explore the potential sources of between-study heterogeneity. RESULTS The results demonstrated that elevated serum HE4 favored the diagnosis of renal fibrosis across all trials (SMD = 1.41; 95% confidence interval, 0.82-2.01; P < .001). The bubble graph indicated statistically robust result. The pooled SMD was similar after removing any single study for sensitivity analysis. CONCLUSION The present study suggests a positive association between circulating HE4 and renal fibrosis. Further studies are needed to investigate the effects of interventions on HE4, and the value of HE4 as a biomarker.
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Lee S, Choi S, Lee Y, Chung D, Hong S, Park N. Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer. J Obstet Gynaecol Res 2016; 43:220-227. [PMID: 27862665 DOI: 10.1111/jog.13181] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/18/2016] [Accepted: 08/16/2016] [Indexed: 11/26/2022]
Abstract
AIM Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo-response against anti-cancer drugs and prognosis of epithelial ovarian cancer. METHODS HE4-depleted cells and HE4-overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H-score. RESULTS Knockdown of HE4 in OVCAR-3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell-growth-related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti-tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4-overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H-score > 4. CONCLUSION HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients.
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Affiliation(s)
- Seungho Lee
- Department of Obstetrics and Gynecology, Gachon University, Gil Medical Center, Incheon, Republic of Korea
| | - Seowon Choi
- Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Yookyung Lee
- Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Seoul, Republic of Korea
| | - Donghae Chung
- Department of Pathology, Gachon University, Gil Medical Center, Incheon, Republic of Korea
| | - Suntaek Hong
- Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Nohhyun Park
- Department of Obstetrics and Gynecology, Seoul National University, College of Medicine, Seoul, Republic of Korea
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Zhu L, Zhuang H, Wang H, Tan M, Schwab CL, Deng L, Gao J, Hao Y, Li X, Gao S, Liu J, Lin B. Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer. Oncotarget 2016; 7:729-44. [PMID: 26575020 PMCID: PMC4808029 DOI: 10.18632/oncotarget.6327] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 10/30/2015] [Indexed: 12/16/2022] Open
Abstract
Overexpression of Human epididymis protein 4 (HE4) related with a role in ovarian cancer tumorigenesis while little is known about the molecular mechanism alteration by HE4 up regulation. Here we reported that overexpressed HE4 promoted ovarian cancer cells proliferation, invasion and metastasis. Furthermore, human whole genome gene expression profile microarrays revealed that 231 differentially expressed genes (DEGs) were altered in response to HE4, in which MAPK signaling, ECM receptor, cell cycle, steroid biosynthesis pathways were involved. The findings suggested that overexpressed HE4 played an important role in ovarian cancer progression and metastasis and that HE4 has the potential to serve as a novel therapeutic target for ovarian cancer.
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Affiliation(s)
- Liancheng Zhu
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Huiyu Zhuang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China.,Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing 100043, China
| | - Huimin Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Mingzi Tan
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Carlton L Schwab
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA
| | - Lu Deng
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Jian Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Yingying Hao
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Xiao Li
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Song Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Juanjuan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning 110004, China
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46
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Diagnostic Value of HE4 in Distinguishing Malignant from Benign Pelvic Masses. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2016. [DOI: 10.1007/s40944-016-0079-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Ørbo A, Arnes M, Lyså LM, Borgfeldt C, Straume B. HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia. Br J Cancer 2016; 115:725-30. [PMID: 27537387 PMCID: PMC5023780 DOI: 10.1038/bjc.2016.247] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/04/2016] [Accepted: 07/12/2016] [Indexed: 11/12/2022] Open
Abstract
Background: The aim of the present study was to investigate whether changes in the tissue expression of human epididymis-specific protein 4 (HE4) could predict therapy resistance and relapse after progestin hormone therapy for medium- and low-risk endometrial hyperplasia. Methods: Endometrial biopsies were obtained from women participating in a multicentre RCT performed according to the CONSORT guidelines; the women were randomly assigned to either LNG-IUS; 10 mg of oral medroxyprogesterone acetate (MPA) administered for 10 days per cycle; or 10 mg of oral MPA administered daily for 6 months. Of the 153 women who completed therapy, 141 had adequate material for immunohistochemistry in pre- and post-treatment biopsies. An antibody to HE4 (clone 12A2 monoclonal IgG1 antibody, Fujirebio Diagnostics, Inc.) was used for the immunohistochemical staining of the pre- and post-treatment biopsies from each participant. The expression of HE4 staining was evaluated by the histological score (H-score) using light microscopy. Results: Changes in the expression of HE4 (H-score) during therapy were related to the therapy group (P<0.001) and therapy response (P<0.001) of the individuals but could not predict relapse (P>0.05). Changes in the intracellular bodies were shown to predict both the therapy response (P=0.038) and relapse (P=0.014). Conclusions: Changes in the expression of HE4 during progestin therapy regimens can predict therapy response or indicate progestin resistance for medium- and low-risk endometrial hyperplasia.
