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Matsutoka K, Shoda K, Higuchi Y, Nakayama T, Saito R, Maruyama S, Takiguchi K, Nakata Y, Furuya S, Shiraishi K, Kawaguchi Y, Amemiya H, Masuda K, Ichikawa D. Enhancing Preoperative Diagnosis Accuracy of Stage III Gastric Cancer with Circulating circRNAs. Ann Surg Oncol 2025; 32:333-341. [PMID: 39433719 DOI: 10.1245/s10434-024-16387-2] [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: 06/18/2024] [Accepted: 10/07/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND The prognosis remains poor for stage III gastric cancer, and neoadjuvant chemotherapy is increasingly used to improve outcomes. Accurate diagnosis prior to treatment is essential to develop appropriate treatment strategies for poor prognosis subgroups. This study aims to enhance the accuracy of pre-treatment gastric cancer diagnosis using a biological approach centered on circulating circular RNA (circRNA). MATERIALS AND METHODS We conducted a comprehensive analysis of circRNA expression profiles using two Gene Expression Omnibus datasets to identify circRNA candidates associated with stage III gastric cancer. Subsequently, we validated these circRNA biomarkers in two independent clinical cohorts comprising a total of 174 patients with gastric cancer and non-disease controls through real-time polymerase chain reaction (PCR). RESULTS Genome-wide circRNA analysis identified a panel of four biomarkers capable of diagnosing pathologically confirmed stage III (pStage III) gastric cancer. In a training cohort (n = 83), a clinically applicable panel of four circRNAs was developed (AUC 0.81), which was successfully validated in an independent clinical cohort (n = 82; AUC 0.76). To assess clinical utility, we combined clinical imaging (cStage) with the circRNA panel. Among those initially diagnosed as cStage III but later confirmed as pStage I/II, 86% were accurately diagnosed using the molecular biological approach with circRNAs. CONCLUSIONS We have developed a circRNA-based non-invasive liquid biopsy that can improve the diagnostic performance of pStage III gastric cancer before treatment. Our circRNA model could provide a sophisticated and personalized approach to assist in treatment planning for patients with advanced gastric cancer.
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Affiliation(s)
- Koichi Matsutoka
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Katsutoshi Shoda
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
| | - Yudai Higuchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Takashi Nakayama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Ryo Saito
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Suguru Maruyama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Koichi Takiguchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yuki Nakata
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Shinji Furuya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Kensuke Shiraishi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yoshihiko Kawaguchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Hidetake Amemiya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | | | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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Nian Z, Deng M, Ye L, Tong X, Xu Y, Xu Y, Chen R, Wang Y, Mao F, Xu C, Lu R, Mao Y, Xu H, Shen X, Xue X, Guo G. RNA epigenetic modifications in digestive tract cancers: Friends or foes. Pharmacol Res 2024; 206:107280. [PMID: 38914382 DOI: 10.1016/j.phrs.2024.107280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Digestive tract cancers are among the most common malignancies worldwide and have high incidence and mortality rates. Thus, the discovery of more effective diagnostic and therapeutic targets is urgently required. The development of technologies to accurately detect RNA modification has led to the identification of numerous RNA chemical modifications in humans (epitranscriptomics) that are involved in the occurrence and development of digestive tract cancers. RNA modifications can cooperatively regulate gene expression to facilitate normal physiological functions of the digestive system. However, the dysfunction of relevant RNA-modifying enzymes ("writers," "erasers," and "readers") can lead to the development of digestive tract cancers. Consequently, targeting dysregulated enzyme activity could represent a potent therapeutic strategy for the treatment of digestive tract cancers. In this review, we summarize the most widely studied roles and mechanisms of RNA modifications (m6A, m1A, m5C, m7G, A-to-I editing, pseudouridine [Ψ]) in relation to digestive tract cancers, highlight the crosstalk between RNA modifications, and discuss their roles in the interactions between the digestive system and microbiota during carcinogenesis. The clinical significance of novel therapeutic methods based on RNA-modifying enzymes is also discussed. This review will help guide future research into digestive tract cancers that are resistant to current therapeutics.
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Affiliation(s)
- Zekai Nian
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Ming Deng
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Lele Ye
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yixi Xu
- School of public administration, Hangzhou Normal University, Hangzhou, China
| | - Yiliu Xu
- Research Center of Fluid Machinery Engineering & Technology, Jiangsu University, Zhenjiang, China
| | - Ruoyao Chen
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yulin Wang
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Feiyang Mao
- Second Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Chenyv Xu
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ruonan Lu
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yicheng Mao
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Hanlu Xu
- Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangyang Xue
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Gangqiang Guo
- Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
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3
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Imamura T, Komatsu S, Nishibeppu K, Kiuchi J, Ohashi T, Konishi H, Shiozaki A, Yamamoto Y, Moriumura R, Ikoma H, Ochiai T, Otsuji E. Urinary microRNA-210-3p as a novel and non-invasive biomarker for the detection of pancreatic cancer, including intraductal papillary mucinous carcinoma. BMC Cancer 2024; 24:907. [PMID: 39069624 DOI: 10.1186/s12885-024-12676-x] [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: 08/18/2023] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach. METHODS We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers. RESULTS (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine. CONCLUSIONS Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC. TRIAL REGISTRATION Not applicable.
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MESH Headings
- Humans
- MicroRNAs/urine
- MicroRNAs/blood
- MicroRNAs/genetics
- Female
- Male
- Biomarkers, Tumor/urine
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/blood
- Pancreatic Neoplasms/urine
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/blood
- Middle Aged
- Aged
- Adenocarcinoma, Mucinous/urine
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/diagnosis
- ROC Curve
- Case-Control Studies
- Gene Expression Regulation, Neoplastic
- Adult
- Carcinoma, Pancreatic Ductal/urine
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/blood
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Affiliation(s)
- Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yusuke Yamamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Toshiya Ochiai
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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4
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Omar A, Govan D, Penny C. Epigenetic regulation in colorectal cancer: The susceptibility of microRNAs 145, 143 and 133b to DNA demethylation and histone deacetylase inhibitors. PLoS One 2023; 18:e0289800. [PMID: 37561735 PMCID: PMC10414600 DOI: 10.1371/journal.pone.0289800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
Globally, colorectal cancer (CRC) is a major health concern. Despite improvements in CRC treatment, mortality rates remain high. Genetic instability and epigenetic dysregulation of gene expression are instigators of CRC development that result in genotypic differences, leading to often variable and unpredictable treatment responses. Three miRNAs, miR-143, -145 and -133b, are most commonly downregulated in CRC and are proposed here as potential tumour suppressors. Although the downregulation of these miRNAs in CRC is largely unexplained, epigenetic silencing has been postulated to be a causative regulatory mechanism. Potential epigenetic modulation of miRNA expression, by means of histone acetylation and DNA methylation, was assessed in this study by treating early (SW1116) and late stage (DLD1) CRC cells with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-Aza-2'C) and the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), respectively. Subsequent quantification of miRNA expression revealed that while all the selected miRNAs were susceptible to DNA demethylation in early- and late-stage CRC cells, susceptibility to DNA demethylation was significantly pronounced in late-stage DLD1 cells. Conversely, although histone acetylation moderately affected miRNA expression in early-stage CRC, it had a marginal effect on the expression of miRNAs in late-stage CRC cells. Overall, this study provides further understanding of the contribution of epigenetics to the regulation of putative tumour suppressor miRNAs in CRC.
