|
1
|
Sun HT. Helicobacter pylori-related serum indicators: Cutting-edge advances to enhance the efficacy of gastric cancer screening. World J Gastrointest Oncol 2025; 17:100739. [PMID: 40092953 PMCID: PMC11866254 DOI: 10.4251/wjgo.v17.i3.100739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/08/2024] [Accepted: 01/03/2025] [Indexed: 02/14/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection induces pathological changes via chronic inflammation and virulence factors, thereby increasing the risk of gastric cancer development. Compared with invasive examination methods, H. pylori-related serum indicators are cost-effective and valuable for the early detection of gastric cancer (GC); however, large-scale clinical validation and sufficient understanding of the specific molecular mechanisms involved are lacking. Therefore, a comprehensive review and analysis of recent advances in this field is necessary. In this review, we systematically analyze the relationship between H. pylori and GC and discuss the application of new molecular biomarkers in GC screening. We also summarize the screening potential and application of anti-H. pylori immunoglobulin G and virulence factor-related serum antibodies for identifying GC risk. These indicators provide early warning of infection and enhance screening accuracy. Additionally, we discuss the potential combination of multiple screening indicators for the comprehensive analysis and development of emerging testing methods to improve the accuracy and efficiency of GC screening. Although this review may lack sufficient evidence due to limitations in existing studies, including small sample sizes, regional variations, and inconsistent testing methods, it contributes to advancing personalized precision medicine in high-risk populations and developing GC screening strategies.
Collapse
Affiliation(s)
- Hao-Tian Sun
- Cancer Institute, University College London, London WC1E 6BT, United Kingdom
| |
Collapse
|
|
2
|
Fasina YO, Obanla TO, Ekunseitan DA, Dosu G, Richardson J, Apalowo OO. Role of trefoil factors in maintaining gut health in food animals. Front Vet Sci 2024; 11:1434509. [PMID: 39628866 PMCID: PMC11612906 DOI: 10.3389/fvets.2024.1434509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/21/2024] [Indexed: 12/06/2024] Open
Abstract
It is imperative to preserve the integrity of the gastrointestinal system in spite of the persistent existence of harmful chemicals and microbial flora in the gut. This is made possible by essential healing initiators called Trefoil factors which helps in mucosal reconstitution and tissue development on the gastrointestinal surface. The trefoil factors are a class of abundant secreted proteins that are essential for epithelial continuity (TFFs). Trefoil factor family (TFF) proteins are biologically active peptides that play significant role in safeguarding, restoring and continuity of the gastrointestinal tract (GIT) epithelium, through collaborative modulations with mucins in the mucosal layer. These peptides are readily produced in reaction to epithelial damage in the digestive tract, thereby contributing to the healing and restituting of the epithelial layers of the intestine. In addition, considerable evidence indicated that TFF peptides trigger proliferation, migration and angiogenesis, all which are crucial processes for wound healing. There is also increasing evidence that TFF peptides modulate the mucosal immune system. These protective properties, suggest that dietary manipulation strategies targeted at enhancing the expression and synthesis of TFF peptides at optimal levels in the GIT epithelium, may constitute a plausible alternative strategy to the use of in-feed antibiotic growth promoters to maintain epithelial integrity and promote resistance to enteric pathogens. This review describes TFF peptides, with importance to their biological functions and involvement in gastrointestinal mucosal protection and repair in food animals.
Collapse
Affiliation(s)
- Yewande O. Fasina
- Department of Animal Sciences, North Carolina Agricultural and Technical State University, Greensboro, NC, United States
| | | | | | | | | | | |
Collapse
|
|
3
|
Zhong C, Chen D, Gong D, Sheng X, Lin Y, Li R, Li Y. Transcriptomic response of overexpression ZNF32 in breast cancer cells. Sci Rep 2024; 14:28407. [PMID: 39557972 PMCID: PMC11574142 DOI: 10.1038/s41598-024-80125-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024] Open
Abstract
Breast cancer is one of the deadliest malignancies in women worldwide. Zinc finger protein 32 (ZNF32) has been reported to be involved in autophagy and stem cell like properties of breast cancer cells. However, the effects, mechanisms, target genes and pathways of ZNF32 in breast cancer development have not been fully explored. In this study, stable ZNF32 overexpression breast cancer cell line was generated, and we used RNA-seq and RT-qPCR to quantify and verify the changes in transcription levels in breast cancer cells under ZNF32 overexpression. Transcriptome analysis showed that high expression of ZNF32 is accompanied by changes in downstream focal adhesion, ECM-receptor interaction, PI3K-AKT, HIPPO and TNF signaling pathways, which are critical for the occurrence and development of cancer. Multiple differentially expressed genes (DEGs) were significantly involved in cell proliferation, adhesion and migration, including 11 DEGs such as CA9, CRLF1 and ENPP2P with fundamental change of regulation modes. All the 11 DEGs were validated by RT-qPCR, and 9 of them contained potential transcriptional binding sequences of ZNF32 in their promoter region. This study provides a holistic perspective on the role and molecular mechanism of ZNF32 in breast cancer progression.
Collapse
Affiliation(s)
- Chaosong Zhong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China
- College of Animal and Veterinary Sciences, Southwest Minzu University, No. 16, South Section 4, First Ring Road, Chengdu, 610041, Sichuan, China
| | - Dingshuang Chen
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China
- College of Animal and Veterinary Sciences, Southwest Minzu University, No. 16, South Section 4, First Ring Road, Chengdu, 610041, Sichuan, China
| | - Di Gong
- School of Basic Medical Science, Chengdu University, Chengdu, China
| | - Xueqing Sheng
- College of Animal and Veterinary Sciences, Southwest Minzu University, No. 16, South Section 4, First Ring Road, Chengdu, 610041, Sichuan, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China
- College of Animal and Veterinary Sciences, Southwest Minzu University, No. 16, South Section 4, First Ring Road, Chengdu, 610041, Sichuan, China
| | - Ruiwen Li
- Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanyan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Education Ministry, Southwest Minzu University, Chengdu, China.
- College of Animal and Veterinary Sciences, Southwest Minzu University, No. 16, South Section 4, First Ring Road, Chengdu, 610041, Sichuan, China.
| |
Collapse
|
|
4
|
Zhao J, Tian W, Zhang X, Dong S, Shen Y, Gao X, Yang M, Lv J, Hu F, Han J, Zhan Q, An F. The diagnostic value of serum trefoil factor 3 and pepsinogen combination in chronic atrophic gastritis: a retrospective study based on a gastric cancer screening cohort in the community population. Biomarkers 2024; 29:384-392. [PMID: 39234749 DOI: 10.1080/1354750x.2024.2400927] [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: 05/12/2024] [Accepted: 08/31/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND Chronic atrophic gastritis (CAG) is an important precursor of gastric cancer(GC), and there is currently a lack of reliable non-invasive diagnostic markers. This study aims to find a biomarker for non-invasive screening of CAG in the community. METHODS A total of 540 individuals were enrolled (test set = 385, validation set = 155). ROC curve analysis was used to evaluate the diagnostic significance of serum Trefoil Factor 3 (TFF3) alone or in combination with pepsinogen (PG) for CAG in the test and validation set. Furthermore, the diagnostic value of TFF3 and PG in different Helicobacter pylori (H. pylori) infection states was studied. RESULTS When compared with chronic superficial gastritis (CSG), the expression level of serum TFF3 in the CAG was higher (27 ng/ml vs 19.61, P < 0.001). ROC curve analysis found that the sensitivity, specificity, and area under the curve (AUC) of CAG diagnosis using serum TFF3 alone at the optimal cut-off value of 26.55 ng/ml were 0.529, 0.87, and 0.739, respectively. When TFF3 was combined with The Ratio of PGI to PGII (PGR), the AUC and specificity reached 0.755 and 0.825, respectively. TFF3 individual or combined with PGR had good predictive value, especially in the H. Pylori negative patients. CONCLUSION TFF3 combined with PGR can effectively predict CAG, especially in patients with H. pylori negative.
Collapse
Affiliation(s)
- Jiamin Zhao
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Wenying Tian
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Xiaoxue Zhang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Shengrong Dong
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Yao Shen
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Xiaojuan Gao
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Mei Yang
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Jiale Lv
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Feifan Hu
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Jinglue Han
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Qiang Zhan
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| | - Fangmei An
- Department of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, China
| |
Collapse
|
|
5
|
Karra S, Sinduja R, Gurushankari B, Elamurugan TP, Mahalakshmy T, Kate V, Nanda N, Rajesh NG, Rajeswari M, Raj R, Shankar G. Development of Panel of Three-Dimensional Biomarkers to Identify Gastric Carcinoma and Precancerous Lesions of the Stomach - An Analytical Cross-Sectional Study. Indian J Clin Biochem 2024. [DOI: 10.1007/s12291-024-01257-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/31/2024] [Indexed: 01/04/2025]
|
|
6
|
Okuda Y, Shimura T, Abe Y, Iwasaki H, Nishigaki R, Fukusada S, Sugimura N, Kitagawa M, Yamada T, Taguchi A, Kataoka H. Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer. J Gastroenterol 2024; 59:572-585. [PMID: 38836911 DOI: 10.1007/s00535-024-02110-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/24/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs). METHODS Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0-III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts. RESULTS Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825-0.956 for stage 0-III CRC and 0.792-0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively. CONCLUSIONS This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity.
