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Zare ME, Nasir Kansestani A, Wu X, Zhou L, Lu J, Huang J, Wang Y, Ma Y, Gao Y, Zhang J. Serum human epididymis Protein-4 outperforms conventional biomarkers in the early detection of non-small cell lung cancer. iScience 2024; 27:111211. [PMID: 39524348 PMCID: PMC11550588 DOI: 10.1016/j.isci.2024.111211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/25/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
We employed a three-step approach to evaluate serum immunoassay-based biomarkers for detecting non-small cell lung cancer (NSCLC). In the first step, we performed a systematic review and meta-analysis and implemented the Laboratory Medicine Best Practices (LMBP) method to identify potential biomarkers. From potential biomarkers, Carcinoembryonic antigen (CEA), cytokeratin 19-fragments (Cyfra 21-1), and human epididymis protein-4 (HE4) were categorized as LMBP "recommend." In the second step, we conducted matched-case-control validation on these recommended biomarkers and SAA, identified as the most accurate in the first step. In the third step, a re-meta-analysis was performed by integrating our experimental results and considering covariates. The final results revealed that HE4 emerged as the most reliable biomarker, offering balanced sensitivity and specificity, with accuracy unaffected by tumor stage, making it suitable for early diagnosis. Our findings support the inclusion of HE4 in clinical guidelines for NSCLC diagnosis, alongside well-established biomarkers such as Cyfra 21-1 and CEA.
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Affiliation(s)
- Mohammad Erfan Zare
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Atefeh Nasir Kansestani
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Xuanlan Wu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Lin Zhou
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Jie Lu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Jun Huang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Yilei Ma
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
- Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, P.R. China
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Zhang SJ, Wu C, Walt DR. A Multiplexed Digital Platform Enables Detection of Attomolar Protein Levels with Minimal Cross-Reactivity. ACS NANO 2024; 18:29891-29901. [PMID: 39422558 DOI: 10.1021/acsnano.4c10340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Protein-based biomarkers are essential for disease diagnostics, yet their low abundance in biofluids often presents significant detection challenges for traditional enzyme-linked immunosorbent assay (ELISA) techniques. While various ultrasensitive methods such as digital ELISA have improved sensitivity, multiplex assays still suffer from considerable cross-reactivities that can compromise result accuracies. To address this challenge, we have developed barcoded Molecular On-bead Signal Amplification for Individual Counting (barcoded MOSAIC), a multiplexed digital ELISA technology that markedly reduces cross-reactivity by pairing barcoded detection antibodies with specific bead types. This approach enables the simultaneous detection of eight analytes from less than 9 μL of blood, with sensitivities ranging from midpicomolar to low-attomolar levels and a collective dynamic range exceeding seven logs across multiple analytes within a single multiplex assay. Additionally, barcoded MOSAIC is compatible with standard immunoassay reagents and workflows, utilizing a rapid, automatable flow cytometric readout for quantification, which makes it a highly accessible benchtop platform that is readily adoptable by both research and clinical laboratories, setting the stage for future translation into point-of-care applications.
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Affiliation(s)
- Stephanie J Zhang
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States
| | - Connie Wu
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States
| | - David R Walt
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, United States
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Wen Y, Jiang N, Wang Z, Xiao Y. Versatile whey acidic protein four-disulfide core domain proteins: biology and role in diseases. Front Cell Dev Biol 2024; 12:1459129. [PMID: 39296934 PMCID: PMC11408880 DOI: 10.3389/fcell.2024.1459129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 08/16/2024] [Indexed: 09/21/2024] Open
Abstract
The Whey acidic protein four-disulfide core (WFDC) protein family consists of proteins with one or more WFDC domains which are ubiquitously expressed throughout the body of human and perform a wide range of functions, including antiprotease, antibacterial, and immunomodulatory functions. Aberrant expression of WFDC proteins is associated with human diseases. However, review on the WFDC protein family is limited and insufficient. Furthermore, a systematic summary of the underlying mechanisms of WFDC protein activity is lacking. In this review, we give a summary of the structural basis and molecular function of these proteins and review the immune regulatory mechanisms and signaling pathways of WFDC proteins in the development of certain diseases. Furthermore, we discuss the diagnostic and prognostic potential of multiple WFDC proteins in the aforementioned conditions, as well as their prospective use. At last, we also discuss the progress of WFDC protein in clinical trials and put forward some research difficulties and the directions of follow-up research. Our review highlights the functional diversity and clinical significance of WFDC proteins family, while providing potential targets for drug development and innovative therapeutic strategies, this review lays the foundation and direction for future research on WFDC proteins.
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Affiliation(s)
- Yifan Wen
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Nan Jiang
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuanyuan Xiao
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
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Wu L, Chen X, Peng T, Tang E, Bai W, Chen L. Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study. Int J Biol Markers 2024; 39:141-148. [PMID: 38619974 DOI: 10.1177/03936155241244802] [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] [Indexed: 04/17/2024]
Abstract
OBJECTIVES This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.
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Affiliation(s)
- Lifang Wu
- Clinical Laboratory, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
| | - Xiang Chen
- Clinical Laboratory, Wenzhou Longwan District Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 325011, Zhejiang, China
| | - Tingting Peng
- Clinical Laboratory, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
| | - Enyan Tang
- Clinical Laboratory, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
| | - Wenjing Bai
- Clinical Laboratory, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
| | - Liya Chen
- Pathology Department, The Dingli Clinical College of Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China
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Yu Z, Nian C, Sun W, Liu X, Nian X. Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis. Clin Chim Acta 2024; 559:119682. [PMID: 38643819 DOI: 10.1016/j.cca.2024.119682] [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: 02/02/2024] [Revised: 04/11/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.
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Affiliation(s)
- Zhi Yu
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Affiliated with the Medical College of Qingdao, Yantai, Shandong 264200, China
| | - Caina Nian
- Department of Interventional Therapy, Yantai Municipal Laiyang Central Hospital, Yantai, Shandong 265200, China
| | - Wenmei Sun
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Affiliated with the Medical College of Qingdao, Yantai, Shandong 264200, China
| | - Xinhua Liu
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Affiliated with the Medical College of Qingdao, Yantai, Shandong 264200, China.
| | - Xueyuan Nian
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Affiliated with the Medical College of Qingdao, Yantai, Shandong 264200, China.
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Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
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Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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Li J, Li Y, Huo L, Sun R, Liu X, Gu Q, Li A, Han S, Liu H, Li Y, Zhang Y. Detection of serum HE4 levels contributes to the diagnosis of lung cancer. Oncol Lett 2023; 25:255. [PMID: 37205918 PMCID: PMC10189848 DOI: 10.3892/ol.2023.13841] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
Lung cancer (LC) is the most frequently diagnosed cancer and is the leading cause of cancer-associated death. Serum markers that exhibit high sensitivity and specificity for LC may assist in the diagnosis and prognosis of LC. The banked serum samples from 599 individuals, including 201 healthy controls, 124 patients with benign lung diseases, and 274 LC cases, were used. The serum concentrations of biomarkers were determined by electrochemiluminescence immunoassay and chemiluminescence immunoassay. The results showed that the serum human epididymis secretory protein 4 (HE4) levels in the LC group were significantly higher than in the healthy and benign lung disease groups. The serum levels of HE4, NSE, and CYFRA21-1 were significantly higher in patients with LC compared to those in the benign lung disease group. The area under the area under the curve (AUC) of HE4 for discriminating LC from healthy controls was 0.851 (95% CI, 0.818-0.884) and 0.739 (95% CI, 0.695-0.783), 0.747 (95% CI, 0.704-0.790), 0.626 (95% CI, 0.577-0.676), and 0.700 (95% CI, 0.653-0.747) for NSE, CYFRA21-1, SCC, and ProGRP, respectively. The AUC value of the combination of serum HE4 combined with NSE, CYFRA21-1, SCC, and proGRP for cancer diagnosis was 0.896 (95% CI, 0.868-0.923). In early LC, the AUC value of HE4 for discriminating early LC from healthy controls was 0.802 (95% CI, 0.758-0.845), 0.728 (95% CI, 0.679-0.778), 0.699 (95% CI, 0.646-0.752), 0.605 (95% CI, 0.548-0.662), and 0.685 (95% CI, 0.630-0.739) for NSE, CYFRA21-1, SCC, and ProGRP, respectively. The AUC value of the combination of serum HE4 with NSE, CYFRA21-1, SCC, and proGRP for early LC was 0.867 (95% CI, 0.831-0.903). Serum HE4 is a promising LC biomarker, particularly for early-stage LC. Measuring serum HE4 levels may improve the diagnostic efficiency of LC.
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Affiliation(s)
- Jun Li
- Department of Clinical Laboratory, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Yuzhu Li
- Department of Radiology, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Lijing Huo
- Department of Clinical Laboratory, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Ruyi Sun
- Department of Neurology, Zunhua Renmin Hospital, Zunhua, Hebei 064200, P.R. China
| | - Xiao Liu
- Department of Clinical Laboratory, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
| | - Quan Gu
- Department of Medical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Anping Li
- Department of Medical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Sugui Han
- Nuclear Medicine Clinical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Hongmei Liu
- Nuclear Medicine Clinical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Yufeng Li
- The Cancer Institute, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Yumin Zhang
- Department of Medical Laboratory, Tangshan People's Hospital, Tangshan, Hebei 063000, P.R. China
- Correspondence to: Dr Yumin Zhang, Department of Medical Laboratory, Tangshan People's Hospital, 65 Shengli Road, Tangshan, Hebei 063000, P.R. China, E-mail:
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Ling P, Tang L, Lin M, Bu C, Yin Y, Wang F, Chen D, Jiang SW. HE4 overexpression in mice leads to leydig cell hyperplasia and spermatogensis impairment: Pathological implications for oligospermia. Mol Cell Endocrinol 2023; 568-569:111916. [PMID: 37031914 DOI: 10.1016/j.mce.2023.111916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/11/2023]
Abstract
Previous studies have shown that HE4 cancer biomarker promoted cancer cell proliferation and tumor growth in mouse xenograft models. Interestingly, HE4 levels are significantly increased in the seminal plasma of oligoasthenospermia patients, raising a question on HE4 role(s) in spermatogenesis. We constructed an HE4 overexpression mouse model (HE4-OE), and observed that HE4-OE male adult mice had small testes, low sperm counts, and elevated serum/testis testosterone levels. These mice exhibited disorganized seminiferous tubules and impaired spermatogenesis. HE4 overexpression concentrated in Leydig cells, and these cells had hyperplasia and increased testosterone biosynthesis. Mechanistic studies indicated that the impaired spermatogenesis was likely caused by a local and direct action of HE4 in the testis rather than by a hypothalamus/pituitary-initiated dysregulation. The new findings reveal a novel HE4 function in male reproductive system, and suggest the existence of a subtype of primary oligoasthenospermia characterized by HE4 overexpression, Leydig cell hyperplasia, and elevated testosterone levels.