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Affiliation(s)
- Aadilah Omar
- Department of Internal Medicine, Oncology Division, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Republic of South Africa (RSA)
| | - Drishna Govan
- Department of Internal Medicine, Oncology Division, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Republic of South Africa (RSA)
| | - Clement Penny
- Department of Internal Medicine, Oncology Division, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, Republic of South Africa (RSA)
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Takashima Y, Komatsu S, Ohashi T, Kiuchi J, Nishibeppu K, Kamiya H, Arakawa H, Ishida R, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Otsuji E. Plasma miR-1254 as a predictive biomarker of chemosensitivity and a target of nucleic acid therapy in esophageal cancer. Cancer Sci 2023; 114:3027-3040. [PMID: 37190912 PMCID: PMC10323105 DOI: 10.1111/cas.15830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/06/2023] [Accepted: 04/09/2023] [Indexed: 05/17/2023] Open
Abstract
This study investigated novel tumor suppressor microRNAs (miRNAs) that decrease in plasma and predict chemosensitivity to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC) and revealed their usefulness as novel therapeutic agents. We selected four miRNA candidates (miR-323, 345, 409, and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to NAC and an NCBI database review. Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P = 0.0021, area under the receiver-operating characteristic curve 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P = 0.0710) and were an independent factor predicting a higher response to chemotherapy (P = 0.0022, odds ratio 7.86) and better prognosis (P = 0.0235, hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to cisplatin in mice. Plasma miR-1254 might be a useful biomarker for predicting responses to NAC, and the restoration of plasma miR-1254 levels might improve chemosensitivity in ESCC.
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Affiliation(s)
- Yusuke Takashima
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Shuhei Komatsu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Takuma Ohashi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Jun Kiuchi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Keiji Nishibeppu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hajime Kamiya
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hiroshi Arakawa
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Ryo Ishida
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hiroki Shimizu
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Tomohiro Arita
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hirotaka Konishi
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Atsushi Shiozaki
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Takeshi Kubota
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Hitoshi Fujiwara
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
| | - Eigo Otsuji
- Department of Surgery, Division of Digestive SurgeryKyoto Prefectural University of MedicineKyotoJapan
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Chidambaram S, Kawka M, Gall TM, Cunningham D, Jiao LR. Can we predict the progression of premalignant pancreatic cystic tumors to ductal adenocarcinoma? Future Oncol 2022; 18:2605-2612. [PMID: 35730473 DOI: 10.2217/fon-2021-1545] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent malignant pancreatic tumor. Few studies have shown how often PDACs arise from cystic precursor lesions. This special report aims to summarize the evidence on the progression of precancerous lesions to PDAC. A review of the literature found four studies that discussed pancreatic intraepithelial lesions (PanINs), three that discussed mucinous cystic neoplasms (MCN) and five that discussed intraductal papillary neoplasms (IPMNs). PanINs were the most common precursors lesion, with approximately 80% of PDACs originating from this lesion. The lack of evidence characterizing the features of PDAC precursor cystic lesions potentially leads to a subset of patients undergoing surgery unnecessarily. Advancements in molecular techniques could allow the study of cystic lesions at a genetic level, leading to more personalized management.
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Affiliation(s)
- Swathikan Chidambaram
- Department of Surgery & Cancer, Hammersmith Hospital Campus, Imperial College, London, W12 0HS, UK
- Imperial College London, Exhibition Road, South Kensington, London, SW7 2BU, UK
| | - Michal Kawka
- Imperial College London, Exhibition Road, South Kensington, London, SW7 2BU, UK
| | - Tamara Mh Gall
- Department of Surgery & Cancer, Hammersmith Hospital Campus, Imperial College, London, W12 0HS, UK
- Imperial College London, Exhibition Road, South Kensington, London, SW7 2BU, UK
| | - David Cunningham
- Department of Academic Surgery, The Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, UK
| | - Long R Jiao
- Imperial College London, Exhibition Road, South Kensington, London, SW7 2BU, UK
- Department of Academic Surgery, The Royal Marsden Hospital, 203 Fulham Road, London, SW3 6JJ, UK
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7
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Takaki W, Konishi H, Shoda K, Arita T, Kataoka S, Shibamoto J, Furuke H, Takabatake K, Shimizu H, Komatsu S, Shiozaki A, Fujiwara H, Masuda K, Otsuji E. Significance of Circular FAT1 as a Prognostic Factor and Tumor Suppressor for Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2021; 28:8508-8518. [PMID: 34185205 PMCID: PMC8591040 DOI: 10.1245/s10434-021-10089-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/10/2021] [Indexed: 12/03/2022]
Abstract
Background Circular RNA is a novel endogenous non-coding RNA with a stable loop structure, and theories for its biogenesis and usefulness as a biomarker in various cancers have been proposed. The present study investigated the significance of circular FAT1 (circFAT1) as a novel biomarker in esophageal squamous cell carcinoma (ESCC). Method CircFAT1 expression levels were measured in ESCC cell lines and the effects of downregulating circFAT1 on cell migration and invasion were examined using a transwell assay. The functions of miR-548g, which will be sponged by circFAT1, were assessed. Furthermore, the expression of circFAT1 was evaluated in 51 radically resected ESCC tissue samples using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationships between circFAT1 expression, clinicopathological factors, and patient prognosis were analyzed. Results CircFAT1 expression levels were significantly lower in tumor tissue than in adjacent non-tumorous mucosal tissue (p = 0.01). The downregulation of circFAT1 expression promoted ESCC cell migration and invasive ability, but not proliferation. The expression of miR-548g was upregulated by the downregulation of circFAT1. The overexpression of miR-548g also promoted ESCC cell migration and invasion. Recurrence-free survival (p = 0.02) and cancer-specific survival (p = 0.04) rates were significantly higher in patients with elevated circFAT1 expression levels. Conclusion The expression level of circFAT1 is a novel prognostic marker in ESCC patients. New treatment strategies may be developed using the tumor suppressive functions of circFAT1. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-021-10089-9.
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Affiliation(s)
- Wataru Takaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan.
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan.,First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Satoshi Kataoka
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Jun Shibamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Hirotaka Furuke
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Kazuya Takabatake
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
| | | | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan
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8
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Zhou K, Chang Y, Han B, Li R, Wei Y. MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review). Exp Ther Med 2021; 21:499. [PMID: 33791008 PMCID: PMC8005665 DOI: 10.3892/etm.2021.9930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Triptolide is the main bioactive constituent isolated from the Chinese herb Tripterygium wilfordii Hook F., which possesses a variety of pharmacological properties. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRNAs are implicated in several intracellular processes, whereby their dysregulation contributes to pathogenesis of various diseases. Thus, miRNAs have great potential as biomarkers and therapeutic targets for diseases, and are implicated in drug treatment. Previous studies have reported that specific miRNAs are targeted, and their expression levels can be altered following exposure to triptolide. Thus, miRNAs are emerging as crucial mediators in the pharmacological activities of triptolide. The present review summarizes current literature on miRNAs as target molecules in the pharmacological activities of triptolide, including antitumor, anti-inflammatory, immunosuppressive, renal protective, cardioprotective, antiangiogenesis activities and multiorgan toxicity effects. In addition, the diverse signaling pathways involved are discussed to provide a comprehensive understanding of the underlying molecular mechanisms of triptolide in the regulation of target miRNAs.