Collapse
Affiliation(s)
- Yusuke Okuda
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.
| | - Yuichi Abe
- Division of Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan
| | - Hiroyasu Iwasaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Ruriko Nishigaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Shigeki Fukusada
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Naomi Sugimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Mika Kitagawa
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| | - Tamaki Yamada
- Okazaki Public Health Center, 1-3 Harusaki, Harisaki-Cho, Okazaki, 444-0827, Japan
| | - Ayumu Taguchi
- Division of Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan
- Division of Advanced Cancer Diagnostics, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan
| |
Collapse
|
|
7
|
Qiu J, Qu X, Wang Y, Guo C, Lv B, Jiang Q, Su W, Wang L, Hua K. Single-Cell Landscape Highlights Heterogenous Microenvironment, Novel Immune Reaction Patterns, Potential Biomarkers and Unique Therapeutic Strategies of Cervical Squamous Carcinoma, Human Papillomavirus-Associated (HPVA) and Non-HPVA Adenocarcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204951. [PMID: 36725337 PMCID: PMC10074047 DOI: 10.1002/advs.202204951] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/09/2022] [Indexed: 06/18/2023]
Abstract
Cervical adenocarcinomas (ADCs), including human papillomavirus (HPV)-associated (HPVA) and non-HPVA (NHPVA), though exhibiting a more malignant phenotype and poorer prognosis, are treated identically to squamous cell carcinoma (SCC). This clinical dilemma requires a deeper investigation into their differences. Herein a transcriptomic atlas of SCC, HPVA, and NHPVA-ADC using single-cell RNA (scRNA) and T-cell receptor sequencing (TCR-seq) is presented. Regarding structural cells, the malignancy origin of epithelial cells, angiogenic tip cells and two subtypes of fibroblasts is revealed. The promalignant properties of the structural cells using organoids are further confirmed. Regarding immune cells, myeloid cells with multiple functions other than antigen presentation and exhausted T lymphocytes contribute to immunosuppression. From the perspective of HPV infection, not only is HPV-dependent and independent cervical cancer oncogenesis proposed but also three immune reaction patterns mediated by T cells (coordinated/inactive/imbalanced) are identified. Strikingly, diagnostic biomarkers to distinguish ADC from SCC are discovered and prognostic biomarkers with marker genes for malignant epithelial cells, tip cells, and SPP1/C1QC macrophages are generated. Importantly, the efficacy of anti-CD96 and anti-TIGIT, not inferior to anti-PD1, in animal experiments is confirmed and targeted therapies specifically for HPV-positive SCC, HPVA and NHPVA-ADC, providing essential clues for further clinical trials, are proposed.
Collapse
Affiliation(s)
- Junjun Qiu
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Xinyu Qu
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Yumeng Wang
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Chenyan Guo
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Bin Lv
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Qian Jiang
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| | - Wentao Su
- School of Food Science and TechnologyDalian Polytechnic UniversityDalian116034China
| | - Li Wang
- Institutes of Biomedical SciencesFudan UniversityNo. 130 Dongan RoadShanghai200032China
- Center for Medical Research and InnovationShanghai Pudong HospitalFudan University Pudong Medical Center2800 Gongwei Road, PudongShanghai201399China
| | - Keqin Hua
- Department of GynecologyObstetrics and Gynecology HospitalFudan University419 Fangxie RoadShanghai200011China
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related Diseases413 Zhaozhou RoadShanghai200011China
| |
Collapse
|
|
8
|
Minegishi K, Dobashi Y, Koyama T, Ishibashi Y, Furuya M, Tsubochi H, Ohmoto Y, Yasuda T, Nomura S. Diagnostic utility of trefoil factor families for the early detection of lung cancer and their correlation with tissue expression. Oncol Lett 2023; 25:139. [PMID: 36909373 PMCID: PMC9996639 DOI: 10.3892/ol.2023.13725] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 12/22/2022] [Indexed: 02/23/2023] Open
Abstract
Trefoil factors (TFFs) are upregulated in numerous types of cancer, including those of the breast, the colon, the lung and the pancreas, suggesting their potential utility as biomarkers for screening. In the present study, the clinical relevance of serum or urinary TFFs as biomarkers were comprehensively evaluated and the correlation with TFF expression levels in lung cancer tissue was examined. Serum and urine were collected from 199 patients with lung cancer and 198 healthy individuals. Concentrations of serum and urinary TFF1, TFF2 and TFF3 were measured using ELISA and the potential of TFF levels to discriminate between cancer and non-cancer samples was evaluated. In 100 of the cancer cases, expression of TFF1-3 was analyzed using immunohistochemical staining of paraffin sections. Furthermore, the relationship between TFF levels and clinicopathological factors among these cancer cases was analyzed using immunohistochemistry of tissue specimens, quantified and statistically analyzed. While serum levels of all TFFs measured using ELISA were significantly higher in patients with lung cancer compared with those in healthy individuals, urinary TFFs were lower. Areas under the curve (AUC) of the receiver operating characteristic curves for serum/urinary TFF1, TFF2 and TFF3 were 0.709/0.594, 0.722/0.501 and 0.663/0.665, respectively. Furthermore, the combination of serum TFF1, TFF2, TFF3 and urinary TFF1 and TFF3 demonstrated the highest AUC (0.826). In the clinicopathological analysis, serum TFF1 was higher in the early pathological T-stage (pTis/1/2) compared with the later stage (pT3/4) and TFF2 was higher in the pN0/1 than the pN2 group. With regards to the histological types, urinary TFF1 was higher in squamous cell carcinoma than adenocarcinoma (AC), but TFF2 tended to be higher in AC. Using immunohistochemical analysis, although TFF1 and TFF3 expression showed positive correlation with serum concentrations, TFF2 was inversely correlated. In conclusion, serum and urinary TFF levels are promising predictive biomarkers, and their measurements provide a useful in vivo and non-invasive diagnostic screening tool. In particular, TFF1 and TFF3 could be surrogate markers of clinicopathological profiles of human lung cancer.
Collapse
Affiliation(s)
- Kentaro Minegishi
- Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8500, Japan
| | - Yoh Dobashi
- Department of Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8500, Japan.,Department of Pathology, School of Medicine, International University of Health and Welfare Hospital, Nasushiobara, Tochigi 329-2763, Japan
| | - Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Kyoto 602-8566, Japan
| | - Yuko Ishibashi
- Department of Surgery, Breast Surgery, Tokyo Women's Medical University, Adachi Medical Center, Adachi, Tokyo 123-8558, Japan
| | - Miki Furuya
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hiroyoshi Tsubochi
- Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8500, Japan
| | - Yasukazu Ohmoto
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Tokushima 770-8505, Japan
| | - Tomohiko Yasuda
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.,Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba 270-1694, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| |
Collapse
|
|
9
|
Ha YJ, Shin YJ, Tak KH, Park JL, Kim JH, Lee JL, Yoon YS, Kim CW, Kim SY, Kim JC. Reduced expression of alanyl aminopeptidase is a robust biomarker of non-familial adenomatous polyposis and non-hereditary nonpolyposis colorectal cancer syndrome early-onset colorectal cancer. Cancer Med 2023; 12:10091-10104. [PMID: 36748835 PMCID: PMC10166950 DOI: 10.1002/cam4.5675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Early-onset colorectal cancer (EOCRC) has been increasing in incidence worldwide but its genomic pathogenesis is mostly undetermined. This study aimed to identify robust EOCRC-specific gene expression patterns in non-familial adenomatous polyposis (FAP) and non-hereditary nonpolyposis colorectal cancer syndrome (HNPCC) EOCRC. METHOD We first performed gene expression profiling analysis using RNA sequencing of discovery cohort comprised of 49 EOCRC (age <50) and 50 late-onset colorectal cancer (LOCRC) (age >70) specimens. To obtain robust gene expression data from this analysis, we validated differentially expressed genes (DEGs) through TCGA cohort (EOCRC:59 samples, LOCRC:229 samples) and our validation cohort (EOCRC:72 samples, LOCRC:43 samples) using real-time RT-PCR. After the validation of DEGs, we validated the selected gene at protein levels using Western blotting. To identify whether genomic methylation regulates the expression of a particular gene, we selected methylation sites using The Cancer Genome Atlas (TCGA) datasets and validated them by pyrosequencing in our validation cohort. RESULTS The EOCRC patients included in this study had significantly more prominent family history of cancer than the LOCRC patients (23 [46.9%] vs. 13 [26%], p = 0.050). Alanyl aminopeptidase (ANPEP) was significantly downregulated in the EOCRC tissues (FC = 1.78, p = 0.0007) and was also commonly downregulated in the TCGA cohort (FC = -1.08, p = 0.0021). Moreover, the ANPEP mRNA and protein expression levels were significantly downregulated in the EOCRC tissues of our validation cohort (p = 0.037 and 0.027). In comparisons of the normal and tumor tissues in public datasets, the ANPEP level was significantly lower in the tumor tissue in the TCGA dataset (p < 2.2 × 10-16 ) and GSE196006 dataset (p = 0.0005). Furthermore, the ANPEP expression level did not show a decreasing tendency at a young age in the normal colon tissue of the GTEx dataset. Lastly, the hypermethylation of cg26222247 in ANPEP was identified to be weakly associated with reduced ANPEP expression in our EOCRC cohort. CONCLUSION The reduced expression of ANPEP was identified as a novel biomarker of non-FAP and non-HNPCC EOCRC.