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Affiliation(s)
- Pengyun Ling
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
| | - Lisha Tang
- Clinical Center of Reproductive Medicine, Lianyungang Maternal and Child Health Hospital, Lianyungang Affiliated to Yangzhou University, Jiangsu, China.
| | - Mengyuan Lin
- Center of Reproductive Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China.
| | - Chaozhi Bu
- State Key Laboratory of Reproductive Medicine of Nanjing Medical University, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China.
| | - Yongxiang Yin
- The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China.
| | - Fengchao Wang
- National Institute of Biological Science, Beijing, China.
| | - Daozhen Chen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China; Haidong No.2 People's Hospital of Qinghai Province, Haidong, China.
| | - Shi-Wen Jiang
- State Key Laboratory of Reproductive Medicine of Nanjing Medical University, Research Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China.
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9
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Dubey H, Ranjan A, Durai J, Khan MA, Lakshmy R, Khurana S, Gupta S, Meena J, Ray MD, Tanwar P, Chopra A, Tiwari S. Evaluation of HE4 as a prognostic biomarker in uterine cervical cancer . Cancer Treat Res Commun 2023;34:100672. [PMID: 36525756 DOI: 10.1016/j.ctarc.2022.100672] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/04/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Uterine cervical cancer (UCC) is the fourth most common health problem worldwide among women. Currently available biomarkers CA125, CA199, and CEA for diagnosis or prognostic evaluation of UCC have not got widespread acceptance. METHOD Whole blood samples of 64 patients with UCC were collected along with 63 healthy females and tested for serum levels of HE4 (sHE4). A cut-off value for positive result 64.0 pmol/L was set. Statistical analysis of different clinical variables was done. RESULT Serum level of HE4 has a significant role in the diagnosis of uterine cervical cancer. Its level increases with age, higher parity (P < 0.05), stage (P < 0.16), tumor size, and parametrial invasion. Negative result was seen with vaginal invasion, lymph node involvement & cases which had recurrence. Various histological types showed variable results. So the serum level of HE4 (sHE) level may play a role in the diagnosis & therapeutic monitoring of UCC. But the prognostic evaluation needs further studies. CONCLUSION sHE4 is useful in the diagnosis of cervical cancer, but its prognostic significance is under the question marks. It may be associated with higher values in higher stages. Higher parity of the patient is associated with higher level of HE4 in UCC.
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Affiliation(s)
- Harshita Dubey
- All India Institute of Medical Sciences, New Delhi, India
| | - Amar Ranjan
- Institute Rotary Cancer Hospital, All India Institue of Medical Sciences, New Delhi, India.
| | | | - M A Khan
- All India Institute of Medical Sciences, New Delhi, India
| | - R Lakshmy
- C.N. Center, All India Institute of Medical Sciences, New Delhi, India
| | - Sachin Khurana
- Institute Rotary Cancer Hospital, All India Institue of Medical Sciences, New Delhi, India
| | - Swati Gupta
- All India Institute of Medical Sciences, New Delhi, India
| | - Jyoti Meena
- All India Institute of Medical Sciences, New Delhi, India
| | - M D Ray
- Institute Rotary Cancer Hospital, All India Institue of Medical Sciences, New Delhi, India
| | - Pranay Tanwar
- Institute Rotary Cancer Hospital, All India Institue of Medical Sciences, New Delhi, India
| | - Anita Chopra
- Institute Rotary Cancer Hospital, All India Institue of Medical Sciences, New Delhi, India
| | - Sanat Tiwari
- Bionics Scientific Technologies Pvt. Ltd, New Delhi, India
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Demirbas S, Yerlikaya FH, Yosunkaya S, Can U, Celalettin K. The investigation of levels of endothelial cell-specific molecule, progranuline, clusterin, and human epididymis protein 4 in the differential diagnosis of malignant pleural effusions. Medicine (Baltimore) 2022; 101:e32471. [PMID: 36595996 PMCID: PMC9803442 DOI: 10.1097/md.0000000000032471] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Progranulin (PGRN), endothelial cell-specific molecule-1, clusterin (CLU), and human epididymis protein 4 (HE-4) are novel proteins reported to have diagnostic and prognostic potential in lung cancer. Here, we aimed to identify the markers with high sensitivity and specificity in distinguishing malignant pleural fluids from other pleural fluids. METHODS This prospective, descriptive study was conducted at a medical faculty hospital between 2016 and 2019. The study population consisted of 90 patients <18 years of age with pleural effusion (PE). Levels of pleural fluids of PGRN, endothelial cell-specific molecule-1, CLU, and HE-4 were measured with enzyme-linked immunosorbent assay kits under the manufacturer's manual. RESULTS Of 90 patients, 54 were men, and 36 were women (mean age 65 ± 16 years). Of pleural fluids investigated, 23 (25%) and 67 (74%) were transudates and exudates, respectively. Of exudates, while 27 (40%) and 19 (28%) were parapneumonic PE and tuberculous PE, respectively, 20 (29%) were malignant pleural effusion (MPE). Levels of all biomarkers in exudate fluids were found significantly higher than those of transudate fluids. CLU, HE-4, and PGRN levels in MPE were also found significantly higher than benign fluids (P < .05). Cutoff values were achieved by receiver operating characteristics analysis for CLU, HE-4, and PGRN to distinguish between malignant and benign groups. For diagnosis of MPE, the sensitivity and specificity values were found as 0.66 and 0.67 for a cutoff value of CLU of 18.29 mg/L (P = .00), as 0.76 and 0.76 for a cutoff value of HE-4 of 9.33 mg/L (P = .00), and as 0.66 and 0.67 for a cutoff value of PGRN of 105.91 mg/L (P = .001). CONCLUSION HE-4 having high sensitivity and specificity can be a potential diagnostic marker in distinguishing between malignant and benign effusions, and these findings can constitute a basis for future research.
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Affiliation(s)
- Soner Demirbas
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
- * Correspondence: Soner Demirbas, Meram Faculty of Medicine, Department of Chest Diseases, Necmetin Erbakan University, Selçuklu, Konya 42080, Turkey (e-mail: )
| | - Fatma Hümeyra Yerlikaya
- Department of Biochemistry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Sebnem Yosunkaya
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
| | - Ummugulsum Can
- Department of Biochemistry, Konya Training and Research Hospital, Konya, Turkey
| | - Korkmaz Celalettin
- Department of Chest Diseases, Meram Faculty of Medicine, Necmetin Erbakan University, Konya, Turkey
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11
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Marmor HN, Jackson L, Gawel S, Kammer M, Massion PP, Grogan EL, Davis GJ, Deppen SA. Improving malignancy risk prediction of indeterminate pulmonary nodules with imaging features and biomarkers. Clin Chim Acta 2022; 534:106-114. [PMID: 35870539 PMCID: PMC10057862 DOI: 10.1016/j.cca.2022.07.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/05/2022] [Accepted: 07/12/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Non-invasive biomarkers are needed to improve management of indeterminate pulmonary nodules (IPNs) suspicious for lung cancer. METHODS Protein biomarkers were quantified in serum samples from patients with 6-30 mm IPNs (n = 338). A previously derived and validated radiomic score based upon nodule shape, size, and texture was calculated from features derived from CT scans. Lung cancer prediction models incorporating biomarkers, radiomics, and clinical factors were developed. Diagnostic performance was compared to the current standard of risk estimation (Mayo). IPN risk reclassification was determined using bias-corrected clinical net reclassification index. RESULTS Age, radiomic score, CYFRA 21-1, and CEA were identified as the strongest predictors of cancer. These models provided greater diagnostic accuracy compared to Mayo with AUCs of 0.76 (95 % CI 0.70-0.81) using logistic regression and 0.73 (0.67-0.79) using random forest methods. Random forest and logistic regression models demonstrated improved risk reclassification with median cNRI of 0.21 (Q1 0.20, Q3 0.23) and 0.21 (0.19, 0.23) compared to Mayo for malignancy. CONCLUSIONS A combined biomarker, radiomic, and clinical risk factor model provided greater diagnostic accuracy of IPNs than Mayo. This model demonstrated a strong ability to reclassify malignant IPNs. Integrating a combined approach into the current diagnostic algorithm for IPNs could improve nodule management.
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Affiliation(s)
- Hannah N Marmor
- Department of Thoracic Surgery, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
| | - Laurel Jackson
- Abbott Diagnostics Division, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
| | - Susan Gawel
- Abbott Diagnostics Division, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
| | - Michael Kammer
- Department of Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA.
| | - Pierre P Massion
- Department of Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA
| | - Eric L Grogan
- Department of Thoracic Surgery, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, Veterans Affairs, 1310 24th Avenue South, Nashville, TN 37212, USA
| | - Gerard J Davis
- Abbott Diagnostics Division, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
| | - Stephen A Deppen
- Department of Thoracic Surgery, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, Veterans Affairs, 1310 24th Avenue South, Nashville, TN 37212, USA.
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12
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Jeong H, Lee B, Kim KH, Cho SY, Cho Y, Park J, Lee Y, Oh Y, Hwang BR, Jang AR, Park JH, Park JH, Jeong SH, Lee D, Lee YC, Lim KM, Goldenring JR, Nam KT. WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury. Gastroenterology 2021; 161:953-967.e15. [PMID: 34116028 PMCID: PMC8380710 DOI: 10.1053/j.gastro.2021.05.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/27/2021] [Accepted: 05/29/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models. METHODS Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens. RESULTS Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. CONCLUSIONS WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.
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Affiliation(s)
- Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Buhyun Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | | | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jeongeun Park
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yura Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yeseul Oh
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Ah-Ra Jang
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Jong-Hwan Park
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Ji-Ho Park
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Daekee Lee
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Korea.
| | - James R Goldenring
- Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee.
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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13
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Chatterjee S, Chowdhury S, Basu S. A Model-free Approach for Testing Association. J R Stat Soc Ser C Appl Stat 2021; 70:511-531. [PMID: 38863779 PMCID: PMC11166015 DOI: 10.1111/rssc.12467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The question of association between outcome and feature is generally framed in the context of a model based on functional and distributional forms. Our motivating application is that of identifying serum biomarkers of angiogenesis, energy metabolism, apoptosis, and inflammation, predictive of recurrence after lung resection in node-negative non-small cell lung cancer patients with tumor stage T2a or less. We propose an omnibus approach for testing association that is free of assumptions on functional forms and distributions and can be used as a general method. This proposed maximal permutation test is based on the idea of thresholding, is readily implementable and is computationally efficient. We demonstrate that the proposed omnibus tests maintain their levels and have strong power for detecting linear, nonlinear and quantile-based associations, even with outlier-prone and heavy-tailed error distributions and under nonparametric setting. We additionally illustrate the use of this approach in model-free feature screening and further examine the level and power of these tests for binary outcome. We compare the performance of the proposed omnibus tests with comparator methods in our motivating application to identify preoperative serum biomarkers associated with non-small cell lung cancer recurrence in early stage patients.