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Affiliation(s)
- Kun Zhou
- Shanxi Institute of Energy, Taiyuan, Shanxi 030600, P.R. China
| | - Yinxia Chang
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Bo Han
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Rui Li
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Yanming Wei
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
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Xie XY, Chen XM, Shi L, Liu JW. Increased expression of microRNA-26a-5p predicted a poor survival outcome in osteosarcoma patients: An observational study. Medicine (Baltimore) 2021; 100:e24765. [PMID: 33761638 PMCID: PMC9281968 DOI: 10.1097/md.0000000000024765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 01/26/2021] [Indexed: 01/05/2023] Open
Abstract
MicroRNA (miR)-26a-5p is an oncogene significantly associated with osteosarcoma. We try to evaluate expression of circulating miR-26a-5p in osteosarcoma patients and evaluate its significance.A total of 243 consecutive osteosarcoma patients and 96 healthy participates were enrolled. Circulating miR-26a-5p levels were evaluated by using real-time quantitative reverse transcription polymerase chain reactions (RT-PCR). The association between circulating miR-26a-5p level and survival outcomes was evaluated by univariate and multivariate analysis.Circulating miR-26a-5p levels in osteosarcoma patients was significantly higher than that of healthy volunteers (P < .05). Upregulated miR-26a-5p was significantly related to advanced cancer and metastasis (both P < .05). Moreover, patients with a high serum miR-26a-5p had a poorer overall survival than those with a low serum miR-26a-5p levels (P < .05). Circulating miR-26a-5p level also been showed as independent risk factor for osteosarcoma in multivariate analysis (hazard ratio [HR], 0.38; 95% confidence interval [CI]: 0.11-0.98; P < .01).Circulating miR-26a-5p was significantly upregulated in osteosarcoma patients and remarkably associated with poor prognosis, indicating that circulating miR-26a-5p might serve as a useful diagnostic and prognostic biomarker for osteosarcoma.
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Affiliation(s)
- Xiao-Yu Xie
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing, PR China
| | - Xian-Ming Chen
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing, PR China
| | - Ling Shi
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing, PR China
| | - Jun-Wei Liu
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing, PR China
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10
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Liquid biopsy as a perioperative biomarker of digestive tract cancers: review of the literature. Surg Today 2020; 51:849-861. [PMID: 32979121 DOI: 10.1007/s00595-020-02148-7] [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: 05/26/2020] [Accepted: 08/10/2020] [Indexed: 10/23/2022]
Abstract
Tissue biopsies are the gold-standard for investigating the molecular characterization of tumors. However, a "solid" biopsy is an invasive procedure that cannot capture real-time tumor dynamics and may yield inaccurate information because of intratumoral heterogeneity. In this review, we summarize the current state of knowledge about surgical treatment-associated "liquid" biopsy for patients with digestive organ tumors. A liquid biopsy is a technique involving the sampling and testing of non-solid biological materials, including blood, urine, saliva, and ascites. Previous studies have reported the potential value of blood-based biomarkers, circulating tumor cells, and cell-free nucleic acids as facilitators of cancer treatment. The applications of a liquid biopsy in a cancer treatment setting include screening and early diagnosis, prognostication, and outcome and recurrence monitoring of cancer. This technique has also been suggested as a useful tool in personalized medicine. The transition to precision medicine is still in its early stages. Soon, however, liquid biopsy is likely to form the basis of patient selection for molecular targeted therapies, predictions regarding chemotherapy sensitivity, and real-time evaluations of therapeutic effects.
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11
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The clinical significance of serum miRNA-224 expression in hepatocellular carcinoma. Clin Exp Hepatol 2020; 6:20-27. [PMID: 32166120 PMCID: PMC7062117 DOI: 10.5114/ceh.2020.93052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/21/2019] [Indexed: 01/01/2023] Open
Abstract
Aim of the study Micro-ribonucleic acids (miRNA) are small single stranded RNA molecules. They act as key regulators of several cellular processes such as proliferation, apoptosis, tumor differentiation, invasion and metastasis. Hepatocellular carcinoma (HCC) represents the most common primary liver cancer. miRNA-224 is an oncomiR that is highly upregulated in HCC tissues. The aim of the present study was to measure the relative expression of circulating miRNA-224 in the serum of patients with HCV-related liver cirrhosis and HCC and to assess its usefulness in the diagnosis of HCC. Material and methods Forty-eight patients were classified into two groups: 24 HCV-related HCC patients (HCC group), and 24 HCV-related liver cirrhosis patients (LC group). A third group included 24 healthy volunteers (control group). Clinical examination, imaging studies and routine laboratory investigations, including serum α-fetoprotein (AFP), were done. Quantification of serum miRNA-224 expression was performed using real time reverse transcription polymerase chain reaction (RT-PCR). Results The relative expression of serum miRNA-224 was significantly higher in HCC patients compared to LC patients and healthy control subjects. Its level correlated positively with the serum concentration of AFP and with Barcelona Clinic Liver Cancer (BCLC) stage of HCC. By combining miRNA-224 relative expression with AFP, their diagnostic sensitivity, specificity and accuracy increased significantly (95.0%, 92.1% and 93.2%, respectively) compared with either of the two markers alone in discriminating HCC from liver cirrhosis. Conclusions Serum miRNA-224 relative expression may aid in the diagnosis of HCC. Better diagnostic performance is obtained if miRNA-224 is combined with other tumor markers such as AFP.
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Abdulmawjood B, Roma-Rodrigues C, Fernandes AR, Baptista PV. Liquid biopsies in myeloid malignancies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:1044-1061. [PMID: 35582281 PMCID: PMC9019201 DOI: 10.20517/cdr.2019.88] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022]
Abstract
Hematologic malignancies are the most common type of cancer affecting children and young adults, and encompass diseases, such as leukemia, lymphoma, and myeloma, all of which impact blood associated tissues such as the bone marrow, lymphatic system, and blood cells. Clinical diagnostics of these malignancies relies heavily on the use of bone marrow samples, which is painful, debilitating, and not free from risks for leukemia patients. Liquid biopsies are based on minimally invasive assessment of markers in the blood (and other fluids) and have the potential to improve the efficacy of diagnostic/therapeutic strategies in leukemia patients, providing a useful tool for the real time molecular profiling of patients. The most promising noninvasive biomarkers are circulating tumor cells, circulating tumor DNA, microRNAs, and exosomes. Herein, we discuss the role of assessing these circulating biomarkers for the understanding of tumor progression and metastasis, tumor progression dynamics through treatment and for follow-up.