Collapse
Affiliation(s)
- Ye Jin Ha
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Yun Jae Shin
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.,Department of Bioinformatics, University of Science and Technology (UST), Daejeon, South Korea
| | - Ka Hee Tak
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Jong Lyul Park
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Jeong Hwan Kim
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Jong Lyul Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yong Sik Yoon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chan Wook Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seon Young Kim
- Personalized Genomic Medicine Research Center, Daejeon, South Korea.,Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.,Department of Bioinformatics, University of Science and Technology (UST), Daejeon, South Korea
| | - Jin Cheon Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.,Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| |
Collapse
|
|
10
|
Latorre G, Pizarro M, Ford J, Gándara V, Muñoz G, Araya J, Bellolio E, Villaseca MÁ, Fuentes-López E, Cortés P, Rollán A, Bufadel M, Araya R, Vargas J, Espino A, Sharp A, Agüero C, Donoso A, Bresky G, Pedrero P, Rueda C, Calvo A, Odagaki T, Moriyama T, Ishida T, Parra-Blanco A, Camargo M, González R, Corvalán A, Riquelme A. Evaluation of Trefoil Factor 3 as a Non-Invasive Biomarker of Gastric Intestinal Metaplasia and Gastric Cancer in a High-Risk Population. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 46:411-418. [PMID: 35580739 DOI: 10.1016/j.gastrohep.2022.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/07/2022] [Accepted: 04/01/2022] [Indexed: 01/06/2023]
|
|
11
|
Turan H, Vitale SG, Kahramanoglu I, Della Corte L, Giampaolino P, Azemi A, Durmus S, Sal V, Tokgozoglu N, Bese T, Arvas M, Demirkiran F, Gelisgen R, Ilvan S, Uzun H. Diagnostic and prognostic role of TFF3, Romo-1, NF-кB and SFRP4 as biomarkers for endometrial and ovarian cancers: a prospective observational translational study. Arch Gynecol Obstet 2022; 306:2105-2114. [PMID: 35461390 PMCID: PMC9633503 DOI: 10.1007/s00404-022-06563-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/01/2022] [Indexed: 12/24/2022]
Abstract
Purpose This study aimed to evaluate trefoil factor 3 (TFF3), secreted frizzled-related protein 4 (sFRP4), reactive oxygen species modulator 1 (Romo1) and nuclear factor kappa B (NF-κB) as diagnostic and prognostic markers of endometrial cancer (EC) and ovarian cancer (OC). Methods Thirty-one patients with EC and 30 patients with OC undergone surgical treatment were enrolled together with 30 healthy controls in a prospective study. Commercial ELISA kits determined serum TFF-3, Romo-1, NF-кB and sFRP-4 concentrations. Results Serum TFF-3, Romo-1 and NF-кB levels were significantly higher in patients with EC and OC than those without cancer. Regarding EC, none of the serum biomarkers differs significantly between endometrial and non-endometrioid endometrial carcinomas. Mean serum TFF-3 and NF-кB levels were significantly higher in advanced stages. Increased serum levels of TFF-3 and NF-кB were found in those with a higher grade of the disease. Regarding OC, none of the serum biomarkers differed significantly among histological subtypes. Significantly increased serum levels of NF-кB were observed in patients with advanced-stage OC than those with stage I and II diseases. No difference in serum biomarker levels was found between those who had a recurrence and those who had not. The sensibility and specificity of these four biomarkers in discriminating EC and OC from the control group showed encouraging values, although no one reached 70%. Conclusions TFF-3, Romo-1, NF-кB and SFRP4 could represent new diagnostic and prognostic markers for OC and EC. Further studies are needed to validate our results.
Collapse
Affiliation(s)
- Hasan Turan
- Department of Gynecologic Oncology, Health Science University, Cam Sakura Training and Research Hospital, Istanbul, Turkey
| | - Salvatore Giovanni Vitale
- Obstetrics and Gynecology Unit, Department of General Surgery and Medical Surgical Specialties, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy.
| | | | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples, Naples, Italy
| | - Pierluigi Giampaolino
- Department of Public Health, University of Naples Federico II, Via Sergio Pansini, Naples, Italy
| | - Asli Azemi
- Department of Biochemistry, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sinem Durmus
- Department of Biochemistry, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Veysel Sal
- Department of Obstetrics and Gynecology, Memorial Bahcelievler Hospital, Istanbul, Turkey
| | - Nedim Tokgozoglu
- Department of Gynecologic Oncology, Okmeydanı Training and Research Hospital, Istanbul, Turkey
| | - Tugan Bese
- Department of Gynecologic Oncology, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Macit Arvas
- Department of Gynecologic Oncology, American Hospital, Istanbul, Turkey
| | - Fuat Demirkiran
- Department of Gynecologic Oncology, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Remise Gelisgen
- Department of Biochemistry, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sennur Ilvan
- Department of Pathology, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hafize Uzun
- Department of Biochemistry, School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| |
Collapse
|
|
12
|
Verma R, Sharma PC. Identification of stage-specific differentially expressed genes and SNPs in gastric cancer employing RNA-Seq based transcriptome profiling. Genomics 2021; 114:61-71. [PMID: 34839019 DOI: 10.1016/j.ygeno.2021.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 11/23/2021] [Indexed: 12/24/2022]
Abstract
We analysed over 400 million reads obtained from Illumina sequencing of six pairs of libraries representing two each of stage I, II, and III gastric tumors and corresponding normal tissues to identify differentially expressed genes (DEGs), single nucleotide polymorphisms (SNPs), and transcription factors (TFs). In total, 2207 DEGs including 972 upregulated genes and 1235 downregulated genes were detected. Of these, several stage-specific signature genes were identified. The protein-protein interaction networks involving DEGs and TFs were constructed. The KEGG pathway analysis of SNP harbouring genes revealed their involvement in different cancer related pathways like apoptosis, mTOR pathway, and MAPK signaling pathway. The SNP analysis showed implication of host genes in GO categories like immune system process, regulation of signaling, response to stress, and transport. A biased chromosomal distribution of DEGs and SNP harbouring genes was observed. Our study would provide further insights into the complex regulatory mechanisms operating during gastric tumorigenesis.
Collapse
Affiliation(s)
- Renu Verma
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Prakash Chand Sharma
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India.
| |
Collapse
|
|
13
|
Sugiyama M, Machida N, Yasunaga A, Terai N, Fukasawa H, Ono HK, Kobayashi R, Nishiyama K, Hashimoto O, Kurusu S, Yoshioka K. Vaginal mucus in mice: developmental and gene expression features of epithelial mucous cells during pregnancy†. Biol Reprod 2021; 105:1272-1282. [PMID: 34416757 DOI: 10.1093/biolre/ioab157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 07/12/2021] [Accepted: 08/16/2021] [Indexed: 01/18/2023] Open
Abstract
The vagina is the site of copulation and serves as the birth canal. It also provides protection against external pathogens. In mice, due to the absence of cervical glands, the vaginal epithelium is the main producer of vaginal mucus. The development and differentiation of vaginal epithelium-constituting cells and the molecular characteristics of vaginal mucus have not been thoroughly examined. Here, we characterized vaginal mucous cell development and the expression of mucus-related factors in pregnant mice. The vaginal mucous epithelium layer thickened and became multilayered after Day 12 of pregnancy and secreted increasing amounts of mucus until early postpartum. Using histochemistry and transmission electron microscopy, we found supra-basal mucous cells as probable candidates for precursor cells. In vaginal mucous cells, the expression of TFF1, a stabilizer of mucus, was high, and some members of mucins and antimicrobial peptides (MUC5B and DEFB1) were expressed in a stage-dependent manner. In summary, this study presents the partial characterization of vaginal epithelial mucous cell lineage and expression of genes encoding several peptide substances that may affect vaginal tissue homeostasis and mucosal immunity during pregnancy and parturition.