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Schirinzi A, Cazzolla AP, Mascolo E, Palmieri G, Pesce F, Gesualdo L, Santacroce L, Ballini A, Lovero R, Di Serio F. Determination of the Upper Reference Limit of Human Epididymis Secretory Protein 4 (HE4) in Healthy Male Individuals and Correlation with Renal and Fertility Markers. Endocr Metab Immune Disord Drug Targets 2021; 21:912-918. [PMID: 32767951 DOI: 10.2174/1871530320666200807121050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Elevated human epididymis secretory protein 4 (HE4) serum levels have been widely investigated in patients with ovarian cancer. However, high levels of HE4 can be also found in other tumors and in renal fibrosis. To date, the HE4 assay manufacturer features the reference value only for the female pre- and post-menopausal population. The aim of this study was to determine the upper reference limit (URL) of HE4 in a well-defined and large cohort of healthy male individuals and investigate potential factors influencing HE4 levels in healthy subjects. METHODS The study included 307 Italian healthy male individuals. HE4 was measured using a chemiluminescent assay (Abbott Laboratories, Wiesbaden, Germany). The URL was calculated using the non-parametric percentile method. Differences in HE4 concentrations according to age, estimated glomerular filtration rate (eGFR), free and bioavailable testosterone were also evaluated. RESULTS The 97.5th percentile URL of serum HE4 in our study population was 57 pmol/L (90% CI). After stratifying subjects according to age, we found that the URL of HE4 was higher in older (> 50 years) than in younger subjects (18-30 years old), and overlapping with the URL in males from 31 to 50 years old (P=4.769e-16, r=0.44). A strong negative correlation between HE4 and eGFR was observed (P=8.412e-12, r=-0.38). Moreover, a statistically significant negative correlation was also found between HE4 and free and bioavailable testosterone. CONCLUSION This study determined the URL of HE4 in a large cohort of healthy male subjects. Our findings indicate that the HE4 age-dependent differences in males need to be taken into account. The definition of the HE4 URL in males and the correlation observed with eGFR and testosterone should foster the clinical use of HE4 beyond gynecologic cancer.
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Affiliation(s)
| | - Angela Pia Cazzolla
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Elisa Mascolo
- Clinic Pathology Unit, Polyclinic University Hospital, Bari, Italy
| | | | - Francesco Pesce
- Nephrology, Dialysis and Transplantation Unit, DETO, University "Aldo Moro", Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, DETO, University "Aldo Moro", Bari, Italy
| | - Luigi Santacroce
- Ionian Department (DJSGEM), Microbiology and Virology Laboratory, University of Bari "Aldo Moro", Bari, Italy
| | - Andrea Ballini
- Department of Biosciences, Biotechnologies and Biopharmaceutics, Campus Universitario "Ernesto Quagliariello", University of Bari "Aldo Moro", Bari, Italy
| | - Roberto Lovero
- Clinic Pathology Unit, Polyclinic University Hospital, Bari, Italy
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15
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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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16
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Human Epididymis Protein 4 Levels in Neonates with Respiratory Disorder. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1509379. [PMID: 32337222 PMCID: PMC7154981 DOI: 10.1155/2020/1509379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 03/16/2020] [Indexed: 11/17/2022]
Abstract
Results There were no differences found in the HE4 levels determined for the mothers' blood samples and umbilical cord blood samples in all investigated groups. In comparison with healthy children, the elevated HE4 levels were observed in neonates with TTN. Significant positive correlation between HE4 and CRP as well as PCT levels was observed in all investigated neonates. The receiver operating characteristic (ROC) curve analysis demonstrated the cut-off value for the serum HE4 in the researched neonates at the level of 318.5 pmol/L, yielding the sensitivity of 73.9% and specificity of 66.7% for the early diagnosis of TTN. Conclusions Serum HE4 could be considered as a candidate biomarker for the early diagnosis of pulmonary dysfunction in the newborns.
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17
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Yang B, Ren N, Guo B, Xin H, Yin Y. Measuring serum human epididymis secretory protein autoantibody as an early biomarker of lung cancer. Transl Cancer Res 2020; 9:735-741. [PMID: 35117419 PMCID: PMC8797310 DOI: 10.21037/tcr.2019.11.50] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/22/2019] [Indexed: 01/17/2023]
Abstract
BACKGROUND Lung cancer (LC) is one of the most common types of malignant tumors and is the most prominent cause of tumor-related death worldwide. LC is a heterogeneous disease caused by somatic cell mutations and dysregulation in several signaling pathways. Understanding these pathways provides the basis for detecting LC. LC screening and diagnosis in current clinic still rely on computed tomography (CT), but its high false positive rates and cost may prevent it from being a routine screening method. Therefore, the discovery of new non-invasive and more valuable biomarkers may present an improved diagnostic approach for LC, and potentially provide more useful information for the prognosis and treatment of LC in patients. This study investigated the potential of detecting serum autoantibodies produced against human epididymis secretory protein 4 (HE4) for LC diagnosis in high-risk groups. METHODS Serum samples from 61 patients with LC were included in this study, and another 53 serum samples from healthy donors or benign lung diseases (BLD) patients were collected as the control group. The samples were analyzed with enzyme-linked immunosorbent assays (ELISA). RESULTS ELISA results showed significantly higher levels of serum autoantibodies against HE4 in samples from LC patients compared to the control group (P<0.001). Analysis of HE4 autoantibodies showed a receiver operating characteristic (ROC) curve indicating 67.21% sensitivity, 96.23% specificity, and an area under the curve (AUC) of 0.848. Levels of HE4 autoantibodies can discriminate early-stage LC patients from the control group with a 54.76% sensitivity. CONCLUSIONS Detecting serum HE4 autoantibody levels may be a potential biomarker in high-risk groups of LC. We present a new method for the diagnosis of LC in the clinic.
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Affiliation(s)
- Bin Yang
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Na Ren
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Bo Guo
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Hua Xin
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Yiyu Yin
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130000, China
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Wang A, Jin C, Tian X, Wang Y, Li H. Knockdown of HE4 suppresses aggressive cell growth and malignant progression of ovarian cancer by inhibiting the JAK/STAT3 pathway. Biol Open 2019; 8:8/9/bio043570. [PMID: 31477564 PMCID: PMC6777355 DOI: 10.1242/bio.043570] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human epididymis protein 4 (HE4) is well known to be a predictor of ovarian cancer clinically. HE4 is reported to play crucial roles in ovarian cancer progression and metastasis. The purpose of the present study was to explore its biological role and molecular mechanism in ovarian cancer. In our study, we found that expression levels of HE4 in tissues, serum and urine in ovarian cancer were upregulated compared to healthy and benign groups. HE4 expression was elevated in ovarian cancer cells. Knockdown of HE4 dampened cell proliferation and Ki67 expression, as well as enhanced apoptosis, caspase-3 activity and cleaved-caspase-3 expression. In addition, HE4 downregulation repressed invasion and migration capabilities of ovarian cancer cells. Western blot analyses showed that knockdown of HE4 reduced the levels of matrix metalloproteinases (MMP-2 and MMP-9) and inhibited epithelial to mesenchymal transition (EMT) in ovarian cancer cells. In vivo animal experiments revealed that HE4 downregulation constrained the growth of xenograft tumor. Mechanism research showed that knockdown HE4 inhibited the activity of JAK/STAT3 pathway in vitro and in vivo. In conclusion, our findings reported that knockdown of HE4 suppresses aggressive cell growth and malignant progression of ovarian cancer by inhibiting the JAK/STAT3 pathway, which provides valuable insights to contribute to develop novel HE4-targeted therapies. Summary: Our findings reported that HE4 knockdown suppresses aggressive cell growth and malignant progression of ovarian cancer by inhibiting the JAK/STAT3 pathway, which could provide a valuable insight into developing novel HE4-targeted therapies.
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Affiliation(s)
- Aihong Wang
- Department of Gynecologic and Obstetrics, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Canhui Jin
- Department of Gastrointestinal Tumor Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Xiaoyu Tian
- Department of Gynecologic and Obstetrics, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Ying Wang
- Department of Gynecologic and Obstetrics, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Hongyu Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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He YP, Li LX, Tang JX, Yi L, Zhao Y, Zhang HW, Wu ZJ, Lei HK, Yu HQ, Nian WQ, Gan L. HE4 as a biomarker for diagnosis of lung cancer: A meta-analysis. Medicine (Baltimore) 2019; 98:e17198. [PMID: 31574828 PMCID: PMC6775374 DOI: 10.1097/md.0000000000017198] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 06/21/2019] [Accepted: 08/22/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The aim of our study was to assess the value of serum human epididymis protein 4 (HE4) to diagnose lung cancer and provide reliable scientific conclusions to guide clinical practice. METHODS A systematic search of the PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, and WANFANG databases was conducted to identify all studies examining serum HE4 in the diagnosis of lung cancer published up to June, 2017. The Quality Assessment of Diagnostic Accuracy Studies tool was used to evaluate the methodological quality of each trial. The meta-analysis was performed using STATA software and Review Manager 5.3. RESULTS There were 21 studies involving 1883 cases and 1696 controls included in our meta-analysis. The pooled sensitivity and specificity of HE4 for diagnosing lung cancer were 0.73 (95% confidence interval [CI] 0.68-0.78) and 0.86 (95% CI 0.81-0.91), respectively. The positive likelihood ratio and negative likelihood ratio were 5.4 (95% CI 3.8-7.5) and 0.31 (95% CI 0.26-0.37), respectively. The diagnostic odds ratio was 17 (95% CI 12-26). The area under the curve of the summary receiver-operating characteristic curve was 0.86 (95% CI 0.83-0.89). Race, assay method, type of cancer, sample size, and publication date might be sources of heterogeneity in our meta-analysis. Subgroup analyses showed that the sensitivity in Caucasians was higher than that in Asians (0.81, 95% CI 0.71-0.91; and 0.71, 95% CI 0.66-0.77, respectively), but the specificity in Asians was better than that in Caucasians (0.87, 95% CI 0.81-0.92; and 0.85, 95% CI 0.73-0.97, respectively). The chemiluminescent microparticle immunoassay had the highest sensitivity, with 0.79 (95% CI 0.73-0.97), and the enzyme-linked immunosorbent assay had the highest specificity, with 0.87 (95% CI 0.79-0.94). HE4 had high diagnostic efficacy when screening for small cell lung cancer with the highest specificity (0.90, 95% CI 0.77-1.00). CONCLUSIONS HE4 is a relatively promising and effective biomarker for the diagnosis of lung cancer. Furthermore, given the limitations of our study, additional large-scale and well-designed studies are needed in the future.