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Affiliation(s)
- Bilal Abdulmawjood
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus Caparica, Caparica 2829-516, Portugal
| | - Catarina Roma-Rodrigues
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus Caparica, Caparica 2829-516, Portugal
| | - Alexandra R Fernandes
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus Caparica, Caparica 2829-516, Portugal
| | - Pedro V Baptista
- UCIBIO, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus Caparica, Caparica 2829-516, Portugal
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13
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El-Ahwany EGE, Mourad L, Zoheiry MMK, Abu-Taleb H, Hassan M, Atta R, Hassanien M, Zada S. MicroRNA-122a as a non-invasive biomarker for HCV genotype 4-related hepatocellular carcinoma in Egyptian patients. Arch Med Sci 2019; 15:1454-1461. [PMID: 31749873 PMCID: PMC6855160 DOI: 10.5114/aoms.2019.86621] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/22/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection persists in most infected individuals and can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have a crucial role in various liver diseases, especially HCC. The expression profiles of circulating microRNAs have been studied aiming at the identification of novel non-invasive biomarkers. This study aims to develop a non-invasive diagnostic tool based on measuring the serum levels of different miRNAs in order to detect HCV-induced HCC at the early stages of the disease. MATERIAL AND METHODS Five main miRNAs (miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a) were selected according to the literature that demonstrated their unique expression pattern during HCC development. Serum samples were collected from 42 cases of chronic hepatitis C (CHC) without cirrhosis, 45 cases of CHC with cirrhosis (LC), 38 cases of HCC with HCV, and 40 healthy individuals serving as a control. The five miRNAs were measured using real-time reverse transcription PCR. The conventional HCC markers α-fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) were measured with commercial kits. RESULTS Serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a were significantly lower (p < 0.01) in HCC than in CHC and LC groups. As a single marker, miRNA-122a had the highest sensitivity for HCC, followed by miRNA-199a, miRNA-145, miRNA-139, and miRNA-125a. CONCLUSIONS These findings indicate that measurement of serum levels of miRNA-122a, miRNA-125a, miRNA-139, miRNA-145, and miRNA-199a can differentiate HCC from CHC and LC. Our results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for HCV-induced HCC.
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Affiliation(s)
| | - Lobna Mourad
- Department of Biology, The American University, Cairo, Egypt
| | - Mona M. K. Zoheiry
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Hoda Abu-Taleb
- Department of Environmental Research, Theodor Bilharz Research Institute, Giza, Egypt
| | - Marwa Hassan
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Raafat Atta
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Moataz Hassanien
- Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Suher Zada
- Department of Biology, The American University, Cairo, Egypt
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Gao W, Pang D, Yu S. Serum level of miR-142-3p predicts prognostic outcome for colorectal cancer following curative resection. J Int Med Res 2019; 47:2116-2125. [PMID: 30922137 PMCID: PMC6567755 DOI: 10.1177/0300060519834815] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE MicroRNA (miR)-142-3p may function as a tumor suppressor in the development of various cancers. In this study, we measured serum levels of miR-142-3p in patients with colorectal cancer (CRC) to evaluate the diagnostic and prognostic value of miR-142-3p. METHODS Serum samples from 363 consecutive CRC patients and 156 healthy controls were retrospectively collected. Serum miR-142-3p levels were measured using real-time quantitative reverse transcription polymerase chain reaction. All patients were followed up regularly after tumor resection. The correlation between serum miR-142-3p level and survival outcomes was analyzed. RESULTS Serum levels of miR-142-3p were significantly lower in CRC patients than in healthy volunteers. A low serum miR-142-3p level was significantly associated with advanced cancer. Survival analysis demonstrated that patients with a low serum miR-142-3p had a lower 5-year overall survival rate than patients with a high serum miR-142-3p level (67.4% vs. 76.9%). Serum miR-142-3p level was also shown to be an independent risk factor for CRC in multivariate analysis (hazard ratio, 2.68; 95% confidence interval: 1.21-7.95). CONCLUSIONS Serum miR-142-3p might serve as a useful diagnostic and prognostic marker for CRC.
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Affiliation(s)
- Wencang Gao
- 1 Oncology Department, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,2 The Second Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,3 Pangde Xiang Famous Chinese Medical Inheriting Studio of Zhejiang Province, Hangzhou, Zhejiang, PR China
| | - Dexiang Pang
- 1 Oncology Department, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,2 The Second Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,3 Pangde Xiang Famous Chinese Medical Inheriting Studio of Zhejiang Province, Hangzhou, Zhejiang, PR China
| | - Senquan Yu
- 1 Oncology Department, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,2 The Second Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.,3 Pangde Xiang Famous Chinese Medical Inheriting Studio of Zhejiang Province, Hangzhou, Zhejiang, PR China
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Kiuchi J, Komatsu S, Imamura T, Nishibeppu K, Shoda K, Arita T, Kosuga T, Konishi H, Shiozaki A, Okamoto K, Fujiwara H, Ichikawa D, Otsuji E. Low levels of tumour suppressor miR-655 in plasma contribute to lymphatic progression and poor outcomes in oesophageal squamous cell carcinoma. Mol Cancer 2019; 18:2. [PMID: 30609933 PMCID: PMC6320607 DOI: 10.1186/s12943-018-0929-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 12/26/2018] [Indexed: 01/07/2023] Open
Abstract
Recent studies identified that low levels of tumour suppressor microRNAs (miRNAs) in plasma/serum relate to tumour progression and poor outcomes in cancers. We selected six candidates (miR-126, 133b, 143, 203, 338-3p, 655) of tumour suppressor miRNAs in oesophageal squamous cell carcinoma (ESCC) by a systematic review of NCBI database. Of these, miR-655 levels were significantly down-regulated in plasma of ESCC patients compared to healthy volunteers by test- and validation-scale analyses. Low levels of plasma miR-655 were significantly associated with lymphatic invasion, lymph node metastasis and advanced stage. Univariate and multivariate analysis revealed that the low level of plasma miR-655 was an independent risk factor of lymphatic progression and a poor prognostic factor. Overexpression of miR-655 in ESCC cells inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition. Increased plasma miR-655 levels by the subcutaneous injection significantly inhibited lymph node metastasis in mice. Low levels of miR-655 in plasma relate to lymphatic progression and poor outcomes, and the restoration of the plasma miR-655 levels might inhibit tumour and lymphatic progression in ESCC.
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Affiliation(s)
- Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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16
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Fadaka AO, Pretorius A, Klein A. Biomarkers for Stratification in Colorectal Cancer: MicroRNAs. Cancer Control 2019; 26:1073274819862784. [PMID: 31431043 PMCID: PMC6704426 DOI: 10.1177/1073274819862784] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 06/08/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. In spite of the fact that the death rates have declined over the previous decade, particularly because of enhanced screening or potential treatment alternatives, CRC still remains the third leading cause of cancer-related mortality in the world, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Unlike prostate and lung cancer, CRC is not easily detectable in its early stage, which may also account for its high mortality rate. MicroRNAs (miRNAs) are a class of noncoding RNAs. The roles of these noncoding RNAs have been implicated in cancer pathogenesis, most especially CRC, due to their ability to posttranscriptionally regulate the expression of oncogenes and tumor suppressor genes. Dysregulated expression of many miRNAs regulates the expression of hundreds of growth regulatory genes and pathways that are important in the multistep model of colorectal carcinogenesis. If CRC is detected early, it is a largely treatable disease. Early diagnosis, including the identification of premalignant adenomas, is regarded a major concept for improving patient survival in CRC treatment. Several lines of research suggest that miRNAs are closely implicated in the metastatic process in CRC and some of these miRNAs could be useful as promising clinical tools for identifying specific stages of CRC due to their differential expression. This review discusses the correlation between CRC staging relative to the specific expression of miRNA for early detection, treatment, and disease management.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - Ashley Pretorius
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - Ashwil Klein
- Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
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He D, Yue Z, Li G, Chen L, Feng H, Sun J. Low Serum Levels of miR-101 Are Associated with Poor Prognosis of Colorectal Cancer Patients After Curative Resection. Med Sci Monit 2018; 24:7475-7481. [PMID: 30341274 PMCID: PMC6204656 DOI: 10.12659/msm.909768] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Recent studies showed low expression of microRNA (miR)-101 in various malignancies. However, the association of serum miR-101 and colorectal cancer (CRC) remains unknown. We investigated diagnostic and prognostic significance of serum miR-101 in CRC. MATERIAL AND METHODS A total of 263 consecutive CRC patients and 126 healthy controls were enrolled in this study. Serum miR-101 levels were measured using real-time quantitative reverse transcription polymerase chain reactions. The association between serum miR-101 level and survival outcome was analyzed. RESULTS Serum miR-101 in CRC patients was significantly lower than in healthy volunteers (P<0.001). Low serum miR-101 level was significantly associated with advanced cancer stage. Moreover, survival analysis demonstrated that patients with a low serum miR-101 had poorer 5-year overall survival than patients with a high serum miR-101 level (p=0.041). Serum miR-101 level also were confirmed as an independent risk factor for CRC in multivariate analysis (hazard ratio, 1.468; 95%CI, 0.981-1.976; p<0.001). CONCLUSIONS Serum miR-101 level was significantly downregulated in CRC patients and was closely correlated with poor clinical outcome, suggesting that serum miR-101 might be a useful diagnostic and prognostic marker for CRC.