Collapse
Affiliation(s)
- Makoto Sugiyama
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Nao Machida
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Arata Yasunaga
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan.,Department of Animal Science, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Nanako Terai
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Hanae Fukasawa
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Hisaya K Ono
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Ryosuke Kobayashi
- Laboratory of Genome Science, Biological Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Keita Nishiyama
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Osamu Hashimoto
- Faculty of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
| | - Shiro Kurusu
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Kazuki Yoshioka
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| |
Collapse
|
|
14
|
Yang L, Zhang X, Zhang J, Liu Y, Ji T, Mou J, Fang X, Wang S, Chen J. Low expression of TFF3 in papillary thyroid carcinoma may correlate with poor prognosis but high immune cell infiltration. Future Oncol 2021; 18:333-348. [PMID: 34756116 DOI: 10.2217/fon-2020-1183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies and has a favorable prognosis. However, optimal treatments and prognostic markers have not been clearly identified. Methods: Gene expression data from primary PTC were downloaded from the Gene Expression Omnibus database and subjected to two analyses of differentially expressed genes (DEGs), followed by intersecting individual and integrated DEGs analyses as well as gene set enrichment analysis. Analysis of data from Sequence Read Archive and The Cancer Genome Atlas, immunohistochemistry and qRT-PCR of TFF3 were performed to validate the results. Finally, the relationship between gene expression and disease-free survival as well as immune cell infiltration were investigated. Results: Six critical DEGs and several tumor-enriched signaling pathways were identified. Immunohistochemistry and qRT-PCR validated the low expression of TFF3 in PTC. TFF3 and FCGBP are coexpressed in PTC, and patients with lower gene expression had worse disease-free survival but higher immune cell infiltration. Conclusion: TFF3 was significantly underexpressed and may function with FCGBP synergistically in PTC.
Collapse
Affiliation(s)
- Lei Yang
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Xiwei Zhang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiyin Zhang
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Yuwei Liu
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Tingting Ji
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Jianing Mou
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Xiaolian Fang
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Shengcai Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Jun Chen
- Beijing Engineering Research Center of Pediatric Surgery, Engineering and Transformation Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| |
Collapse
|
|
15
|
Keles Yucel ZP, Afacan B, Atmaca İlhan H, Kose T, Emingil G. The trefoil factor family 1 (TFF-1) and 3 (TFF-3) are upregulated in the saliva, gingival crevicular fluid and serum of periodontitis patients. Oral Dis 2021; 28:1240-1249. [PMID: 33660336 DOI: 10.1111/odi.13820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 02/03/2021] [Accepted: 02/23/2021] [Indexed: 12/01/2022]
Abstract
OBJECTIVE This study aimed to investigate the levels of trefoil factor family (TFF)-1, TFF-3 and interleukin (IL)-1β in gingival crevicular fluid (GCF), saliva and serum of patients with gingivitis, stage 3 periodontitis and healthy individuals. MATERIALS AND METHODS A total of 100 individuals consisting of 25 periodontally healthy, 25 gingivitis and 50 stage 3 periodontitis, were enrolled in the study. Clinical periodontal examinations were recorded and GCF, saliva and serum samples were obtained. TFF-1, TFF-3 and IL-1β were measured by ELISA. RESULTS TFF-1 and TFF-3 levels in both GCF, saliva and serum were higher in periodontitis patients than healthy controls (p < .001) and gingivitis group (p < .01). The levels of these peptides in all biofluids were similar between gingivitis and healthy control groups (p > .05). GCF, saliva and serum IL-1β levels were also higher in periodontitis patients than the controls (p < .01). Periodontitis patients had elevated GCF and saliva IL-β levels than gingivitis group (p < .001). CONCLUSION Elevated TFF-1 and TFF-3 levels both locally and systemically in periodontitis in parallel to increased IL-1β levels might suggest that these peptides are involved in host response during the periodontal tissue destruction.
Collapse
Affiliation(s)
| | - Beral Afacan
- Department of Periodontology, Faculty of Dentistry, Adnan Menderes University, Aydin, Turkey
| | - Harika Atmaca İlhan
- Department of Biology, Section of Molecular Biology, Faculty of Science, Celal Bayar University, Manisa, Turkey
| | - Timur Kose
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Gulnur Emingil
- Department of Periodontology, Faculty of Dentistry, Ege University, Izmir, Turkey
| |
Collapse
|
|
16
|
Alteration of protein expression and spliceosome pathway activity during Barrett's carcinogenesis. J Gastroenterol 2021; 56:791-807. [PMID: 34227026 PMCID: PMC8370908 DOI: 10.1007/s00535-021-01802-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 06/18/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Barrett's esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis-and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC. METHODS During endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5). RESULTS Comparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry. CONCLUSIONS Our results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.
Collapse
|
|
17
|
Dodla P, Bhoopalan V, Khoo SK, Miranti C, Sridhar S. Gene expression analysis of human prostate cell lines with and without tumor metastasis suppressor CD82. BMC Cancer 2020; 20:1211. [PMID: 33298014 PMCID: PMC7724878 DOI: 10.1186/s12885-020-07675-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/22/2020] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Tetraspanin CD82 is a tumor metastasis suppressor that is known to down regulate in various metastatic cancers. However, the exact mechanism by which CD82 prevents cancer metastasis is unclear. This study aims to identify genes that are regulated by CD82 in human prostate cell lines. METHODS We used whole human genome microarray to obtain gene expression profiles in a normal prostate epithelial cell line that expressed CD82 (PrEC-31) and a metastatic prostate cell line that does not express CD82 (PC3). Then, siRNA silencing was used to knock down CD82 expression in PrEC-31 while CD82 was re-expressed in PC3 to acquire differentially-expressed genes in the respective cell line. RESULTS Differentially-expressed genes with a P < 0.05 were identified in 3 data sets: PrEC-31 (+CD82) vs PrEC-31(-CD82), PC3-57 (+CD82) vs. PC3-5 V (-CD82), and PC3-29 (+CD82) vs. PC3-5 V (-CD82). Top 25 gene lists did not show overlap within the data sets, except (CALB1) the calcium binding protein calbindin 1 which was significantly up-regulated (2.8 log fold change) in PrEC-31 and PC3-29 cells that expressed CD82. Other most significantly up-regulated genes included serine peptidase inhibitor kazal type 1 (SPINK1) and polypeptide N-acetyl galactosaminyl transferase 14 (GALNT14) and most down-regulated genes included C-X-C motif chemokine ligand 14 (CXCL14), urotensin 2 (UTS2D), and fibroblast growth factor 13 (FGF13). Pathways related with cell proliferation and angiogenesis, migration and invasion, cell death, cell cycle, signal transduction, and metabolism were highly enriched in cells that lack CD82 expression. Expression of two mutually inclusive genes in top 100 gene lists of all data sets, runt-related transcription factor (RUNX3) and trefoil factor 3 (TFF3), could be validated with qRT-PCR. CONCLUSION Identification of genes and pathways regulated by CD82 in this study may provide additional insights into the role that CD82 plays in prostate tumor progression and metastasis, as well as identify potential targets for therapeutic intervention.
Collapse
Affiliation(s)
- Pushpaja Dodla
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Vanitha Bhoopalan
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Sok Kean Khoo
- Department of Cell and Molecular Biology, Grand Valley State University, Allendale, MI, 49401, USA
| | - Cindy Miranti
- Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724, USA
| | - Suganthi Sridhar
- Department of Integrative Biology, University of South Florida, 140, 7Th Avenue S, University of South Florida, St. Petersburg, FL, 33701, USA.
| |
Collapse
|
|
18
|
NK6 Homeobox 2 Regulated Gastrokin-2 Suppresses Gastric Cancer Cell Proliferation and Invasion via Akt Signaling Pathway. Cell Biochem Biophys 2020; 79:123-131. [PMID: 33009998 DOI: 10.1007/s12013-020-00948-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2020] [Indexed: 01/23/2023]
Abstract
This study aims to explore the role of Gastrokin-2 (GKN2) in gastric cancer and its function in the progression and metastasis of gastric cancer. The expression of GKN2 in the patient samples was examined by qRT-PCR and western blot. The transcription factor NK6 Homeobox 2 (NKX6-2), which binds to the GKN2 promoter, was predicted by cBioportal and JSPAR. Binding between NKX6-2 and the GKN2 promoter was analyzed by dual-luciferase assay. MTT assay and transwell assay were used to detect changes in gastric cancer cell viability and migration after GKN2 overexpression, which was achieved by transfection of GKN2 overexpression vector. Akt signaling pathway markers were assessed by western blot. GKN2 is downregulated in gastric cancer and low GKN2 expression is correlated to poor survival, metastasis, and higher clinical stages. NKX6-2 binds the promoter region of GKN2 and regulate its expression. GKN2 overexpression inhibits the proliferation, migration, and invasion of gastric cancer cells, which was mediated by Akt signaling pathway. NKX6-2 regulated GKN2 inhibits the proliferation and invasion of gastric cancer cells by inhibiting Akt signaling pathway. GKN2 can be used as a potential diagnostic and therapeutic target for patients with clinical gastric cancer.