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Affiliation(s)
- Yong-Peng He
- Department of Biochemistry and Molecular Biology, College of Basic Medical sciences, Southwest Medical University, Luzhou
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Li-Xian Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Jia-Xi Tang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Lin Yi
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Yi Zhao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Hai-Wei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Zhi-Juan Wu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Hai-Ke Lei
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Hui-Qing Yu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Wei-Qi Nian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Lin Gan
- Department of Biochemistry and Molecular Biology, College of Basic Medical sciences, Southwest Medical University, Luzhou
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20
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Yan L, Hu ZD. Diagnostic accuracy of human epididymis secretory protein 4 for lung cancer: a systematic review and meta-analysis. J Thorac Dis 2019; 11:2737-2744. [PMID: 31463101 DOI: 10.21037/jtd.2019.06.72] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Several studies have assessed the diagnostic accuracy of serum human epididymis secretory protein 4 (HE4) for lung cancer, but their results were heterogeneous. The aim of this study was to systematically review the available studies and pool their results using meta-analysis. Methods PubMed, EMBASE and Web of Science databases were searched up to January 1, 2019 to identify studies investigating the diagnostic accuracy of HE4 for lung cancer. We assessed the quality of eligible studies with the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The overall diagnostic sensitivity, specificity, positive and negative likelihood ratios were pooled using a bivariate model. Deeks's test was applied to detect the degree of publication bias. Results A total of 16 studies with 18 cohorts (1,756 lung cancers and 1,446 controls) were included. HE4 had a pooled sensitivity of 0.65 (95% CI: 0.54-0.75), specificity of 0.88 (95% CI: 0.82-0.92), positive likelihood ration of 5.3 (95% CI: 3.7-7.6) and negative likelihood ratio of 0.40 (95% CI: 0.30-0.52). Patient selection bias and partial verification bias were the major design weaknesses of available studies. No publication bias was observed. Conclusions HE4 has moderate diagnostic accuracy for lung cancer. Its result should be interpreted in parallel with clinical findings and the results of other conventional tests. Further studies are still needed to rigorously evaluate the diagnostic accuracy of HE4 for lung cancer.
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Affiliation(s)
- Li Yan
- Department of Respiratory and Critical Care Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Zhi-De Hu
- Department of Laboratory Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
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21
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Muley T, He Y, Rolny V, Wehnl B, Escherich A, Warth A, Stolp C, Schneider MA, Meister M, Herth FJ, Dayyani F. Potential for the blood-based biomarkers cytokeratin 19 fragment (CYFRA 21-1) and human epididymal protein 4 (HE4) to detect recurrence during monitoring after surgical resection of adenocarcinoma of the lung. Lung Cancer 2019; 130:194-200. [PMID: 30885344 DOI: 10.1016/j.lungcan.2019.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/14/2019] [Accepted: 02/18/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVES The biomarkers cytokeratin 19 fragment (CYFRA 21-1) and human epididymis protein 4 (HE4) are useful in the diagnosis, prognosis, and monitoring of non-small cell lung cancer (NSCLC), but their combination has not been investigated yet. The objective of this analysis was to evaluate the ability of CYFRA 21-1 and HE4 to predict recurrence as part of follow-up monitoring in patients with adenocarcinoma (ADC) of the lung. MATERIALS AND METHODS Serum samples were collected from patients with stage I-IIIA ADC preoperatively and during follow-up at 3, 6, 12, 18, and 24 months and then every 6-12 months up to 5 years post-R0 resection. Samples were analyzed for CYFRA 21-1 and HE4 via electrochemiluminescence immunoassay. All cases of disease recurrence were verified by imaging. The diagnostic performance of CYFRA 21-1, HE4, and their combination to predict recurrence was assessed by Receiver Operating Characteristic (ROC) and corresponding area under the curve (AUC). RESULTS 115 patients with ADC were included (N = 612 biomarker measurements); median age was 63 years; most had stage I-II disease (n = 97; 84.3%). All patients underwent surgical resection; 44 patients (38%) also received adjuvant chemotherapy and 16 (14%) received radiation therapy. At the median timepoint for the last blood sample collection (37 months), 31 patients (27%) had experienced recurrence. Both CYFRA 21-1 and HE4 were able to detect recurrence (AUC and 95% confidence interval [CI]): 75.9% (66.0-85.8%) and 75.4% (65.9-84.8%), respectively, but this increased with the combination (78.8% [69.0-88.6%]). At a sensitivity of 80%, the respective specificities (95% CI) for CYFRA 21-1, HE4, and the combination were 57.1% (53.0-61.2%), 57.1% (53.0-61.2%), and 69.7% (65.8-73.4%). CONCLUSION Serial measurements of serum CYFRA 21-1 and HE4 levels could provide a valuable method for follow-up monitoring of patients with ADC to detect recurrence.
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Affiliation(s)
- Thomas Muley
- Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Germany; Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
| | - Ying He
- Roche Diagnostics GmbH, Penzberg, Germany.
| | | | | | | | - Arne Warth
- Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany; Pathological Institute, University of Heidelberg, Heidelberg, Germany.
| | - Christa Stolp
- Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Germany.
| | - Marc A Schneider
- Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Germany; Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
| | - Michael Meister
- Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Germany; Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
| | - Felix J Herth
- Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), Germany; Department of Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Germany.
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22
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Fang R, Zhu Y, Khadka VS, Zhang F, Jiang B, Deng Y. The Evaluation of Serum Biomarkers for Non-small Cell Lung Cancer (NSCLC) Diagnosis. Front Physiol 2018; 9:1710. [PMID: 30555348 PMCID: PMC6281717 DOI: 10.3389/fphys.2018.01710] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 11/14/2018] [Indexed: 12/18/2022] Open
Abstract
Introduction: Lung cancer ranks top in the cause of cancer death globally. The identification of effective biomarkers is essential for non-small cell lung cancer (NSCLC) diagnosis. Methods: The expression levels of prolactin (PRL), CEA, and CYFR21 in serum were assayed by ELISA. The blood samples were attained from 44 NSCLC cases and 44 healthy controls. Logistic regression and receiver operating characteristic (ROC) analyses were applied to evaluate the diagnostic efficacy and create diagnostic mathematical models. Results: Serum PRL, CEA, and CYFR21 levels were significantly higher in patients with NSCLC than the healthy controls (all P-values <0.001). According to the model to predict NSCLC patients from the healthy controls, a combination of PRL, CEA, and CYFR21 biomarkers was more effective than individual biomarker alone, with AUC = 0.960 (95% CI: 0.921–0.999), sensitivity = 0.909, specificity = 0.955, positive predicted value = 0.952, and negative predicted value = 0.913. Conclusion: Prolactin can be used as a potential serum biomarker for the diagnosis of NSCLC. A panel of PRL, CEA, and CYFRA21 was found as promising serum biomarkers for the diagnosis of NSCLC with relatively high sensitivity and specificity.
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Affiliation(s)
- Rui Fang
- Bioinformatics Core, Department of Complementary and Integrative Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Yong Zhu
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Vedbar S Khadka
- Bioinformatics Core, Department of Complementary and Integrative Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
| | - Fan Zhang
- Vermont Genetics Network, University of Vermont, Burlington, VT, United States
| | - Bin Jiang
- National Medical Centre of Colorectal Disease, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Youping Deng
- Bioinformatics Core, Department of Complementary and Integrative Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
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23
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Choi SI, Jang MA, Jeon BR, Shin HB, Lee YK, Lee YW. Clinical Usefulness of Human Epididymis Protein 4 in Lung Cancer. Ann Lab Med 2018; 37:526-530. [PMID: 28840992 PMCID: PMC5587827 DOI: 10.3343/alm.2017.37.6.526] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 03/23/2017] [Accepted: 06/21/2017] [Indexed: 11/25/2022] Open
Abstract
Human epididymis protein 4 (HE4) has been suggested as a useful new biomarker of lung cancer; however, few relevant large-scale studies have been published. In this study, we evaluated the utility of serum HE4 for lung cancer detection. HE4 levels were measured in serum samples from 100 lung cancer patients, 57 patients with benign lung diseases, and 274 healthy controls by using a chemiluminescent immunoassay, and variations in HE4 levels were analyzed by clinical status such as lung cancer, benign lung disease, and healthy condition, Tumor, Lymph Nodes, Metastasis (TNM) stage, tumor score, and histological cancer type. Lung cancer patients had significantly higher serum HE4 levels than patients with benign lung diseases and healthy controls (P<0.0001). The area under the ROC curve for HE4 was 0.84 (95% confidence interval, 0.78–0.89; P<0.0001) between lung cancer patients and healthy controls. Serum HE4 levels were significantly higher in patients with advanced disease (according to TNM stage) than in healthy controls (P<0.0001). HE4 levels were significantly elevated in patients with tumors of all types, those of different histological subgroups, and those with the smallest tumors (P=0.002). This report supports the potential of serum HE4 as an ancillary diagnostic marker for lung cancer detection.
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Affiliation(s)
- Soo In Choi
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Mi Ae Jang
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Byung Ryul Jeon
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hee Bong Shin
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - You Kyoung Lee
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Yong Wha Lee
- Department of Laboratory Medicine & Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea.
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24
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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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25
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Wan J, Wang Y, Cai G, Liang J, Yue C, Wang F, Song J, Wang J, Liu M, Luo J, Li L. Elevated serum concentrations of HE4 as a novel biomarker of disease severity and renal fibrosis in kidney disease. Oncotarget 2018; 7:67748-67759. [PMID: 27589683 PMCID: PMC5356516 DOI: 10.18632/oncotarget.11682] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/26/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Human epididymis protein 4 (HE4), has recently been reported as a mediator of renal fibrosis. However, serum HE4 levels appear in a large number of patient samples with chronic kidney disease (CKD), and the relationship of these levels to disease severity and renal fibrosis is unknown. METHODS In 427 patients at different stages of CKD excluding gynecologic cancer and 173 healthy subjects, serum HE4 concentrations were tested by chemiluminescent microparticle immunoassay. Renal biopsy was performed on 259 of 427 subjects. Histological findings were evaluated using standard immunohistochemistry. RESULTS The levels of serum HE4 were higher in CKD patients than in healthy subjects, and higher levels were associated with more severe CKD stages. Patients with more severe renal fibrosis tended to have higher HE4 levels, and correlation analysis showed a significant correlation between HE4 and degree of renal fibrosis (r = 0.938, P < 0.0001). HE4 can be a predictor of renal fibrosis in CKD patients; the area under the receiver-operating characteristic curve (AUC-ROC) was 0.99, higher than the AUC-ROC of serum creatinine (0.89). CONCLUSION Elevated levels of serum HE4 are associated with decreased kidney function, and also with an advanced stage of renal fibrosis, suggesting that HE4 may serve as a valuable clinical biomarker for renal fibrosis of CKD.