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Affiliation(s)
- Dedong He
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Zhongyi Yue
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Guangjun Li
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Liping Chen
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Hailong Feng
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Jianwei Sun
- Scientific Research and Postgraduate Education, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
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18
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Komatsu S, Ichikawa D, Kawaguchi T, Takeshita H, Miyamae M, Ohashi T, Okajima W, Imamura T, Kiuchi J, Arita T, Konishi H, Shiozaki A, Fujiwara H, Okamoto K, Otsuji E. Plasma microRNA profiles: identification of miR-23a as a novel biomarker for chemoresistance in esophageal squamous cell carcinoma. Oncotarget 2018; 7:62034-62048. [PMID: 27566562 PMCID: PMC5308709 DOI: 10.18632/oncotarget.11500] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND This study aims to explore novel microRNAs in plasma for predicting chemoresistance in preoperative chemotherapy of patients with esophageal squamous cell carcinoma (ESCC) using a microRNA array-based approach. RESULTS (1) Four candidate microRNAs (miR-223, 103a, 23b and 23a), which were highly expressed in the pretreatment plasma of patients with a low histopathologic response, were selected. (2) In a large-scale validation analysis by quantitative RT–PCR, plasma levels of miR-223, miR-23b and miR-23a were significantly higher in patients with a low histopathologic response than in those with a high histopathologic response (p = 0.0345, p = 0.0125 and p = 0.0114). (3) Of all candidate microRNAs, miR-23a expression of pretreatment ESCC tumor tissues was significantly higher in ESCC patients with a low histopathologic response than in those with a high histopathologic response (p = 0.0278). (4) After overexpressing each candidate in ESCC cells, miR-23a induced significant chemoresistance to both 5-fluorouracil and cisplatin, and miR-223 to cisplatin in vitro. (5) A high level of plasma miR-23a, which tended to correlate with lymphatic invasion (p = 0.0808) and deep depth of invasion (p = 0.0658), was an independent risk factor for chemoresistance in ESCC (p = 0.0222; odds ratio: 12.4; range 1.46–105). MATERIALS AND METHODS We used the Toray® 3D-Gene microRNA array-based approach to compare plasma microRNA levels between patients with a high or a low histopathologic response to chemotherapy. All patients underwent a preoperative chemotherapy regimen with cisplatin plus 5-fluorouracil. CONCLUSIONS Plasma miR-23a might be a useful biomarker for predicting chemoresistance in ESCC patients.
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Affiliation(s)
- Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Takeshita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Li SG, Shi QW, Yuan LY, Qin LP, Wang Y, Miao YQ, Chen Z, Ling CQ, Qin WX. C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018. [PMID: 29523159 PMCID: PMC5845216 DOI: 10.1186/s13046-018-0698-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied. METHODS Cells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis. RESULTS Triptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein. CONCLUSIONS The triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.
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Affiliation(s)
- Shu-Guang Li
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.,Department of Endocrinology, General Hospital of Wuhan, People's Liberation Army, Wuhan, People's Republic of China
| | - Qian-Wei Shi
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.,Guang An' men Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China
| | - Ling-Yan Yuan
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Li-Ping Qin
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yan Wang
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yu-Qing Miao
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Zhe Chen
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Chang-Quan Ling
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
| | - Wen-Xing Qin
- Department of oncology, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Hirajima S, Ohashi T, Imamura T, Kiuchi J, Arita T, Konishi H, Shiozaki A, Moriumura R, Ikoma H, Okamoto K, Taniguchi H, Itoh Y, Otsuji E. Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. Oncotarget 2018; 7:53820-53836. [PMID: 27462777 PMCID: PMC5288224 DOI: 10.18632/oncotarget.10781] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Aims This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. Results (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. Methods We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. Conclusions Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shoji Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Yang W, Ma J, Zhou W, Zhou X, Cao B, Zhang H, Zhao Q, Fan D, Hong L. Molecular mechanisms and clinical implications of miRNAs in drug resistance of esophageal cancer. Expert Rev Gastroenterol Hepatol 2017; 11:1151-1163. [PMID: 28838272 DOI: 10.1080/17474124.2017.1372189] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
With the increasing incidence of esophageal cancer, drug resistance is becoming a major obstacle to successful cancer therapy since chemotherapy is regarded as a curative approach to inhibit cancer cell proliferation. Despite the great progress in anticancer treatment achieved during the last decades, the mechanisms of multidrug resistance have not been completely elucidated. Recently, accumulating studies and pre-clinical reports highlighted the role of miRNAs in the drug resistance of esophageal cancer. Areas covered: In this review, we mainly summarized the current advances of miRNAs in esophageal cancer and the mechanisms underlying drug resistance. We also reviewed the potential role of miRNAs as biomarkers for predicting drug response and prognosis. Finally, we envisaged the future orientation and challenges in translating the existing knowledge of drug resistance related miRNAs into clinical applications. Expert commentary: Based on the current knowledge of certain miRNAs, we believe that miRNAs would be helpful to overcome the drug resistance and provide personalized treatment for patients with esophageal cancer. The aims of this study were to provide a comprehensive summary on the emerging role of miRNAs in the drug resistance of esophageal cancer and attract broad attention of more researchers on this field.
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Affiliation(s)
- Wanli Yang
- a State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Jiaojiao Ma
- a State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Wei Zhou
- a State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Xin Zhou
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Bo Cao
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Hongwei Zhang
- c Department of Digestive Surgery , Xijing Hospital, Fourth Military Medical University , Xi'an , China
| | - Qingchuan Zhao
- c Department of Digestive Surgery , Xijing Hospital, Fourth Military Medical University , Xi'an , China
| | - Daiming Fan
- a State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Liu Hong
- a State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
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Low plasma levels of miR-101 are associated with tumor progression in gastric cancer. Oncotarget 2017; 8:106538-106550. [PMID: 29290969 PMCID: PMC5739754 DOI: 10.18632/oncotarget.20860] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 08/15/2017] [Indexed: 12/16/2022] Open
Abstract
Background Several studies have identified the decreased expression of the tumor suppressor miR-101 in various cancers. In this study, we tested miR-101 as a potential therapeutic target and novel plasma biomarker for gastric cancer (GC). Results The miR-101 expression level was significantly lower in GC tissues (P = 0.0038) and GC cell lines (P = 0.0238) than in normal gastric mucosa. Both exosomal and plasma miR-101 were significantly downregulated in GC patients compared with healthy volunteers (P = 0.0281 and P < 0.0001, respectively). Low miR-101 plasma level was significantly associated with advanced T factor, advanced disease stage, and peritoneal metastasis and predicted poor prognosis in GC patients (P = 0.0368; hazard ratio, 3.079; 95% confidence interval: 1.06–11.08). Overexpression of miR-101 in GC cells induced apoptosis by inhibiting MCL1 and suppressed cell migration and invasion by regulating ZEB1. Conclusions Depletion of the tumor suppressor miRNA-101 in plasma is related to tumor progression and poor outcomes. Low plasma miR-101 may be a biomarker for GC, and its restoration might be a novel anticancer treatment strategy.