Collapse
|
|
19
|
Ochiai Y, Yamaguchi J, Kokuryo T, Yokoyama Y, Ebata T, Nagino M. Trefoil Factor Family 1 Inhibits the Development of Hepatocellular Carcinoma by Regulating β-Catenin Activation. Hepatology 2020; 72:503-517. [PMID: 31733149 DOI: 10.1002/hep.31039] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Recent studies have suggested that trefoil factor family 1 (TFF1) functions as a tumor suppressor in gastric and pancreatic carcinogenesis. APPROACH AND RESULTS To investigate the role of TFF1 in hepatocarcinogenesis, we performed immunohistochemical staining of surgically resected human liver samples, transfected a TFF1 expression vector into hepatocellular carcinoma (HCC) cell lines, and employed a mouse model of spontaneous HCC development (albumin-cyclization recombination/Lox-Stop-Lox sequence-Kirsten rat sarcoma viral oncogene homologG12D [KC]); the model mouse strain was bred with a TFF1-knockout mouse strain to generate a TFF1-deficient HCC mouse model (KC/TFF1-/- ). TFF1 expression was found in some human samples with HCC. Interestingly, TFF1-positive cancer cells showed a staining pattern contradictory to that of proliferating cell nuclear antigen, and aberrant DNA hypermethylation in TFF1 promoter lesions was detected in HCC samples, indicating the tumor-suppressive role of TFF1. In vitro, induction of TFF1 expression resulted in impaired proliferative activity and enhanced apoptosis in HCC cell lines (HuH7, HepG2, and HLE). These anticancer effects of TFF1 were accompanied by the loss of nuclear β-catenin expression, indicating inactivation of the β-catenin signaling pathway by TFF1. In vivo, TFF1 deficiency in KC mice accelerated the early development and growth of HCC, resulting in poor survival rates. In addition, immunohistochemistry revealed that the amount of nuclear-localized β-catenin was significantly higher in KC/TFF1-/- mice than in KC mice and that human HCC tissue showed contradictory expression patterns for β-catenin and TFF1, confirming the in vitro observations. CONCLUSIONS TFF1 might function as a tumor suppressor that inhibits the development of HCC by regulating β-catenin activity.
Collapse
Affiliation(s)
- Yosuke Ochiai
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junpei Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toshio Kokuryo
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
20
|
Yusufu A, Shayimu P, Tuerdi R, Fang C, Wang F, Wang H. TFF3 and TFF1 expression levels are elevated in colorectal cancer and promote the malignant behavior of colon cancer by activating the EMT process. Int J Oncol 2019; 55:789-804. [PMID: 31432157 PMCID: PMC6741840 DOI: 10.3892/ijo.2019.4854] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 06/27/2019] [Indexed: 12/19/2022] Open
Abstract
Reports on the roles of the secreted trefoil factor (TFF)1 and 3 in colorectal cancer (CRC) and their underlying mechanisms of action in tumorigenesis are not common and are controversial. In the present study, the mRNA expression and promoter methylation of TFF1 and TFF3 in cancer and adjacent normal tissues were investigated, and their association with other clinical factors and patient prognosis were evaluated. Moreover, the association between TFF3 and epithelial mesenchymal transition (EMT) was explored by overexpressing or inhibiting TFF3 expression. The results revealed that the mRNA level of TFF1 and TFF3 in the cancer tissues was significantly higher than that in the matched adjacent normal tissues (P=0.034 and P=0.007, respectively), and a higher expression of TFF3, but not TFF1, was predominantly associated with clinicopathological factors and a poorer prognosis. No correlation was observed between promoter methylation and the expression of TFF1 or TFF3. The overexpression of TFF3 promoted the proliferation, migration and invasiveness of HT29 cells, and induced an increase in the expression of Twist1, Snail and Vimentin, while causing a decrease in E-cadherin expression. On the contrary, the knockdown of TFF3 resulted in opposite effects in the LoVo cells. On the whole, the findings of this study indicate that TFF3 may be a promising new factor for the estimation of the survival of patients with CRC, and may promote the malignant progression of CRC by activating the EMT process. Therefore, TFF3 may be a future potential therapeutic target for CRC.
Collapse
Affiliation(s)
- Aikeremu Yusufu
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Xin Jiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Paerhati Shayimu
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Xin Jiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Rousidan Tuerdi
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Xin Jiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| | - Cheng Fang
- Department of Gastrointestinal Surgery, Xi Jing Digestive Disease Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Fei Wang
- Department of Gastrointestinal Surgery, Xi Jing Digestive Disease Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Haijiang Wang
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Xin Jiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
| |
Collapse
|
|
21
|
Aberrant DNA Polymerase Beta Enhances H. pylori Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice. Cancers (Basel) 2019; 11:cancers11060843. [PMID: 31216714 PMCID: PMC6627457 DOI: 10.3390/cancers11060843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/11/2019] [Accepted: 06/14/2019] [Indexed: 11/16/2022] Open
Abstract
H. pylori is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase beta (Pol β) impacts BER efficiency and has been reported in approximately 30-40% of gastric carcinoma tumors. In this study, we examined whether reduced BER capacity associated with mutation in the POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.
Collapse
|
|
22
|
Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, Bleotu C, Diaconu CC, Chivu-Economescu M. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019; 25:2029-2044. [PMID: 31114131 PMCID: PMC6506585 DOI: 10.3748/wjg.v25.i17.2029] [Citation(s) in RCA: 275] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/03/2019] [Accepted: 04/20/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.
Collapse
Affiliation(s)
- Laura Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Faculty of Medicine, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Cristina Mambet
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Saviana Nedeianu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| |
Collapse
|
|
23
|
Fabisiak A, Bartoszek A, Kardas G, Fabisiak N, Fichna J. Possible application of trefoil factor family peptides in gastroesophageal reflux and Barrett's esophagus. Peptides 2019; 115:27-31. [PMID: 30831146 DOI: 10.1016/j.peptides.2019.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 02/16/2019] [Accepted: 02/24/2019] [Indexed: 12/14/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a chronic disorder of the digestive tract characterised mainly by a heartburn. Being one of the most common gastrointestinal diseases, the prevalence of GERD reaches up to 25.9% in Europe. Barrett's esophagus (BE) is an acquired condition characterized by the replacement of the normal stratified squamous epithelium with metaplastic columnar epithelium. BE is believed to develop mainly from chronic GERD and is the most important risk factor of esophageal adenocarcinoma. Despite the availability of drugs such as proton pomp inhibitors and antacids, GERD is still a burden to local economy and impairs health-related quality of life in patients. Also, the endoscopic surveillance in patients with BE is burdensome and expensive what drives the need for biomarker of intestinal metaplasia and dysplasia. Trefoil factor family (TFF), consisting of TFF1, TFF2 and TFF3 peptides is gaining more and more attention due to its unique biochemical features and numerous functions. In this review the role of TFF1, TFF2 and TFF3 as potential treatment option and/or biomarker in the upper GI tract is discussed with particular focus on GERD and BE.
Collapse
Affiliation(s)
- Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Poland
| | - Adrian Bartoszek
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Grzegorz Kardas
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Natalia Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Gastroenterology, Faculty of Military Medicine, Medical University of Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
| |
Collapse
|
|
24
|
Deoxynivalenol inhibits the expression of trefoil factors (TFF) by intestinal human and porcine goblet cells. Arch Toxicol 2019; 93:1039-1049. [PMID: 30854615 DOI: 10.1007/s00204-019-02425-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/04/2019] [Indexed: 12/13/2022]
Abstract
Trefoil factors (TFFs) are bioactive peptides expressed by several epithelia, including the intestine, where they regulate key functions such as tissue regeneration, barrier function and inflammation. Although food-associated mycotoxins, including deoxynivalenol (DON), are known to impact many intestinal functions, modulation of TFFs during mycotoxicosis has never been investigated. Here, we analyzed the effect of DON on TFFs expression using both human goblet cells (HT29-16E cells) and porcine intestinal explants. Results showed that very low doses of DON (nanomolar range) inhibit the secretion of TFFs by human goblet cells (IC50 of 361, 387 and 243 nM for TFF1, 2 and 3, respectively) and prevent wound healing. RT-qPCR analysis demonstrated that the inhibitory effect of DON is related to a suppression of TFFs mRNA expression. Experiments conducted on porcine intestinal explants confirmed the results obtained on cells. Finally, the use of specific inhibitors of signal pathways demonstrated that DON-mediated suppression of TFFs expression mainly involved Protein Kinase R and the MAP kinases (MAPK) p38 and ERK1/2. Taken together, our results show for the first time that at very low doses, DON suppresses the expression and production of intestinal TFFs and alters wound healing. Given the critical role of TFFs in tissue repair, our results suggest that DON-mediated suppression of TFFs contributes to the alterations of intestinal integrity the caused by this toxin.