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Affiliation(s)
- Jianxin Wan
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yanhong Wang
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Gaorong Cai
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jianbo Liang
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Caifeng Yue
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Fen Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Junli Song
- Reproductive Medicine Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jianfeng Wang
- Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, People's Republic of China
| | - Min Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jinmei Luo
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Laisheng Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
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26
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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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27
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Isaksson S, Jönsson P, Monsef N, Brunnström H, Bendahl PO, Jönsson M, Staaf J, Planck M. CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma. PLoS One 2017; 12:e0186284. [PMID: 29049328 PMCID: PMC5648153 DOI: 10.1371/journal.pone.0186284] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 09/28/2017] [Indexed: 12/25/2022] Open
Abstract
Objectives Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC), recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease. Material and methods Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE), Cancer antigen 125 (CA 125), Human epididymis protein 4 (HE4) and Carbohydrate antigen (CA 19–9) were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37%) patients were diagnosed with recurrent disease. Results Sixty-eight (64%) patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS), CA 125 and/or CA 19–9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4–5.7, p = 0.006). Conclusion High pre-operative serum CA 19–9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas.
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Affiliation(s)
- Sofi Isaksson
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- * E-mail:
| | - Per Jönsson
- Department of Thoracic Surgery, Lund University, Skåne University Hospital, Lund, Sweden
| | - Nastaran Monsef
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Hans Brunnström
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Pär-Ola Bendahl
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Mats Jönsson
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Johan Staaf
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Maria Planck
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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28
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Small DM, Doherty DF, Dougan CM, Weldon S, Taggart CC. The role of whey acidic protein four-disulfide-core proteins in respiratory health and disease. Biol Chem 2017; 398:425-440. [PMID: 27930359 DOI: 10.1515/hsz-2016-0262] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 10/13/2016] [Indexed: 11/15/2022]
Abstract
Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including anti-protease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics. Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.
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Baldauf MC, Orth MF, Dallmayer M, Marchetto A, Gerke JS, Rubio RA, Kiran MM, Musa J, Knott MML, Ohmura S, Li J, Akpolat N, Akatli AN, Özen Ö, Dirksen U, Hartmann W, de Alava E, Baumhoer D, Sannino G, Kirchner T, Grünewald TGP. Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets. Oncotarget 2017; 9:1587-1601. [PMID: 29416716 PMCID: PMC5788584 DOI: 10.18632/oncotarget.20098] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/23/2017] [Indexed: 12/26/2022] Open
Abstract
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1-NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Their high expression was validated by immunohistochemistry and proved to depend on EWSR1-FLI1-binding to highly active proximal super-enhancers. Automated cut-off-finding and combination-testing in a tissue-microarray comprising 174 samples demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined strong BCL11B- and GLG1-immunoreactivity. Collectively, we show that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple, and cost-efficient way to diagnose Ewing sarcoma by immunohistochemistry. These markers may significantly reduce the number of misdiagnosed patients, and thus improve patient care.
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Affiliation(s)
- Michaela C Baldauf
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Martin F Orth
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Marlene Dallmayer
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Aruna Marchetto
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Julia S Gerke
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Rebeca Alba Rubio
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Merve M Kiran
- Department of Pathology, Medical Faculty, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Julian Musa
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Maximilian M L Knott
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Shunya Ohmura
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Jing Li
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Nusret Akpolat
- Department of Pathology, Turgut Ozal Medical Center, Inonu University, Malatya, Turkey
| | - Ayse N Akatli
- Department of Pathology, Turgut Ozal Medical Center, Inonu University, Malatya, Turkey
| | - Özlem Özen
- Department of Pathology, Başkent University Hospital, Ankara, Turkey
| | - Uta Dirksen
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute for Pathology, University Hospital Münster, Westfalian Wilhelms University, Münster, Germany
| | - Enrique de Alava
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERONC, Seville, Spain
| | - Daniel Baumhoer
- Bone Tumour Reference Center, Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Giuseppina Sannino
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thomas Kirchner
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas G P Grünewald
- Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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Kemal YN, Demirag GN, Bedir AM, Tomak L, Derebey M, Erdem DL, Gör U, Yücel I. Serum human epididymis protein 4 levels in colorectal cancer patients. Mol Clin Oncol 2017; 7:481-485. [PMID: 28894584 DOI: 10.3892/mco.2017.1332] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 07/04/2017] [Indexed: 01/12/2023] Open
Abstract
Tumour markers are widely used for the diagnosis, staging and monitoring of colorectal cancer (CRC) patients in clinical practice. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most frequently used biomarkers in CRC patients. A number of studies have recently investigated the presence of human epididymis protein 4 (HE4) overexpression in certain cancer types. Its significance in ovarian and endometrial cancer has been well-demonstrated. The aim of the present study was to evaluate the significance of serum HE4 levels in CRC patients. A total of 46 newly diagnosed CRC patients and 36 age- and gender-matched healthy subjects were included in the study. The concentrations of CEA and CA19-9 were also determined and compared according to HE4 levels. HE4 positivity was determined in 13 of the 46 cases (28.3%) in the CRC group, but no HE4-positive subjects were identified in the control group (0%; P=0.009). The area under the receiver operating characteristic curve for HE4 positivity was 0.641 (95% CI: 0.523-0.760). HE4 was statistically significantly positive in patients with stage III-IV disease and in those with high CA 19-9 levels (all P<0.01). To the best of our knowledge, this is the first study to investigate HE4 expression in CRC patients, and the findings suggest that it may be a useful biomarker, particularly in stage III-IV patients.
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Affiliation(s)
- Yasemi N Kemal
- Department of Medical Oncology, Samsun Training and Research Hospital, Samsun 55100, Turkey
| | - Guzi N Demirag
- Department of Medical Oncology, Faculty of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
| | - Abdulkeri M Bedir
- Department of Biochemistry, Faculty of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
| | - Leman Tomak
- Department of Biostatistics, Faculty of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
| | - Murat Derebey
- Department of General Surgery, Faculty of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
| | - Di Lek Erdem
- Department of Medical Oncology, Medical Park Samsun Hospital, Samsun 55200, Turkey
| | - Ufuk Gör
- Department of Biochemistry, Faculty Of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
| | - Idris Yücel
- Department of Medical Oncology, Faculty Of Medicine, Ondokuz Mayis University, Samsun 55270, Turkey
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Zhong H, Qian Y, Fang S, Yang L, Li L, Gu W. HE4 expression in lung cancer, a meta-analysis. Clin Chim Acta 2017; 470:109-114. [PMID: 28499820 DOI: 10.1016/j.cca.2017.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 05/04/2017] [Accepted: 05/06/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND The prognostic role of Human epididymis protein 4 (HE4) expression in lung cancer remains controversial. We performed this meta-analysis to assess the prognostic value of HE4 expression in lung cancer. METHODS A systematic literature search was conducted to identify eligible studies in PubMed, Embase and Wanfang databases. The pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to assess the relationship. RESULTS A total of 1412 patients from 8 studies were included in this meta-analysis. The results of univariate analysis (HR=1.73, 95% CI: 1.19-2.52, P=0.004) and multivariate analysis (HR=2.49, 95% CI: 1.89-3.28, P<0.001) demonstrated that high HE4 expression in lung cancer patients was correlated with poor overall survival (OS). We observed through further stratified analysis of the results of the univariate analysis that high HE4 expression was associated with worse OS in Asian lung cancer patients (HR=2.48, 95% CI: 1.88-3.26, P<0.001). However, there was no significant association between high HE4 expression and poor OS in Caucasian patients (HR=1.12, 95% CI: 0.80-1.55, P=0.513). CONCLUSION High serum HE4 level was a marker of poor prognosis in lung cancer patients, particularly in Asian patients with lung cancer.
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Affiliation(s)
- Hai Zhong
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Yingying Qian
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Surong Fang
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Linfei Yang
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Lingzhi Li
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Wei Gu
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China.
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Yılmaz SA, Altınkaya SÖ, Kerimoglu ÖS, Tazegül Pekin A, Akyürek F, Ilhan TT, Benzer N, Unlu A, Yuksel H, Celik C. The role of human epididymis secretory protein E4 in patients with endometrial cancer and premalignant endometrial lesions. J OBSTET GYNAECOL 2016; 37:58-63. [PMID: 28006994 DOI: 10.3109/01443615.2016.1174199] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We evaluated the concentrations of human epididymis secretory protein E4 (HE4) and Ca-125 in relation to clinicopathologic features in patients with endometrial cancer and premalignant endometrial lesions. Women with abnormal uterine bleeding (n = 167) who underwent endometrial sampling were divided into four groups. Group 1: endometrial cancer (n = 68), group 2: atypical endometrial hyperplasia (n = 12), group 3: endometrial hyperplasia without atypia (n = 39) and group 4: controls (n = 48). Women with endometrial cancer exhibited higher concentrations of HE4 levels than controls (91.4 pmol/L vs. 46.2 pmol/L, p < 0.001). HE4 levels were significantly higher in patients with lymphatic involvement, deep myometrial invasion, lymphovascular space involvement and non-endometrioid histology (p < 0.001). The sensitivity, specificity, positive and negative predictive values for HE4 in detecting endometrial cancer were 72.7%, 84.4%, 80% and 78.4%, respectively. Preoperative HE4 levels are more elevated in women with endometrial cancer than those with benign endometrium as well as in women with prognostic high-risk factors with endometrial cancer. HE4 may be used as an additional marker in combination with other clinicopathologic features for planning the treatment.