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Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer. Sci Rep 2017; 7:5708. [PMID: 28720759 PMCID: PMC5515843 DOI: 10.1038/s41598-017-06137-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/08/2017] [Indexed: 12/16/2022] Open
Abstract
This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.
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24
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Sun KX, Chen Y, Chen S, Liu BL, Feng MX, Zong ZH, Zhao Y. The correlation between microRNA490-3p and TGFα in endometrial carcinoma tumorigenesis and progression. Oncotarget 2016; 7:9236-49. [PMID: 26843615 PMCID: PMC4891037 DOI: 10.18632/oncotarget.7061] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 01/18/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the translation of messenger RNAs by binding their 3′-untranslated region (3′ UTR). MiR-490-3p has been reported to be a suppressor in various human cancers; however, little is known about the biological functions of miR-490-3p in endometrial cancer (EC). In our study, we found that MiR-490-3p mRNA expression was significantly lower in ECs than in normal endometrial tissues. MiR-490-3p mRNA expression was also negatively associated with depth of invasion (mucosa vs. muscular and serosa) and lymph node metastasis (negative vs. positive) in EC. MiR-490-3p overexpression reduced proliferation; promoted G1 arrest and apoptosis; suppressed migration and invasion; and reduced TGFα, NF-kB, cyclin D1, survivin, matrix metalloproteinase 2 (MMP2) mRNA and protein expression, and improved Bax mRNA and protein expression. The dual-luciferase reporter assay indicated that miR-490-3p directly targeted TGFα by binding its 3′ untranslated region. MiR-490-3P transfection also suppressed tumor development and TGFα expression (as determined by immunohistochemistry and western blotting) in vivo in the xenograft mouse model. This is the first demonstration that miR-490-3P might act as a suppressor in EC tumorigenesis and progression by targeting TGFα. Our results provide a theoretical basis for the further study on the molecular target for endometrial cancer.
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Affiliation(s)
- Kai-Xuan Sun
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Ying Chen
- Department of Gynecology, The Fourth Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Shuo Chen
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Bo-Liang Liu
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Miao-Xiao Feng
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Zhi-Hong Zong
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, P.R. China
| | - Yang Zhao
- Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
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Circulating MicroRNAs: A Next-Generation Clinical Biomarker for Digestive System Cancers. Int J Mol Sci 2016; 17:ijms17091459. [PMID: 27598137 PMCID: PMC5037738 DOI: 10.3390/ijms17091459] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/25/2016] [Accepted: 08/26/2016] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that post-transcriptionally regulate gene expression and play important roles in various physiological and developmental processes such as oncogenic or tumor suppressive regulators. Specific miRNA expression signatures have been identified in a number of human cancers. Cell-free miRNAs have recently been stably detected in plasma and serum (circulating miRNAs), and their presence in blood has attracted the attention of researchers due to their potential as non-invasive biomarkers. Circulating miRNAs have emerged as tumor-associated biomarkers that reflect not only the existence of early-stage tumors, but also the dynamics and status of advanced stage tumors, tumor recurrence, and drug sensitivities. This methodology for liquid biopsy may provide non-invasive and reproductive biomarkers and individualized therapeutic strategies for cancer patients. We herein review the current phase of biological and clinical research on the circulating miRNAs of solid cancers, particularly digestive tract cancers, and discuss future perspectives. The present review may be beneficial for future research on miRNAs used to detect various cancers.
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Circulating MicroRNA-26a in Plasma and Its Potential Diagnostic Value in Gastric Cancer. PLoS One 2016; 11:e0151345. [PMID: 27010210 PMCID: PMC4806920 DOI: 10.1371/journal.pone.0151345] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/08/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In the past decades, a good deal of studies has provided the possibility of the circulating microRNAs (miRNAs) as noninvasive biomarkers for cancer diagnosis. The aim of our study was to detect the levels of circulating miRNAs in tissues and plasmas of gastric cancer (GC) patients and evaluate their diagnostic value. METHODS Tissue samples were collected from 85 GC patients. Plasma samples were collected from 285 GC patients and 285 matched controls. Differentially expressed miRNAs were filtered with by Agilent Human miRNA Microarray and TaqMan low density array (TLDA) with pooled samples, followed by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation. Receiver operating characteristic (ROC) curves were structured to evaluate the diagnostic accuracy of the miRNAs. The plasma level of miR-26a in GC patients of different clinical stages was compared. RESULTS Four miRNAs (miR-26a, miR-142-3p, miR-148a, and miR-195) revealed coincidentally decreased levels in tissue and plasma of the GC patients compared with controls, and ROC curves were constructed to demonstrate that miR-26a had a highest area under the ROC curve (AUC) of 0.882. Furthermore, miR-26a was stably detected in the plasma of GC patients with different clinical characteristics. CONCLUSION Plasma miR-26a may provide a novel and stable marker of gastric cancer.
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Konishi H, Ichikawa D, Arita T, Otsuji E. Microarray Technology and Its Applications for Detecting Plasma microRNA Biomarkers in Digestive Tract Cancers. Methods Mol Biol 2016; 1368:99-109. [PMID: 26614071 DOI: 10.1007/978-1-4939-3136-1_8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Many cancers are known to be regulated by microRNAs (miRNAs), and the relationships between tissue miRNA expression levels and the amounts of miRNA circulating in the plasma (or plasma miRNA) have been examined in many types of cancers, including digestive tract cancers. The role of plasma miRNAs has yet to be elucidated in detail; therefore a comprehensive analysis of plasma miRNAs using microarrays should assist in establishing the utility of liquid biopsy or companion diagnosis. We here described the 3D-Gene(®) miRNA microarray (TORAY) currently used in our laboratory and introduced a trial application in digestive tract cancer diagnosis.
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Affiliation(s)
- Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Japan.
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Japan
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Profiling of circulating microRNAs in patients with Barrett's esophagus and esophageal adenocarcinoma. J Gastroenterol 2016; 51:560-70. [PMID: 26585599 PMCID: PMC4880635 DOI: 10.1007/s00535-015-1133-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 10/06/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Circulating microRNAs (miRNAs) have been suggested as novel markers for various diseases. The goal of this pilot study was to identify circulating miRNAs differentially expressed comparing Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and controls. METHODS MicroRNA expression profiling was performed by qPCR array using plasma from six controls and eight BE and eight EAC patients. Validation was performed by analyzing the expression of six selected miRNAs, by qRT-PCR in 115 plasma samples of controls, BE, and EAC patients. Diagnostic accuracy was evaluated by area under the curve (AUC) analysis. RESULTS We identified three miRNAs that were elevated in EAC and four miRNAs that were elevated in BE. Further validation showed that miRNA-382-5p was significantly increased and miRNA-133a-3p significantly decreased in EAC. miRNA-194-5p and miRNA-451a were significantly increased and miRNA-136-5p significantly decreased in BE versus controls. A combination of three or more miRNAs was found to have a good diagnostic performance in discriminating BE from controls (AUC: 0.832), EAC from controls (AUC: 0.846), and BE from EAC (AUC: 0.797). CONCLUSION Our data suggest that circulating miRNAs are differentially expressed in BE and EAC. The miRNAs identified may be used for future non-invasive screening of BE and EAC.