Collapse
|
|
25
|
Disruption of the Tff1 gene in mice using CRISPR/Cas9 promotes body weight reduction and gastric tumorigenesis. Lab Anim Res 2018; 34:257-263. [PMID: 30671113 PMCID: PMC6333602 DOI: 10.5625/lar.2018.34.4.257] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/07/2018] [Accepted: 12/08/2018] [Indexed: 01/27/2023] Open
Abstract
Trefoil factor 1 (TFF1, also known as pS2) is strongly expressed in the gastrointestinal mucosa and plays a critical role in the differentiation of gastric glands. Since approximately 50% of all human gastric cancers are associated with decreased TFF1 expression, it is considered a tumor suppressor gene. TFF1 deficiency in mice results in histological changes in the antral and pyloric gastric mucosa, with severe hyperplasia and dysplasia of epithelial cells, resulting in the development of antropyloric adenoma. Here, we generated TFF1-knockout (KO) mice, without a neomycin resistant (NeoR) cassette, using the clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRSIPR/Cas9) system. Though our TFF1-KO mice showed phenotypes very similar to the previous embryonic stem (ES)-cell-based KO mice, they differed from the previous reports in that a reduction in body weight was observed in males. These results demonstrate that these newly established TFF1-KO mice are useful tools for investigating genetic and environmental factors influencing gastric cancer, without the effects of artificial gene insertion. Furthermore, these findings suggest a novel hypothesis that TFF1 expression influences gender differences.
Collapse
|
|
26
|
Lin X, Zhang H, Dai J, Zhang W, Zhang J, Xue G, Wu J. TFF3 Contributes to Epithelial-Mesenchymal Transition (EMT) in Papillary Thyroid Carcinoma Cells via the MAPK/ERK Signaling Pathway. J Cancer 2018; 9:4430-4439. [PMID: 30519349 PMCID: PMC6277656 DOI: 10.7150/jca.24361] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 08/24/2018] [Indexed: 12/20/2022] Open
Abstract
Trefoil factor 3 (TFF3) was found to be overexpressed in many types of tumours. Evidence has shown that TFF3 plays an important role in tumour proliferation, migration and invasion metastasis. However, the impact of TFF3 on patients' clinicopathological characteristics and underlying mechanisms remain unknown in papillary thyroid carcinoma (PTC). In this study, the expression of TFF3 and the epithelial-mesenchymal transition (EMT) transcriptional factor Snail in PTC and para-carcinoma specimens was evaluated by immunohistochemistry (IHC) and Western blot, and the possible associations with lymph node (LN) metastasis and other clinicopathological parameters were analysed. In vitro, the effect of TFF3 on the malignant behaviour of TPC-1 cells was evaluated by cell proliferation assays, cell adhesion assays, colony formation assays, wound-healing assays and transwell chamber invasion assays. EMT markers and regulatory molecules were detected by quantitative RT-PCR (qRT-PCR) and Western blot analysis in the TFF3-knockdown groups and shRNA control group. The results showed that TFF3 was upregulated in PTC tissue and was associated with lymph node metastasis (P=0.0001), pathological grade (P=0.0002) and Snail expression (P=0.0001). The knockdown of TFF3 markedly inhibited the abilities of TPC-1 cell proliferation, adhesion, colony formation, migration and invasion. Mechanically, the results demonstrated that TFF3 might activate the MAPK/ERK signalling pathways, affect the expression of the transcription factors snail and slug in addition to affecting EMT associated markers E-cadherin and N-cadherin, and accelerate the progression of EMT in TPC-1 cells. These findings indicate that TFF3 might promote the metastatic potential of PTC by promoting the EMT process through cascades of MAPK/ERK pathways.
Collapse
Affiliation(s)
- Xu Lin
- Department of Histology and Embryology, Hebei North University, Zhangjiakou, 075000, China
| | - Huiqin Zhang
- Department of Ophthalmology, Cangzhou Central Hospital, Cangzhou, 061000, China
| | - Jin Dai
- Department of Histology and Embryology, Hebei North University, Zhangjiakou, 075000, China
| | - Wenjing Zhang
- Department of Histology and Embryology, Hebei North University, Zhangjiakou, 075000, China
| | - Jing Zhang
- Department of Histology and Embryology, Hebei North University, Zhangjiakou, 075000, China
| | - Gang Xue
- Department of Otorhinolaryngology Head and Neck Surgery, Hebei North University, Zhangjiakou, 075000, China
| | - Jingfang Wu
- Department of Histology and Embryology, Hebei North University, Zhangjiakou, 075000, China
| |
Collapse
|
|
27
|
Screening Biomarker as an Alternative to Endoscopy for the Detection of Early Gastric Cancer: The Combination of Serum Trefoil Factor Family 3 and Pepsinogen. Gastroenterol Res Pract 2018; 2018:1024074. [PMID: 29977284 PMCID: PMC5994275 DOI: 10.1155/2018/1024074] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 04/03/2018] [Indexed: 12/12/2022] Open
Abstract
Objective The serum pepsinogen test has limitation in its predictive power as a noninvasive biomarker for gastric cancer screening. We aimed to investigate whether the combination of TFF3 and pepsinogen could be an effective biomarker for the detection of gastric cancer even in the early stages. Methods In total, 281 patients with early gastric cancer (EGC), who underwent endoscopic submucosal dissection in Korea, and 708 healthy individuals from Japan were enrolled in the derivation cohort. The validation cohort included 30 Korean patients with EGC and 30 Korean healthy control blood donors. Serum TFF3 levels were examined using enzyme-linked immunosorbent assay. Results Using a cutoff of 6.73 ng/mL in the derivation cohort, the sensitivity of the combination of tests for EGC detection was superior (87.5%) to that of TFF3 (80.4%) or pepsinogen test alone (39.5%). Similarly, in the validation cohort, the sensitivity of TFF3 plus pepsinogen was higher (90.4%) than that of TFF3 (80.0%) or pepsinogen test alone (33.3%). Conclusion The combination of serum TFF3 and pepsinogen is a more effective noninvasive biomarker for gastric cancer detection compared with pepsinogen or TFF3 alone, even in EGC. This trial is registered with NCT03046745.
Collapse
|
|
28
|
Nucleotide-mediated SPDEF modulates TFF3-mediated wound healing and intestinal barrier function during the weaning process. Sci Rep 2018; 8:4827. [PMID: 29555969 PMCID: PMC5859294 DOI: 10.1038/s41598-018-23218-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/07/2018] [Indexed: 12/14/2022] Open
Abstract
Most alterations during weaning involve physiological changes in intestinal structure and function. Here, we evaluated the molecular mechanisms regulating the effects of nucleotides on weaning. Nucleotide treatment induced Trefoil factor 3 (TFF3) expression and IPEC-J2 cell growth and reduced wound width. Treatment with nucleosides and TFF3 in lipopolysaccharide-challenged IPEC-J2 cells increased intestinal transepithelial electrical resistance and decreased intestinal permeability. Additionally, nucleosides improved intestinal barrier function through induction of TFF3-mediated phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase 1/2, p38, and Janus kinase/signal transducer and activator of transcription signaling pathways. Among selected differentially expressed genes, SAM pointed domain containing ETS transcription factor (SPDEF) expression was elevated by nucleotides in a concentration-dependent manner. Moreover, SPDEF directly regulated TFF3 expression via binding to the promoter. In vivo, nucleotide supplementation improved growth performance, serum stress levels, and intestinal morphology. Our findings provide insights into the molecular mechanisms of intestinal development during weaning in pigs.
Collapse
|
|
29
|
Binato R, Santos EC, Boroni M, Demachki S, Assumpção P, Abdelhay E. A common molecular signature of intestinal-type gastric carcinoma indicates processes related to gastric carcinogenesis. Oncotarget 2018; 9:7359-7371. [PMID: 29484116 PMCID: PMC5800908 DOI: 10.18632/oncotarget.23670] [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: 03/22/2017] [Accepted: 12/11/2017] [Indexed: 12/11/2022] Open
Abstract
Gastric carcinoma (GC) is one of the most aggressive cancers and the second leading cause of cancer death in the world. According to the Lauren classification, this adenocarcinoma is divided into two subtypes, intestinal and diffuse, which differ in their clinical, epidemiological and molecular features. Several studies have attempted to delineate the molecular signature of gastric cancer to develop new and non-invasive screening tests that improve diagnosis and lead to new treatment strategies. However, a consensus signature has not yet been identified for each condition. Thus, this work aimed to analyze the gene expression profile of Brazilian intestinal-type GC tissues using microarrays and compare the results to those of non-tumor tissue samples. Moreover, we compared our intestinal-type gastric carcinoma profile with those obtained from populations worldwide to assess their similarity. The results identified a molecular signature for intestinal-type GC and revealed that 38 genes differentially expressed in Brazilian intestinal-type gastric carcinoma samples can successfully distinguish gastric tumors from non-tumor tissue in the global population. These differentially expressed genes participate in biological processes important to cell homeostasis. Furthermore, Kaplan-Meier analysis suggested that 7 of these genes could individually be able to predict overall survival in intestinal-type gastric cancer patients.