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Affiliation(s)
- Setenay Arzu Yılmaz
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Sündüz Özlem Altınkaya
- b Department of Gynecology & Obstetrics , Faculty of Adnan Menderes University , Aydın , Turkey
| | - Özlem Seçilmiş Kerimoglu
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Aybike Tazegül Pekin
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Fikret Akyürek
- c Department of Biochemistry , Faculty of Selçuk University , Konya , Turkey
| | - Tolgay Tuyan Ilhan
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Nilgün Benzer
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Ali Unlu
- c Department of Biochemistry , Faculty of Selçuk University , Konya , Turkey
| | - Hasan Yuksel
- b Department of Gynecology & Obstetrics , Faculty of Adnan Menderes University , Aydın , Turkey
| | - Cetin Celik
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
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Qu W, Li J, Duan P, Tang Z, Guo F, Chen H, Zhu X, Jiang SW. Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies. Expert Rev Mol Diagn 2016; 16:1271-1282. [PMID: 27784171 DOI: 10.1080/14737159.2016.1251317] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Serum epididymis protein 4 (HE4) represents a useful biomarker for the management of ovarian cancer and endometrial cancer patients. However, HE4 levels are affected by many physiopathological conditions or disorders that should be taken into consideration for an efficient application of this biomarker. Areas covered: The review provides an up-to-date reference on the multiple physiopathological factors that cause fluctuation of HE4 serum levels, and evaluates their impact on HE4-test in clinical settings. Potential mechanisms underlying the regulation of HE4 expression are also discussed. The review is based on data from literature search of PubMed and the author's opinions. Expert commentary: Studies have shown that physiopathological factors such as age, infection/inflammation, renal function, menopause and hormonal levels impose significant impacts on HE4 serum levels. HE4 amount shed into the circulation is related to HE4 expression and secretion by tumor as well as normal tissues, which is affected by cancer heterogeneity, vascular permeability, renal clearance and HE4 degradation. Investigation on interfering factors builds a basis for the construction of a quantitative logarithm for individualized application of HE4-test in clinical settings.
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Affiliation(s)
- Wanglei Qu
- a Department of Obstetrics and Gynecology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Jinping Li
- b Department of Biomedical Science , Mercer University School of Medicine , Savannah , GA , USA
| | - Ping Duan
- a Department of Obstetrics and Gynecology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Zuoqing Tang
- c Department of Medical Genetics, School of Basic Medical Sciences , Capital Medical University , Beijing , China
| | - Fengbiao Guo
- b Department of Biomedical Science , Mercer University School of Medicine , Savannah , GA , USA
- d Department of Histology and Embryology , Shantou University Medical College , Shantou , Guangdong , China
| | - Haibin Chen
- d Department of Histology and Embryology , Shantou University Medical College , Shantou , Guangdong , China
| | - Xueqiong Zhu
- a Department of Obstetrics and Gynecology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Shi-Wen Jiang
- a Department of Obstetrics and Gynecology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
- b Department of Biomedical Science , Mercer University School of Medicine , Savannah , GA , USA
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Weissensteiner J, Babušíková E. Bone Metabolism of the Patient with a Malignant Melanoma during the Entry Examination and the Check-up of Whole-body Bone Scintigraphy. Prague Med Rep 2016; 117:129-134. [PMID: 27668530 DOI: 10.14712/23362936.2016.14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Malignant melanoma is a malignancy located predominantly in the skin and the incidence of melanoma increases. We compared the markers of bone metabolism - osteocalcin (OC), beta-carboxyterminal cross-linked telopeptide of type I collagen (β-CrossLaps, β-CTx) and tumour marker - human epididymis protein 4 (HE4) in the serum with finding during the entry examination and the check-up of whole-body bone scintigraphy of the patient with a malignant melanoma. Serum concentrations of OC, β-CTx, HE4 were determined in 1 patient (female, age 64 years) with malignant melanoma and correlated with the presence of equivocal bone metastases detected by whole-body bone scintigraphy (the entry examination and check-up after 6 months). Concentrations of bone metabolism markers decreased during six months and we observed progress in bone metastases. The change of the markers levels during the entry examination and the check-up of the whole-body bone scintigraphy with equivocal finding of bone metastases could be a sign of a possible initiating progression of malignant melanoma despite a clinically negative finding that does not prove the progression of the disease.
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Affiliation(s)
| | - Eva Babušíková
- Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
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35
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Nagy B, Nagy B, Fila L, Clarke LA, Gönczy F, Bede O, Nagy D, Újhelyi R, Szabó Á, Anghelyi A, Major M, Bene Z, Fejes Z, Antal-Szalmás P, Bhattoa HP, Balla G, Kappelmayer J, Amaral MD, Macek M, Balogh I. Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis. Chest 2016; 150:661-72. [PMID: 27105680 DOI: 10.1016/j.chest.2016.04.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 04/04/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Increased expression of the human epididymis protein 4 (HE4) was previously described in lung biopsy samples from patients with cystic fibrosis (CF). It remains unknown, however, whether serum HE4 concentrations are elevated in CF. METHODS Seventy-seven children with CF from six Hungarian CF centers and 57 adult patients with CF from a Czech center were enrolled. In addition, 94 individuals with non-CF lung diseases and 117 normal control subjects with no pulmonary disorders were analyzed. Serum HE4 levels were measured by using an immunoassay, and their expression was further investigated via the quantification of HE4 messenger RNA by using quantitative reverse transcription polymerase chain reaction in CF vs non-CF respiratory epithelium biopsy specimens. The expression of the potential regulator miR-140-5p was analyzed by using an UPL-based quantitative reverse transcription polymerase chain reaction assay. HE4 was measured in the supernatants from unpolarized and polarized cystic fibrosis bronchial epithelial cells expressing wild-type or F508del-CFTR. RESULTS Median serum HE4 levels were significantly elevated in children with CF (99.5 [73.1-128.9] pmol/L) compared with control subjects (36.3 [31.1-43.4] pmol/L; P < .0001). This observation was replicated in adults with CF (115.7 [77.8-148.7] pmol/L; P < .0001). In contrast, abnormal but lower HE4 concentrations were found in cases of severe bronchitis, asthma, pneumonia, and bronchiectasis. In patients with CF, the concentrations of HE4 were positively correlated with overall disease severity and C-reactive protein concentrations, whereas a significant inverse relationship was found between HE4 and the spirometric FEV1 value. Relative HE4 mRNA levels were significantly upregulated (P = .011) with a decreased miR-140-5p expression (P = .020) in the CF vs non-CF airway biopsy specimens. Twofold higher HE4 concentrations were recorded in the supernatant of polarized F508del-CF transmembrane conductance regulator/bronchial epithelial cells compared with wild-type cells. CONCLUSIONS HE4 serum levels positively correlate with the overall severity of CF and the degree of pulmonary dysfunction. HE4 may thus be used as a novel inflammatory biomarker and possibly also as a measure of treatment efficacy in CF lung disease.
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Affiliation(s)
- Béla Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| | - Béla Nagy
- Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Libor Fila
- Department of Pulmonology, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic
| | - Luka A Clarke
- University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Lisboa, Portugal
| | | | - Olga Bede
- Department of Pediatrics, Szent-Györgyi Albert Medical University, Szeged, Hungary
| | - Dóra Nagy
- Department of Pediatrics, Szent-Györgyi Albert Medical University, Szeged, Hungary
| | | | - Ágnes Szabó
- Department of Pediatrics, Szent-Györgyi Albert Medical University, Szeged, Hungary
| | | | - Miklós Major
- Markusovszky Lajos County Hospital, Szombathely, Hungary
| | - Zsolt Bene
- Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsolt Fejes
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Antal-Szalmás
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Harjit Pal Bhattoa
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Balla
- Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - János Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Margarida D Amaral
- University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Lisboa, Portugal
| | - Milan Macek
- Department of Biology and Medical Genetics, Motol University Hospital, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
| | - István Balogh
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Division of Clinical Genetics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Zeng Q, Liu M, Zhou N, Liu L, Song X. Serum human epididymis protein 4 (HE4) may be a better tumor marker in early lung cancer. Clin Chim Acta 2016; 455:102-6. [PMID: 26851650 DOI: 10.1016/j.cca.2016.02.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 02/02/2016] [Accepted: 02/02/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND Human epididymis protein 4 (HE4) had been shown to be an ideal biomarker in ovarian cancer. However, there were fewer reports on its application in lung cancer. We explored the diagnostic value of serum HE4 as a biomarker in early lung cancer by comparing it with other biomarkers. METHODS 162 individuals including 112 cases of lung cancer at early stage and 50 healthy people as controls were enrolled. The serum concentrations of biomarkers were determined with the Roche Elecsys assays. RESULTS In comparison to the other biomarkers such as carcinoembryonic antigen (CEA), neuron-specific-enolase (NSE), serum cytokeratin 19 fragment (CYFRA 21-1) and progastrinreleasing peptide (proGRP), serum HE4 was one of the biomarkers with the highest sensitivity (43.8%) and specificity (95.0%) for early lung cancer diagnosis. In terms of histological results, serum HE4 was the best biomarker both in adenocarcinoma (AC) and squamous carcinoma (SC), and serum proGRP was the best in small cell lung cancer (SCLC). The combination of proGRP, NSE and HE4 could determine the histological type of lung cancer with a very high accuracy of 93.8%. CONCLUSIONS These findings suggested that serum HE4 was a better biomarker in early lung cancer than other frequently-used biomarkers.
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Affiliation(s)
- Qian Zeng
- Clinical laboratory of Shandong Cancer Hospital & Institute, PR China; School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medicine Science, PR China
| | - Meiqin Liu
- Clinical laboratory of Shandong Cancer Hospital & Institute, PR China
| | - Na Zhou
- Clinical laboratory of Shandong Cancer Hospital & Institute, PR China; School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medicine Science, PR China
| | - Lisheng Liu
- Clinical laboratory of Shandong Cancer Hospital & Institute, PR China
| | - Xianrang Song
- Clinical laboratory of Shandong Cancer Hospital & Institute, PR China.
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Nagy B, Bhattoa HP, Steiber Z, Csobán M, Szilasi M, Méhes G, Müller M, Lázár J, Kappelmayer J, Antal-Szalmás P. Serum human epididymis protein 4 (HE4) as a tumor marker in men with lung cancer. Clin Chem Lab Med 2015; 52:1639-48. [PMID: 24829194 DOI: 10.1515/cclm-2014-0041] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Accepted: 04/09/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND Human epididymis protein 4 (HE4) is a reliable tumor marker for ovarian cancer, but only limited data are available on HE4 levels in lung malignancies. METHODS HE4 levels were measured at diagnosis in 98 men with lung cancer at different stages of the disease, and these results were compared to an age-matched healthy male cohort (n=98). The concentrations of classical tumor markers were also determined, and their efficacy was compared to that of HE4. RESULTS Compared to healthy controls, patients with lung neoplasm showed significantly higher HE4 levels [118.2 (80.6-150.1) pmol/L vs. 62.2 (47.2-76.1) pmol/L; p<0.001]. Although age and smoking modulated HE4 levels in the healthy cohort, no such effect was observed in the patient population. The area under the receiver operating characteristic curve (ROC-AUC) for HE4 was 0.848 (95% CI 0.792-0.904) for differentiating lung cancer patients from healthy controls, with a cut-off value of 97.6 pmol/L (sensitivity: 64.3%, specificity: 95.9%). HE4 levels were significantly elevated in all stages of lung cancer, and even in patients without clinical symptoms (p<0.05), but no difference was found between the different histological subgroups. A significant correlation was found between HE4 values and the tumor size determined by CT/MRI (Spearman's ρ=0.227, p=0.030). The combination of HE4 with CEA and CA 125 considerably enhanced the diagnostic efficacy [ROC-AUC: 0.963 (95% CI 0.937-0.990), sensitivity: 91.8%, specificity: 92.8%]. CONCLUSIONS Our data suggest that serum HE4, especially in combination with CEA and CA 125, qualifies as a surrogate diagnostic marker in men with lung cancer.