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Miyamae M, Komatsu S, Ichikawa D, Kawaguchi T, Hirajima S, Okajima W, Ohashi T, Imamura T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Ochiai T, Okamoto K, Taniguchi H, Otsuji E. Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer. Br J Cancer 2015; 113:1467-76. [PMID: 26505678 PMCID: PMC4815891 DOI: 10.1038/bjc.2015.366] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 09/16/2015] [Accepted: 09/23/2015] [Indexed: 01/03/2023] Open
Abstract
Background: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. Methods: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. Results: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT–PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17–436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. Conclusions: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.
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Affiliation(s)
- Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Shoji Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Toshiya Ochiai
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, 355-5 Kamanzadoori Marutamachi Haruobicho, Kamigyo-ku, Kyoto 602-8026, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Liu X, Kwong A, Sihoe A, Chu KM. Plasma miR-940 may serve as a novel biomarker for gastric cancer. Tumour Biol 2015; 37:3589-97. [PMID: 26456959 DOI: 10.1007/s13277-015-4019-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 07/19/2015] [Indexed: 02/07/2023] Open
Abstract
It was reported that circulating microRNAs could be applied as non-invasive biomarkers for cancer monitoring. The purpose of this study was to identify plasma miRNA that may serve as a novel biomarker for gastric cancer and to evaluate its clinical application. MicroRNA profiles were generated from plasma samples of 5 patients with gastric cancer (GC) versus 5 healthy controls (HC). MicroRNA-940 (miR-940) was one of the most downregulated miRNAs with fold change of 0.164. It was revealed that the expression of miR-940 was downregulated in both the initial set (N = 30, P < 0.0001) and the validation set (N = 80, P < 0.0001) of plasma samples of patients with gastric cancer. The sensitivity was obviously higher than the current biomarkers CEA and CA19-9 (81.25 % vs. 22.54 % and 15.71 %). MiR-940 was also significantly downregulated in gastric cancer tissue samples (N = 34, P = 0.0015), as well as in cancer cell lines (N = 7). Importantly, miR-940 was significantly highly expressed in stomach tissue samples than in other types of tissue samples including the liver, breast, thyroid, and lung. Moreover, there was a trend of lower expression of miR-940 from early to advanced stage of gastric cancer. Target prediction suggested that miR-940 regulated cell signaling including NF-κB and Wnt/β-catenin, as well as pathways of cell communication and adhesion. These pathways play critical roles in gastric cancer initiation and progression. It is the first report that miR-940 may mainly express in the stomach. Downregulation of plasma miR-940 may serve as a novel biomarker for detection of gastric cancer.
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Affiliation(s)
- Xin Liu
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Ava Kwong
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Alan Sihoe
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Kent-Man Chu
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
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Ishimoto T, Baba H, Izumi D, Sugihara H, Kurashige J, Iwatsuki M, Tan P. Current perspectives toward the identification of key players in gastric cancer microRNA dysregulation. Int J Cancer 2015; 138:1337-49. [DOI: 10.1002/ijc.29627] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 05/27/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Takatsugu Ishimoto
- Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School Singapore; Singapore Singapore
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Daisuke Izumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Hidetaka Sugihara
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Junji Kurashige
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Science; Kumamoto University; Kumamoto Japan
| | - Patrick Tan
- Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School Singapore; Singapore Singapore
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Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer. Gastric Cancer 2015; 18:271-9. [PMID: 24626859 DOI: 10.1007/s10120-014-0363-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 02/23/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recently, circulating microRNAs have been reported to be stably detectable in plasma/serum and to function as potent non-invasive biomarkers in various cancers. We hypothesized that miR-18a could contribute to a novel plasma biomarker in patients with gastric cancer (GC). METHODS We focused on miR-18a, which is a component of miR-17-92 cluster and has been reported as highly expressed in GC tissues. The study involved three steps: (1) confirmation of the higher miR-18a expression in primary GC tissues and GC cell lines than in normal gastric tissues and a fibroblast cell line; (2) evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing 104 GC patients and 65 healthy volunteers; (3) evaluation of monitoring tumor dynamics by the plasma miR-18a assay. RESULTS (1) The miR-18a expressions were significantly higher in GC tissues than in normal gastric tissues (P = 0.0286) and higher in all examined GC cell lines than in the fibroblast cell line. (2) The plasma miR-18a concentrations were significantly higher in GC patients than in healthy controls (P < 0.0001). The value of the area under the receiver-operating characteristic curve was 0.8059. (3) The plasma miR-18a levels were significantly reduced in postoperative samples compared to in preoperative samples (P = 0.0002). In an miR-18a overexpressing cell line, the miR-18a concentration of cultured medium increased in both cell number and time-course dependent manners, suggesting microRNA might be released from cancer cells into the surrounding environment. CONCLUSIONS Circulating miR-18a could be a useful biomarker for screening GC and monitoring tumor dynamics.
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Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Morimura R, Hirajima S, Okajima W, Ohashi T, Imamura T, Konishi H, Shiozaki A, Ikoma H, Okamoto K, Taniguchi H, Otsuji E. Malignant potential in pancreatic neoplasm; new insights provided by circulating miR-223 in plasma. Expert Opin Biol Ther 2015; 15:773-85. [PMID: 25819175 DOI: 10.1517/14712598.2015.1029914] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Recent studies have identified that microRNAs are stably detectable in plasma/serum because of their binding to specific proteins or being packaged in secretory vesicles. METHODS We tested miR-223 as a candidate of novel plasma biomarker in pancreatic cancer (PCa) and intraductal papillary mucinous neoplasm (IPMN). RESULTS i) miR-223 expression was significantly higher in PCa tissues (p = 0.0069) than in normal tissues. ii) Plasma miR-223 levels were significantly higher in 71 PCa patients than 67 healthy volunteers (p < 0.0001). iii) Plasma miR-223 levels were significantly reduced in postoperative samples (p = 0.0297). iv) Plasma miR-223 levels tended to discriminate the malignant potential between benign IPMN and malignant IPMN (p = 0.0963), and the progressive extent of invasiveness between malignant IPMN and pancreatic invasive ductal carcinoma (PIDC) (p = 0.0004). Multivariate logistic regression analysis revealed that a low level of plasma miR-223 was an independent risk factor for PIDC (p = 0.0012, odds ratio 7.90 [95% CI: 2.06 - 41.2]). v) There was no significant correlation between plasma miR-223 levels and the number of any blood cell types in the peripheral blood. CONCLUSION Plasma miR-223 might be a clinically useful biomarker for screening PCa, and predicting malignant potential of IPMN and the invasiveness of PCa.