Collapse
Affiliation(s)
- Renata Binato
- Laboratório de Célula tronco, Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
- Instituto Nacional de Ciência e Tecnologia Para o Controle do Câncer (INCT), Rio de Janeiro, RJ, Brazil
| | - Everton Cruz Santos
- Laboratório de Célula tronco, Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
- Instituto Nacional de Ciência e Tecnologia Para o Controle do Câncer (INCT), Rio de Janeiro, RJ, Brazil
| | - Mariana Boroni
- Laboratório de Bioinformática e Biologia Computacional, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
| | - Samia Demachki
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará (UFPA), Belém, PA, Brazil
| | - Paulo Assumpção
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará (UFPA), Belém, PA, Brazil
| | - Eliana Abdelhay
- Laboratório de Célula tronco, Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
- Instituto Nacional de Ciência e Tecnologia Para o Controle do Câncer (INCT), Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
30
|
Esposito R, Morello S, Vllahu M, Eletto D, Porta A, Tosco A. Gastric TFF1 Expression from Acute to Chronic Helicobacter Infection. Front Cell Infect Microbiol 2017; 7:434. [PMID: 29085807 PMCID: PMC5649190 DOI: 10.3389/fcimb.2017.00434] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/21/2017] [Indexed: 12/26/2022] Open
Abstract
TFF1, a mucin-associated secreted peptide of gastric mucous cells, is known as a protective agent for stomach epithelium under different stimuli, but its role upon Helicobacter infection is still not clear. In this paper we characterized TFFs expression, with particular attention to TFF1, under Helicobacter infection in gastric cell lines. A mouse model was used to distinguish TFF1 mRNA expression between acute and chronic stages of Helicobacter infection. Our results show that TFF1 expression is induced in infected cells; in addition, the inflammatory response upon Helicobacter infection is inversely associated to pre-existing TFF1 protein levels. In infected mice, TFF1 is initially upregulated in gastric antrum in the acute phase of infection, along with IL-1β and IL-6. Then, expression of TFF1 is gradually silenced when the infection becomes chronic and IFN-γ, CXCL5, and CXCL15 reach higher levels. Our data suggest that TFF1 might help cells to counteract bacteria colonization and the development of a chronic inflammation.
Collapse
Affiliation(s)
| | - Silvana Morello
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Megi Vllahu
- Department of Pharmacy, University of Salerno, Fisciano, Italy.,PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, Italy
| | - Daniela Eletto
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Amalia Porta
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | | |
Collapse
|
|
31
|
Diao S, Zheng Q, Gao J, Yao Y, Ren S, Liu Y, Xu Y. Trefoil factor 3 contributes to the malignancy of glioma via regulating HIF-1α. Oncotarget 2017; 8:76770-76782. [PMID: 29100347 PMCID: PMC5652741 DOI: 10.18632/oncotarget.20010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/27/2017] [Indexed: 12/22/2022] Open
Abstract
Trefoil factor 3 (TFF3) plays significant roles in several solid tumors. However, the expression pattern and function of TFF3 in glioblastoma (GBM) have not been reported. Here, we report that expression level of TFF3 significantly elevated in glioma and correlated with the prognosis of glioma patients. Then we found TFF3 promotes proliferation, invasion, and migration and inhibits apoptosis of glioma cells in vitro, and delayed tumor progression in subcutaneous xenograft nude mice, and prolonged the median survival time in orthotopic xenograft mice. Moreover, knockdown of TFF3 reduced the expression of HIF-1α through a hypoxia-independent manner. These findings suggest that targeting TFF3 may offer a novel strategy for therapeutic intervention of malignant gliomas.
Collapse
Affiliation(s)
- Shuo Diao
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Qianqian Zheng
- Department of Pathophysiology, Basic Medical College, China Medical University, Shenyang, People's Republic of China
| | - Jian Gao
- Center of Laboratory Technology and Experimental Medicine, China Medical University, Shenyang, People's Republic of China
| | - Yiqun Yao
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Siyang Ren
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Yongjian Liu
- Department of Interventional Therapy, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Yinghui Xu
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| |
Collapse
|
|
32
|
Fujimoto A, Ishikawa Y, Ishii T, Yamada A, Igarashi Y, Ohmoto Y, Kaise M. Differences between gastric signet-ring cell carcinoma and poorly differentiated adenocarcinoma: A comparison of histopathologic features determined by mucin core protein and trefoil factor family peptide immunohistochemistry. Pathol Int 2017; 67:398-403. [PMID: 28691258 DOI: 10.1111/pin.12559] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 06/09/2017] [Indexed: 12/22/2022]
Abstract
We investigated differences between the pathological features of gastric signet-ring cell carcinoma (sig) and poorly differentiated adenocarcinoma (por) by examining the expressions of the trefoil factor family peptides (TFFs) and mucin core proteins (MUCs). Ninety-seven tissues of 97 gastric cancer patients were selected for this study. After gastrectomy, the major histopathologic types were determined to be sig, solid-type poorly differentiated adenocarcinoma (por1), non-solid type poorly differentiated adenocarcinoma (por2), and well-differentiated tubular adenocarcinoma (tub1). We evaluated the prevalence of positive staining for MUCs (MUC5AC and MUC2) and TFFs (TFF1 and TFF3) and assessed the correlation between MUCs and TFFs in each histopathological type. The rate of MUC2 expression significantly differed between sig and por2 (50.0% vs 11.7%, P = 0.011). TFF3 expression in sig significantly differed from TFF3 expression in both por2 (100% vs 17.6%, P < 0.0001) and por1 (100% vs 33.3%, P = 0.0004). MUC5AC and TFF1 expressions were significantly correlated in por1 (r = 0.705, P = 0.002), por2 (r = 0.535, P = 0.0009), and tub1 (r = 0.470, P = 0.0034), while MUC2 and TFF3 expressions were significantly correlated only in sig (r = 0.593, P = 0.040). The expression and correlation patterns of the TFFs and MUCs suggest that the histopathologic features of gastric sig differ from those of por.
Collapse
Affiliation(s)
- Ai Fujimoto
- Department of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan.,Division for Research and Development of Minimally Invasive Treatment, Cancer Center, Keio University, Tokyo, Japan
| | | | | | - Akihiro Yamada
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Yoshinori Igarashi
- Department of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan
| | - Yasukazu Ohmoto
- Institute of Biomedical Innovation, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Mitsuru Kaise
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| |
Collapse
|
|
33
|
Ehrlich L, Hall C, Meng F, Lairmore T, Alpini G, Glaser S. A Review of the Scaffold Protein Menin and its Role in Hepatobiliary Pathology. Gene Expr 2017; 17:251-263. [PMID: 28485270 PMCID: PMC5765438 DOI: 10.3727/105221617x695744] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome with neuroendocrine tumorigenesis of the parathyroid glands, pituitary gland, and pancreatic islet cells. The MEN1 gene codes for the canonical tumor suppressor protein, menin. Its protein structure has recently been crystallized, and it has been investigated in a multitude of other tissues. In this review, we summarize recent advancements in understanding the structure of the menin protein and its function as a scaffold protein in histone modification and epigenetic gene regulation. Furthermore, we explore its role in hepatobiliary autoimmune diseases, cancers, and metabolic diseases. In particular, we discuss how menin expression and function are regulated by extracellular signaling factors and nuclear receptor activation in various hepatic cell types. How the many signaling pathways and tissue types affect menin's diverse functions is not fully understood. We show that small-molecule inhibitors affecting menin function can shed light on menin's broad role in pathophysiology and elucidate distinct menin-dependent processes. This review reveals menin's often dichotomous function through analysis of its role in multiple disease processes and could potentially lead to novel small-molecule therapies in the treatment of cholangiocarcinoma or biliary autoimmune diseases.