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Affiliation(s)
- Anne Ørbo
- Department of Clinical Pathology, University Hospital of Tromsø, N-9038 Tromsø, Norway.,Research Group for Gynaecologic Oncology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
| | - Marit Arnes
- Research Group for Gynaecologic Oncology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
| | - Lena Myreng Lyså
- Department of Clinical Pathology, University Hospital of Tromsø, N-9038 Tromsø, Norway
| | - Christer Borgfeldt
- Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden
| | - Bjørn Straume
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
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Zhu L, Guo Q, Jin S, Feng H, Zhuang H, Liu C, Tan M, Liu J, Li X, Lin B. Analysis of the gene expression profile in response to human epididymis protein 4 in epithelial ovarian cancer cells. Oncol Rep 2016; 36:1592-604. [PMID: 27430660 DOI: 10.3892/or.2016.4926] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 03/30/2016] [Indexed: 11/05/2022] Open
Abstract
Currently, there are emerging multiple studies on human epididymis protein 4 (HE4) in ovarian cancer. HE4 possesses higher sensitivity and specificity than CA125 in the confirmative early diagnosis for ovarian cancer. Although much attention has been given to explore its clinical application, research of the basic mechanisms of HE4 in ovarian cancer are still unclear. In the present study, we provide fundamental data to identify full-scale differentially expressed genes (DEGs) in response to HE4 by use of human whole-genome microarrays in human epithelial ovarian cancer cell line ES-2 following overexpression and silencing of HE4. We found that a total of 717 genes were upregulated and 898 genes were downregulated in the HE4-overexpressing cells vs. the HE4-Mock cells, and 166 genes were upregulated and 285 were downregulated in the HE4-silenced cells vs. the HE4-Mock cells. An overlap of 16 genes consistently upregulated and 8 genes downregulated in response to HE4 were noted. These DEGs were involved in MAPK, steroid biosynthesis, cell cycle, the p53 hypoxia pathway, and focal adhesion pathways. Interaction network analysis predicted that the genes participated in the regulatory connection. Highly differential expression of the FOXA2, SERPIND1, BDKRD1 and IL1A genes was verified by quantitative real-time PCR in 4 cell line samples. Finally, SERPIND1 (HCII) was validated at the protein level by immunohistochemistry in 107 paraffin-embedded ovarian tissues. We found that SERPIND1 may act as a potential oncogene in the development of ovarian cancer. The present study displayed the most fundamental and full-scale data to show DEGs in response to HE4. These identified genes may provide a theoretical basis for investigations of the underlying molecular mechanism of HE4 in ovarian cancer.