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Lamy PJ, Plassot C, Pujol JL. Serum HE4: An Independent Prognostic Factor in Non-Small Cell Lung Cancer. PLoS One 2015; 10:e0128836. [PMID: 26030627 PMCID: PMC4452338 DOI: 10.1371/journal.pone.0128836] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 04/30/2015] [Indexed: 11/29/2022] Open
Abstract
Human epididymis secretory protein 4 (HE4) is a secreted glycosylated protein encoded by the WAP four-disulfide core domain 2 (WFDC2) gene, located on a chromosome 20 segment that is frequently amplified in many cancers. This study aimed at determining serum HE4 prognostic value in non-small cell lung cancer (NSCLC), following the REMARK guidelines. Serum samples from 346 consecutive patients with histologically proven and previously untreated NSCLC and 41 patients with benign pulmonary disease were collected at the Montpellier-Nimes Academic Hospital. Work-up investigations performed to determine the disease characteristics and treatment algorithms were congruent with international guidelines. HE4 levels in serum were measured with an ELISA test (Fujirebio Diagnostics) that uses two monoclonal antibodies, 2H5 and 3D8, against the C-WFDC domain of HE4. The area under the ROC curve (i.e., overall ability of HE4 to discriminate between controls and patients) was 0.78 (95% confidence interval [CI], 0.738–0.821; z test P <0.0001). Serum HE4 levels were significantly higher in patients with worse performance status, advanced TNM stage and positive nodal status. In the Cox model, overall survival was shorter in patients with high pretreatment serum HE4 (above 140 pmol/L) than in patients with serum H4 level ≤ 140 pmol/L [median survival: 17.7 weeks (95% CI, 11.9 to 24.9) and 46.4 weeks (95% CI, 38.6 to 56.3), respectively; hazard ratio: 1.48 (95% CI, 1.12 to 1.95) for high HE4; adjusted P = 0.0057]. High serum HE4 level at diagnosis is an independent determinant of poor prognosis in NSCLC.
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Affiliation(s)
- Pierre-Jean Lamy
- Department of Biology and Oncogenetics, Montpellier Cancer Institute, Montpellier, France
- ICM-Biobank, Regional Cancer Center, Montpellier, France
- * E-mail:
| | - Carine Plassot
- Department of Statistics and Epidemiology, Institute for Clinical Research, University Montpellier I, Montpellier, France
| | - Jean-Louis Pujol
- Thoracic Oncology Unit, Hospital University Center of Montpellier, Montpellier France
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Ma Q, Wang Q, Zhong D. [Advances of human epididymis protein 4 in lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 18:184-6. [PMID: 25800577 PMCID: PMC6000003 DOI: 10.3779/j.issn.1009-3419.2015.03.10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
人附睾蛋白4（human epididymis 4, HE4）属于乳清酸性4-二硫化中心（WFDC）蛋白家族，具有胰蛋白酶抑制剂的特性。在肺癌患者血清中及恶性胸腔积患者胸水中呈高表达，现有临床数据显示它与肺癌的诊断及预后有一定的相关性，因此可能成为临床上肺癌的诊断及预后评估的新指标。
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Affiliation(s)
- Qing Ma
- Department of Medical Oncology, The General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Qian Wang
- Department of Medical Oncology, The General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Diansheng Zhong
- Department of Medical Oncology, The General Hospital of Tianjin Medical University, Tianjin 300052, China
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40
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The diagnostic accuracy of HE4 in lung cancer: a meta-analysis. DISEASE MARKERS 2015; 2015:352670. [PMID: 25873748 PMCID: PMC4383439 DOI: 10.1155/2015/352670] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 02/20/2015] [Indexed: 12/17/2022]
Abstract
The diagnostic value of serum HE4 in patients with lung cancer remains controversial. Thus, we performed a systematic review and meta-analysis to assess the diagnostic accuracy of serum HE4 for lung cancer. We conducted a comprehensive literature search in PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and WANFANG databases between Jan. 1966 and Nov. 2014. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic curve (SROC) were pooled by Meta-DiSc 1.4 software. A total of seven articles including 715 cases and 549 controls were included for analysis. The summary estimates for serum HE4 in the diagnosis of lung cancer in these studies were pooled SEN 0.72 (95% CI: 0.68-0.75), SPE 0.85 (95% CI: 0.81-0.88), PLR 4.68 (95% CI: 3.23-6.78), NLR 0.31 (95% CI: 0.24-0.39), and DOR 17.14 (95% CI: 9.72-30.20), and the area under the curve (AUC) was 0.8557. This meta-analysis indicated that serum HE4 is a potential tool in the diagnosis of lung cancer. In addition, considering the high heterogeneity and potential publication bias, further studies with rigorous design and large sample size are needed in the future.
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Guo YD, Wang JH, Lu H, Li XN, Song WW, Zhang XD, Zhang WM. The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer. Tumour Biol 2014; 36:2457-64. [PMID: 25432133 PMCID: PMC4428537 DOI: 10.1007/s13277-014-2858-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 11/13/2014] [Indexed: 12/13/2022] Open
Abstract
Human epididymis protein 4 (HE4), represented as an epididymis-specific gene and designated a WAP four-disulfide core domain protein 2 (WFDC2), is amplified in many tumors. However, little is known about its clinical significance and biological function in gastric carcinomas. We found that HE4 was more commonly observed in gastric carcinoma tissues than in normal tissues and was significantly correlated with Lauren classification, TNM stage, and tumor size by immunohistochemistry. The overall survival rate of patients with HE4 low expression was significantly higher than that of the patients with HE4 high expression. In addition, silencing of HE4 expression inhibits cell proliferation and migration and enhances cell apoptosis. Subsequent studies reveal that the Src, Akt, and Erk1/2 signaling may be involved with pro-survival and anti-apoptotic effects of the HE4 on gastric cancer cells. Taken together, this study provides new evidence on promotive effects of the HE4 on gastric cancer progression and indicates that HE4 might be a promising prognostic factor for gastric cancer diagnosis.
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Affiliation(s)
- Yun-Di Guo
- Suzhou Health College, Suzhou, 215009 China
| | - Jing-Hao Wang
- Department of Obstetrics and Gynecology, Fengxian Hospital, Southern Medical University, 201499 Shanghai, China
| | - Huan Lu
- Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, 201400 China
| | | | - Wei-Wei Song
- Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, 201400 China
| | - Xiao-Dan Zhang
- Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, 201400 China
| | - Wen-Ming Zhang
- Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
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Wang H, Zhu L, Gao J, Hu Z, Lin B. Promotive role of recombinant HE4 protein in proliferation and carboplatin resistance in ovarian cancer cells. Oncol Rep 2014; 33:403-12. [PMID: 25354091 DOI: 10.3892/or.2014.3549] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 09/18/2014] [Indexed: 11/06/2022] Open
Abstract
Available evidence on the proliferation-promoting effect of HE4 remains controversial, and few studies have been carried out on the molecular mechanism of chemoresistance mediated by HE4. The aim of the present study was to investigate the influence of exogenous recombinant HE4 protein on proliferation and resistance to carboplatin in ovarian cancer cells. The human ovarian cancer cell line (SKOV-3) was exposed to recombinant HE4 protein (0-1 µg/ml) for different durations based on the schemes. Cell viability was evaluated by Cell Counting Kit-8 and colony formation assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Markers of apoptosis (Bax and Bcl-2) were assessed by western blotting. Furthermore, Affymetrix microarray analysis was performed to investigate transcriptome profiling. The differential expression of four genes was verified by quantitative real-time PCR. The HE4 protein enhanced cell viability, promoted accumulation of cells in the G2/M phase and attenuated carboplatin-induced apoptosis. HE4 markedly decreased the Bax/Bcl-2 ratio. Candidate genes (387) (236 upregulated and 151 downregulated) were obtained by microarray analysis. Among those upregulated, several Gene Ontology (GO) terms related to cell cycle regulation and proliferation were significantly overrepresented and those within the downregulated dataset included genes involved in several aspects of the DNA damage response such as positive regulation of apoptosis. No information concerning the EGFR-MAPK pathways in a recent report on HE4 was acquired. The mRNA expression of the candidate genes determined by quantitative real-time PCR was significantly correlated with the microarray data. The present study indicates that the HE4 protein plays a promotive role in the proliferation and resistance to carboplatin in ovarian cancer cells, implicating the value of HE4 to predict tumor growth potential and resistance to platinum-based chemotherapy in epithelial ovarian cancer (EOC).
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Affiliation(s)
- Huan Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
| | - Liancheng Zhu
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
| | - Jian Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
| | - Zhenhua Hu
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
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Kaijser J, Van Belle V, Van Gorp T, Sayasneh A, Vergote I, Bourne T, Van Calster B, Timmerman D. Prognostic value of serum HE4 levels and risk of ovarian malignancy algorithm scores at the time of ovarian cancer diagnosis. Int J Gynecol Cancer 2014; 24:1173-80. [PMID: 24987915 DOI: 10.1097/igc.0000000000000181] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVES The aim of this study is to assess whether the pretreatment serum HE4 levels or the Risk of Ovarian Malignancy Algorithm (ROMA) scores at the time of initial diagnosis are associated with progression-free survival (PFS) and disease-specific survival (DSS) in patients with ovarian cancer receiving either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. METHODS A survival analysis of 101 cases of invasive ovarian cancer recruited in a previous diagnostic accuracy study was conducted from 2005 to 2009 at the University Hospital KU Leuven, Belgium. Serum HE4 levels (pM) and ROMA scores (%) were obtained before primary treatment. Dates of death were obtained by record linkage with patient hospital files. Progression was evaluated according to the Response Evaluation Criteria in Solid Tumors. Adjusted hazards ratios (HRs) were estimated using multivariable Cox regression. RESULTS Eighty patients (79%) with invasive ovarian cancer underwent primary debulking surgery, whereas 21 (21%) received neoadjuvant chemotherapy. The median DSS was 3.72 years (95% confidence interval [CI], 3.19-4.07). Fifty-two patients (51%) died of disease, and 74 patients (73%) had progressive disease during follow-up. On univariable analysis, elevated pretreatment HE4 levels and ROMA scores were related to worse prognosis. However, after the adjustment for classic prognostic variables, HE4 levels (log2-transformed) and ROMA scores were unrelated to DSS (log-2 HE4: adjusted HR, 1.01; 95% CI, 0.84-1.21 and ROMA: adjusted HR per 10% increase, 0.96; 95% CI, 0.84-1.12) and PFS (log-2 HE4: adjusted HR, 0.98; 95% CI, 0.84-1.13 and ROMA: adjusted HR per 10% increase, 0.98; 95% CI, 0.88-1.11). CONCLUSIONS Pretreatment HE4 levels and ROMA scores are not independent prognostic factors for DSS and PFS after multivariable adjustment in patients with ovarian cancer.