Collapse
Affiliation(s)
- Laurent Ehrlich
- *Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Chad Hall
- †Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Fanyin Meng
- *Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
- ‡Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA
| | - Terry Lairmore
- †Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Gianfranco Alpini
- *Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
- ‡Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA
| | - Shannon Glaser
- *Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
- ‡Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA
| |
Collapse
|
|
34
|
Yuan Z, Chen D, Chen X, Yang H, Wei Y. Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells. Cancer Cell Int 2017; 17:7. [PMID: 28070169 PMCID: PMC5216547 DOI: 10.1186/s12935-016-0379-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 12/25/2016] [Indexed: 01/19/2023] Open
Abstract
Background There remains a great need for effective therapies for cervical cancers, the majority of which are aggressive leaving patients with poor prognosis. Methods and results Here, we identify a novel candidate therapeutic target, trefoil factor 3 (TFF3) which overexpressed in cervical cancer cells and was associated with reduced postoperative survival. Functional studies demonstrated that TFF3 overexpression promoted the proliferation and invasion of cervical cancer cells, and inhibited the apoptosis by inducing the mRNA changes in SiHa and Hela cell lines. Conversely, TFF3 silencing disrupted the proliferation and invasion of cervical cancer cells, and induced the apoptosis via Click-iT EdU test, flow cytometry analysis and two-dimensional Matrigel Transwell analysis. Western blot analysis showed that overexpression of TFF3 repressed E-cadherin (CDH1) expression to promote the invasion of cervical cancer cells. Furthermore, down-regulated CDH1 via overexpression of TFF3 was significantly up-regulated by virtue of inhibitor of p-STAT3. Conclusions These results suggested that TFF3 stimulated the invasion of cervical cancer cells probably by activating the STAT3/CDH1 signaling pathway. Furthermore, overexpression of TFF3 decreased the sensitivity of cervical cancer cells to etoposide by increasing P-glycoprotein (P-gp) functional activity. Overall, our work provides a preclinical proof that TFF3 not only contributes to the malignant progression of cervical cancers and but also is a potential therapeutic target. Electronic supplementary material The online version of this article (doi:10.1186/s12935-016-0379-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Zhaohu Yuan
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180 Guangdong Province China
| | - Dandan Chen
- Department of Radiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180 China
| | - Xiaojie Chen
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180 Guangdong Province China
| | - Huikuan Yang
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180 Guangdong Province China
| | - Yaming Wei
- Department of Blood Transfusion, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180 Guangdong Province China
| |
Collapse
|
|
35
|
Abstract
Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.
Collapse
Affiliation(s)
- Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Kristen A Engevik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Marshall H Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| |
Collapse
|
|
36
|
Hoellen F, Kostara A, Karn T, Holtrich U, El-Balat A, Otto M, Rody A, Hanker LC. Trefoil factor 3 expression in epithelial ovarian cancer exerts a minor effect on clinicopathological parameters. Mol Clin Oncol 2016; 5:422-428. [PMID: 27699037 DOI: 10.3892/mco.2016.994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/08/2016] [Indexed: 11/05/2022] Open
Abstract
The role of trefoil factor 3 (intestinal) (TFF3) has been analyzed in numerous cancers, such as breast and gastrointestinal cancer, and has been associated with poor prognosis. However, the role of TFF3 in ovarian cancers is not clear. Expression analysis of TFF3 in 91 ovarian cancer patients was performed by immunohistochemistry of primary paraffin-embedded tumor samples. The results were scored according to staining intensity and percentage of positive tumor cells resulting in an immune-reactive score (IRS) of 0-12. These results were correlated with clinicopathological characteristics and survival. TFF3 expression in our patient cohort exhibited a tendency towards improved overall and progression-free survival (PFS). In TFF3-positive serous and high-grade serous ovarian cancers, the median PFS was 27.6 months [95% confidence interval (CI): 0-55.7] vs. 15.2 months in TFF3-negative tumors (95% CI: 13.8-16.6) (P=0.183). The median overall survival was 53.9 months in TFF3-positive tumors (95% CI: Non-applicable) vs. 44.4 months in TFF3-negative cases (95% CI: 30.5-58.3) (P=0.36). TFF3 negativity was significantly associated with higher tumor grade (P=0.05). Based on our results, further studies are required in order to elucidate whether survival and chemosensitivity are affected by TFF3 expression in ovarian cancer.
Collapse
Affiliation(s)
- Friederike Hoellen
- Department of Gynecology and Obstetrics, University of Lübeck, D-23538 Lübeck, Germany
| | - Athina Kostara
- Department of Gynecology and Obstetrics, University of Lübeck, D-23538 Lübeck, Germany
| | - Thomas Karn
- Department of Obstetrics and Gynecology, Goethe University, D-60323 Frankfurt, Germany
| | - Uwe Holtrich
- Department of Obstetrics and Gynecology, Goethe University, D-60323 Frankfurt, Germany
| | - Ahmed El-Balat
- Department of Obstetrics and Gynecology, Goethe University, D-60323 Frankfurt, Germany
| | - Mike Otto
- Medical Center for Histopathology, Cytology and Molecular Diagnostics, D-54296 Trier, Germany
| | - Achim Rody
- Department of Gynecology and Obstetrics, University of Lübeck, D-23538 Lübeck, Germany
| | - Lars C Hanker
- Department of Gynecology and Obstetrics, University of Lübeck, D-23538 Lübeck, Germany
| |
Collapse
|
|
37
|
Rui W, Zou Y, Lee J, Nambiar SM, Lin J, Zhang L, Yang Y, Dai G. Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen. J Pharmacol Exp Ther 2016; 358:14-21. [PMID: 27189962 PMCID: PMC4931875 DOI: 10.1124/jpet.115.231316] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/05/2016] [Indexed: 12/16/2022] Open
Abstract
Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.
Collapse
Affiliation(s)
- Wenjuan Rui
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Yuhong Zou
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Joonyong Lee
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Shashank Manohar Nambiar
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Jingmei Lin
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Linjie Zhang
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Yan Yang
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| | - Guoli Dai
- Department of Pharmacology and Immunology, Anhui Medical University, Hefei, China (W.R., L.Z., Y.Y.); Department of Biology, School of Science, Center for Developmental and Regenerative Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana (W.R., Y.Z., S.M.N., G.D.); and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana (J.L.)
| |
Collapse
|
|
38
|
Comparison of serum trefoil factor 3 with the pepsinogen test for the screening of diffuse-type gastric cancer. Clin Exp Med 2016; 17:403-410. [PMID: 27154568 DOI: 10.1007/s10238-016-0426-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 04/27/2016] [Indexed: 02/06/2023]
Abstract
Emerging data show that serum trefoil factor 3 (TFF3) alone and combined with the serum pepsinogen (PG) test can increase the diagnostic yield of gastric cancer. We aimed to evaluate the diagnostic value of serum TFF3 for the screening of gastric cancer in Korean patients, especially for the screening of the diffuse type of gastric cancer, and compared TFF3 to the serum PG test. We enrolled 25 healthy controls and 79 subjects with gastric cancer who underwent endoscopic resection or surgery from June 2006 to June 2015. Data about age, sex, histological type according to the Lauren classification, stage of gastric cancer, and status of H. pylori were collected. Serum levels of PG I and PG II were measured by the latex-enhanced turbidimetric immunoassay, and serum TFF3 levels were measured by enzyme-linked immunosorbent assay. The optimal cutoff value of serum TFF3 was ≥8.9 ng/mL to diagnose gastric cancer, with 73.4 % sensitivity and 92.0 % specificity, which were higher than those of the serum PG I/II ratio, with 69.6 % sensitivity and 68.0 % specificity. The optimal sensitivity and specificity of serum TFF3 for the diagnosis of diffuse-type gastric cancer were 68.0 and 92.0 %, respectively, which were lower than those for the diagnosis of intestinal-type gastric cancer (75.6 and 100 %, respectively). Serum TFF3 is a more stable and useful marker than the serum PG test for the screening of gastric cancer in Korean patients. Serum TFF3 showed good diagnostic power in detecting both intestinal- and diffuse-type gastric cancer although it showed decreased power in diffuse type.
Collapse
|
|
39
|
Li J, Luo Y, Zhang R, Shi H, Zhu W, Shi J. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats. Int J Mol Sci 2015; 16:28386-400. [PMID: 26633367 PMCID: PMC4691052 DOI: 10.3390/ijms161226105] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 12/18/2022] Open
Abstract
The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.
Collapse
Affiliation(s)
- Jiali Li
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
- Beijing Key Laboratory on Drug Dependence Research, Beijing 100191, China.
| | - Yixiao Luo
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
| | - Ruoxi Zhang
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
- Beijing Key Laboratory on Drug Dependence Research, Beijing 100191, China.
| | - Haishui Shi
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
| | - Weili Zhu
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
- Beijing Key Laboratory on Drug Dependence Research, Beijing 100191, China.
| | - Jie Shi
- National Institute on Drug Dependence, Peking University, Beijing 100191, China.
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
- Beijing Key Laboratory on Drug Dependence Research, Beijing 100191, China.
- The State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China.
- Key Laboratory for Neuroscience of the Ministry of Education and Ministry of Public Healthy, Beijing 100191, China.
| |
Collapse
|