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Affiliation(s)
- Liancheng Zhu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Qian Guo
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Shan Jin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Huilin Feng
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Huiyu Zhuang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Cong Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Mingzi Tan
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Juanjuan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xiao Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Lu Q, Chen H, Senkowski C, Wang J, Wang X, Brower S, Glasgow W, Byck D, Jiang SW, Li J. Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines. Oncol Rep 2016; 35:163-70. [PMID: 26497244 DOI: 10.3892/or.2015.4339] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 09/04/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most deadly malignancies, and endometrial cancer represents the most common gynecologic cancer in the USA. Better understanding on the pathologic mechanisms and pathways is required for effective treatment of these malignancies. Recently, human epididymis protein 4 (HE4 or WFDC2), a secretory glycoprotein, was found to be overexpressed in pancreatic and endometrial cancers. In addition, studies have shown that HE4 overexpression in endometrial cancer cell lines led to faster cancer progression in a mouse subcutaneous model. These findings raise a question on the role(s) of secretory, extracellular HE4 in cancer development. In the present study, we found that treatment of pancreatic and endometrial cancer cell lines with purified, extracellular HE4 protein led to a significant increase in cell viability and proliferation. Moreover, extracellular HE4 protein was able to increase DNA synthesis, and modulate the mRNA and protein levels of cell cycle marker PCNA and cell cycle inhibitor p21. These effects appeared to be robust and sustainable and required a relatively low concentration of HE4 protein. The findings indicated the secreted, extracellular HE4 may carry some physiopathological functions. Via paracrine/endocrine actions, circulatory HE4 produced by malignant cells may contribute to pancreatic and endometrial cancer progression and/or metastasis.
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Affiliation(s)
- Qinsheng Lu
- Department of Histology and Embryology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Haibin Chen
- Department of Histology and Embryology, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Christopher Senkowski
- Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery, Memorial Health University Medical Center, Savannah, GA 31404, USA
| | - Jianhao Wang
- School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu 213164, P.R. China
| | - Xue Wang
- Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA
| | - Steven Brower
- Department of Surgery and Surgical Oncology, Beth Israel Medical Center, New York, NY 10003, USA
| | - Wayne Glasgow
- Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA
| | - David Byck
- Department of Obstetrics and Gynecology, Memorial Health University Medical Center, Savannah, GA 31404, USA
| | - Shi-Wen Jiang
- Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA
| | - Jinping Li
- Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA
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50
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Current clinical application of serum biomarkers to detect ovarian cancer. MENOPAUSE REVIEW 2015; 14:254-9. [PMID: 26848298 PMCID: PMC4733894 DOI: 10.5114/pm.2015.55887] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 09/02/2015] [Indexed: 01/02/2023]
Abstract
For the last decades, hundreds of potential serum biomarkers have been assessed in diagnosing of ovarian cancer including the wide spectrum of cytokines, growth factors, adhesion molecules, proteases, hormones, coagulation factors, acute phase reactants, and apoptosis factors but except CA125 none of them have been applied to everyday clinical practice. Nowadays, the growing number of evidence suggests that the classic marker CA125 should be accompanied by HE4 and in fact, Risk of Ovarian Malignancy Algorithm (ROMA) is becoming more and more widespread in clinical practice for the evaluation of adnexal masses. Early ovarian cancer is often asymptomatic, so the challenge still exists to develop serum markers suitable for early diagnosis and screening. Current knowledge strongly points to different mechanisms of pathogenesis, genetic disturbances and clinical course of major histological subtypes of ovarian cancer. Thus, future biomarker/multimarker panels should take into consideration the implications of different molecular patterns and biological behavior of various subtypes of ovarian cancer. Very promising are studies on miRNAs – small non-protein coding gene-regulatory RNA molecules functionally involved in the pathogenesis of cancers acting as oncogenes (oncomirs) or tumor suppressors. The studies devoted to ovarian cancer tissue miRNA profiling have shown that miRNAs could be useful in diagnosing and predicting the OC outcome. They also confirmed that OC is a highly heterogeneous disease, gathering four distinct histological tumor subtypes characterized not only by distinct origin, behavior and response to chemotherapy but also by different patterns of miRNA expression.
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