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Affiliation(s)
- Jeroen Kaijser
- Departments of *Department of Development and Regeneration, KU Leuven, Leuven, Belgium; †Department of Obstetrics and Gynecology, and ‡Leuven Cancer Institute, University Hospital KU Leuven, Leuven, Belgium; §Department of Electrical Engineering (ESAT) and ∥iMinds Future Health Department, KU Leuven, Leuven, Belgium; ¶Department of Obstetrics and Gynecology, Maastricht UMC+, #GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; and **Department of Surgery and Cancer, Queen Charlotte's & Chelsea Hospital, Imperial College, London, United Kingdom
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Karlsen NS, Karlsen MA, Høgdall CK, Høgdall EVS. HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer Epidemiol Biomarkers Prev 2014; 23:2285-95. [PMID: 25169975 DOI: 10.1158/1055-9965.epi-14-0447] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Human epididymis protein 4 (HE4) has received major attention as a potential tumor marker in epithelial ovarian cancer; however, evidence of significant overexpression of HE4 in several other human cancers is expanding. To assess the possible limitations or benefits of HE4 in a clinical setting, this review aims to systematically outline published results of HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors. Our findings suggest scientific basis for a potential diagnostic ability of HE4 in gynecologic cancer and lung cancer, and further research is needed regarding other cancers. Yet, it is important to recognize that other malignancies can cause increased HE4 levels. Furthermore, attention should be paid to the influence of age and renal function on HE4 serum levels in future studies as well as in the clinic for proper interpretation of serum HE4 test results. Cancer Epidemiol Biomarkers Prev; 23(11); 2285-95. ©2014 AACR.
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Affiliation(s)
- Nikoline S Karlsen
- Molecular Unit, Department of Pathology, Herlev University Hospital, Herlev, Denmark
| | - Mona A Karlsen
- Molecular Unit, Department of Pathology, Herlev University Hospital, Herlev, Denmark. Gynecologic Department, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus K Høgdall
- Gynecologic Department, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Estrid V S Høgdall
- Molecular Unit, Department of Pathology, Herlev University Hospital, Herlev, Denmark.
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Kappelmayer J, Antal-Szalmás P, Nagy B. Human epididymis protein 4 (HE4) in laboratory medicine and an algorithm in renal disorders. Clin Chim Acta 2014; 438:35-42. [PMID: 25127713 DOI: 10.1016/j.cca.2014.07.040] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 07/28/2014] [Accepted: 07/29/2014] [Indexed: 01/20/2023]
Abstract
Over the past three decades, cancer antigen (CA) 125 has been utilized for monitoring women who were treated for ovarian cancer. However, this tumor marker showed several limitations such as false elevation in benign pelvic diseases and, in turn, no alterations in ovarian tumors at early stages with a relatively high ratio. For more than ten years, the human epididymis protein 4 (HE4) has become available for the routine laboratory repertoire, showing a higher sensitivity and specificity compared to that of CA125 in ovarian malignancies, but also in other types of tumors based on recently accumulated clinical data. Despite its remarkable diagnostic characteristics, in certain cases, the evaluation of HE4 results may be problematic when patients suffer from additional conditions that may alter HE4 level. Besides the direct effects of age and smoking, menopause status and decreased renal function also show a substantial impact on HE4 values, which should be considered in each patient. For this purpose, we attempted to create a new formula and an algorithm that may be helpful to predict the probability of the presence of ovarian tumor by using the concentrations of HE4 and CA125.
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Affiliation(s)
- János Kappelmayer
- Department of Laboratory Medicine, University of Debrecen, Debrecen, Hungary.
| | - Péter Antal-Szalmás
- Department of Laboratory Medicine, University of Debrecen, Debrecen, Hungary
| | - Béla Nagy
- Department of Laboratory Medicine, University of Debrecen, Debrecen, Hungary
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Ucar EY, Ozkaya AL, Araz O, Akgun M, Meral M, Kaynar H, Saglam L, Aksoy H, Akcay F. Serum and bronchial aspiration fluid HE-4 levels in lung cancer. Tumour Biol 2014; 35:8795-9. [PMID: 24879624 DOI: 10.1007/s13277-014-2134-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/21/2014] [Indexed: 12/21/2022] Open
Abstract
Human epididymis 4 (HE-4) protein has been proposed as a tumor marker for lung and ovarian cancer. This study was designed to measure HE-4 levels in bronchial aspiration fluid (BAF) of patients with lung cancer and to describe the relationship of BAF HE-4 with known systemic increase in serum HE-4 levels. Sixty-four patients with lung cancer, 38 with benign lung disease and 19 healthy subjects, were enrolled in our study. The BAF was obtained during routine bronchoscopic procedure in patient groups. HE-4 levels in serum and BAF were measured with the commercially available kit by an enzyme-linked immunosorbent assay. Serum HE-4 levels were significantly higher in patients with lung cancer group (204.2 ± 22.9 pmol/L) than in benign lung disease group (135 ± 26.9 pmol/L, p = 0.001) and healthy subjects (14.8 ± 7.0 pmol/L, p < 0.0001). No significant difference was observed in terms of BAF HE-4 values in two patient groups. BAF HE-4 levels were significantly higher than those of serum levels in both patient groups (p < 0.0001). Serum HE-4 level was correlated with tumor stage (p = 0.001) and age (p < 0.0001) in the lung cancer group. The areas under the receiver operating characteristic (ROC) curve of serum HE-4 was 0.784 (95 % confidence interval (CI), 0.701-0.867) and that of BAF HE-4 was 0.496 (95 % CI, 0.382-0.610). This study shows that a systemic increase in serum of HE-4 is more prominent than a local increase of HE-4 (BAF), so this may suggest the feasibility of using serum instead of BAF samples for HE-4 measurements in lung cancer cases.
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Affiliation(s)
- Elif Yilmazel Ucar
- Department of Pulmonary Diseases, School of Medicine, Ataturk University, 25240, Erzurum, Turkey,
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Wang X, Fan Y, Wang J, Wang H, Liu W. Evaluating the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer. Tumour Biol 2014; 35:6847-53. [PMID: 25051914 DOI: 10.1007/s13277-014-1943-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 04/03/2014] [Indexed: 12/15/2022] Open
Abstract
We evaluated the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer (SCLC). Serum HE4 level was measured in serum samples from 30 healthy controls and 49 patients with SCLC using enzyme-linked immunosorbent assay. HE4 expression in tumor tissues was analyzed by immunohistochemical staining. The results show that serum HE4 level is significantly higher in SCLC patients than those in healthy controls, which is also the case in tumor tissues where strong intracytoplasmic staining is demonstrable. Using the optimal cutoff value of 84.19 pmol/l, serum HE4 level distinguishes SCLC patients from healthy controls with a sensitivity of 69.4 %, a specificity of 93.3 %, and the area under the receiver operating characteristic curve (AUC) of 0.85. Compared to other well-known tumor markers used in lung cancer diagnosis, HE4 shows the highest sensitivity (69.4 %, 34 of 49) and accuracy (78.5 %, 62 of 79) in diagnosing SCLC, and combinations with other tumor markers further increase the sensitivity and accuracy. These findings suggest that HE4 levels are greatly elevated in sera and tumor tissues of patients with SCLC and serum HE4 is a potential diagnostic marker for patients with SCLC.
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Affiliation(s)
- Ximing Wang
- Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, 710032, China
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Yue W, Zou H, Jin Q, Li CW, Xu T, Fu H, Tzang LC, Sun H, Zhao J, Yang M. Single layer linear array of microbeads for multiplexed analysis of DNA and proteins. Biosens Bioelectron 2014; 54:297-305. [DOI: 10.1016/j.bios.2013.10.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 10/16/2013] [Accepted: 10/21/2013] [Indexed: 10/26/2022]
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HE4 and its evolving role in assessing tumor prognosis in gynecological and systemic malignancies. Arch Gynecol Obstet 2013; 288:713. [DOI: 10.1007/s00404-013-2782-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 02/26/2013] [Indexed: 11/25/2022]
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Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma. Am J Obstet Gynecol 2013; 209:142.e1-6. [PMID: 23583212 DOI: 10.1016/j.ajog.2013.04.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 02/22/2013] [Accepted: 04/04/2013] [Indexed: 11/20/2022]
Abstract
OBJECTIVE The purpose of this study was to evaluate the performance of preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) in the prediction of the presence of metastases in endometrial carcinoma. STUDY DESIGN Preoperative sera were collected from 98 women with a diagnosis of endometrial carcinoma. The concentrations of HE4 and CA125 were assessed by enzyme-linked immunosorbent assay and correlated with the results of the final histopathologic report. RESULTS Fourteen patients had metastases (≥stage IIIA, International Federation of Gynecology and Obstetrics 2009 classification). The serum concentrations of HE4 and CA125 were higher in the group with metastases than in the group without metastases (median [interquartile range], 148.6 pmol/L [71.6-219.1 pmol/L] vs 77.2 pmol/L [52.9-99.3 pmol/L]; P = .001; and 20.0 U/mL [10.1-70.8 U/mL] vs 4.3 U/mL [2.9-10.4 U/mL]; P < .001, respectively). By a multivariate analysis, the combination of HE4 and CA125 (a risk score algorithm) was the only predictive factor for the presence of metastases (odds ratio, 21.562; 95% confidence interval, 5.472-84.963; P < .001), and the grade was the predictor for a deep (≥50%) myometrial invasion by the tumor (odds ratio, 2.005; 95% confidence interval, 1.123-3.581; P = .019). The sensitivity, specificity, positive predictive value, and negative predictive value for the combination of the markers to predict the presence of metastases were 71.4%, 89.5%, 55.6%, and 94.4%, respectively. CONCLUSION A combination of preoperative HE4 and CA125 seems to be a better predictor of metastatic disease than either 1 alone in endometrial carcinoma.
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