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Affiliation(s)
- Shuhei Komatsu
- Kyoto Prefectural University of Medicine, Division of Digestive Surgery, Department of Surgery , 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto , Japan +81 75 251 5527 ; +81 75 251 5522 ;
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DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. Gastric Cancer 2015; 18:43-54. [PMID: 24481854 DOI: 10.1007/s10120-014-0340-8] [Citation(s) in RCA: 165] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 12/30/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC. METHODS Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues (n = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues (n = 29). RESULTS We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2'-deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene. CONCLUSIONS Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC.
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Zhai R, Wei Y, Su L, Liu G, Kulke MH, Wain JC, Christiani DC. Whole-miRNome profiling identifies prognostic serum miRNAs in esophageal adenocarcinoma: the influence of Helicobacter pylori infection status. Carcinogenesis 2014; 36:87-93. [PMID: 25381453 DOI: 10.1093/carcin/bgu228] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cell free circulating microRNAs (cfmiRNAs) have been recognized as robust and stable biomarkers of cancers. However, little is known about the prognostic significance of cfmiRNAs in esophageal adenocarcinoma (EA). In this study, we explored whether specific cfmiRNA profiles could predict EA prognosis and whether Helicobacter pylori (HP) infection status could influence the association between cfmiRNAs and EA survival outcome. We profiled 1075 miRNAs in pooled serum samples from 30 EA patients and 30 healthy controls. The most relevant cfmiRNAs were then assessed for their associations with EA survival in an independent cohort of 82 patients, using Log-rank test and multivariate Cox regression models. Quantitative real-time PCR (qRT-PCR) was used for cfmiRNA profiling. HP infection status was determined by immunoblotting assay. We identified a panel of 18 cfmiRNAs that could distinguish EA patients from healthy subjects (P = 3.0E-12). In overall analysis and in HP-positive subtype patients, no cfmiRNA was significantly associated with EA prognosis. In HP-negative patients, however, 15 cfmiRNAs were significantly associated with overall survival (OS) (all P < 0.05). A combined 2-cfmiRNA (low miR-3935 and high miR-4286) risk score was constructed; that showed greater risk for worse OS (HR = 2.22, P = 0.0019) than individual cfmiRNA alone. Patients with high-risk score had >10-fold increased risk of death than patients with low risk score (P = 0.0302; HR = 10.91; P = 0.0094). Our findings suggest that dysregulated cfmiRNAs may contribute to EA survival outcome and HP infection status may modify the association between cfmiRNAs and EA survival.
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Affiliation(s)
- Rihong Zhai
- Shenzhen Key Laboratory of Translational Medicine of Tumor, Shenzhen University School of Medicine, Shenzhen 518060, China, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA, Medical Oncology and Haematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario M5G 2C4, Canada, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA and Department of Surgery and Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Yongyue Wei
- Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
| | - Li Su
- Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
| | - Geoffrey Liu
- Medical Oncology and Haematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario M5G 2C4, Canada
| | - Mathew H Kulke
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA and
| | | | - David C Christiani
- Medical Oncology and Haematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario M5G 2C4, Canada, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
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Circulating microRNAs as a fingerprint for endometrial endometrioid adenocarcinoma. PLoS One 2014; 9:e110767. [PMID: 25329674 PMCID: PMC4203829 DOI: 10.1371/journal.pone.0110767] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 09/25/2014] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Endometrial cancer is the most common malignancy of the female genital tract worldwide, and endometrial endometrioid adenocarcinoma (EEC) is the major histological type of endometrial cancer. There is a great need for better markers with high sensitivity and specificity to permit early diagnosis and proper management of EEC. The aim of our study is to identify a miRNA classifier within plasma as a noninvasive biomarker for EEC diagnosis. METHODS This study was a retrospective case-control analysis which contained two independent cohorts including 93 participants. First, we screened 375 miRNAs in 29 plasma samples. 9 of the miRNAs were selected to be evaluated their expression by quantitative reverse-transcriptase polymerase chain reaction. A stepwise logistic regression model was then used to establish a new classifier in the validation cohort. Area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy. Co-expression analysis was used to verify the independence of results. RESULTS miR-15b, -27a, and -223 were found to be differentially expressed in the EEC plasma between the two cohorts and had few connections with other miRNAs. The areas under the curve (AUC) were 0.768, 0.813, and 0.768 for miR-15b, -27a, and 223, respectively. miR-27a and CA125 can be combined as a potential non-invasive biomarker for detecting EEC, with the AUC of 0.894. CONCLUSION Our study demonstrated three miRNAs, including miR-15b, -27a, and -233 have a good clinical value in EEC diagnosis. The classifier, including miR-27a and CA125, demonstrated a high accuracy in the diagnosis of EEC and might serve as a novel non-invasive biomarker in the future.
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Xia J, Guo X, Yan J, Deng K. The role of miR-148a in gastric cancer. J Cancer Res Clin Oncol 2014; 140:1451-6. [PMID: 24659367 DOI: 10.1007/s00432-014-1649-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 03/12/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Gastric cancer is one of the most common malignant diseases worldwide, although much progress has been achieved in recent years, the early diagnosis and treatment for gastric cancer are not yet satisfactory and, thus the prognosis is still poor. MicroRNAs (miRNAs) can regulate a variety of physiological and developmental processes, it has been revealed that many miRNAs contribute the initiation and progression of various cancers. MiR-148a is one of the most important miRNAs in gastric cancer, and the aim of this paper is to provide an overview of various roles of miR-148a in gastric cancer. METHODS AND RESULTS We searched studies in electronic databases. MiR-148a was down-regulated in gastric cancer tissues and cell lines, which was resulted from the hypermethylation in its promoter region. Furthermore, miR-148a could regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis. CONCLUSION MiR-148a may serve as a novel biomarker for the diagnosis and as a new therapeutic target in gastric cancer.
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Guo X, Xia J, Deng K. Long non-coding RNAs: emerging players in gastric cancer. Tumour Biol 2014; 35:10591-600. [PMID: 25173641 DOI: 10.1007/s13277-014-2548-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 08/25/2014] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) remains a major public health issue as the second leading cause of cancer-related death and the fourth most common cancer worldwide. Although much progress has been achieved in recent years, the early diagnosis and treatment for GC are not yet satisfactory; thus, the prognosis remains poor. Therefore, identification of novel molecules for early diagnosis, prognosis, and treatment is urgently needed. Long non-coding RNAs (lncRNAs) are a new class of non-coding RNAs that participate in a variety of biological processes such as cell proliferation, cell cycle, differentiation, and apoptosis, mainly by regulation of gene expression at various levels, including chromatin, splicing, transcriptional, and post-transcriptional levels. Some lncRNAs are upregulated in cancer and possess oncogenic properties, while others exhibit aberrant low expression and act as tumor suppressors. In this review, we overview the functional roles and regulatory mechanisms of lncRNAs in GC and evaluate their diagnostic, prognostic, and therapeutic values.
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Affiliation(s)
- Xiaoqiang Guo
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, Jiangsu, China
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Zhou JJ, Zheng S, Sun LF, Zheng L. MicroRNA regulation network in colorectal cancer metastasis. World J Biol Chem 2014; 5:301-307. [PMID: 25225598 PMCID: PMC4160524 DOI: 10.4331/wjbc.v5.i3.301] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 03/19/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer is the third most common cancer worldwide. Metastasis is a major cause of colorectal cancer-related death. Mechanisms of metastasis remain largely obscure. MicroRNA is one of the most important epigenetic regulators by targeting mRNAs post-transcriptionally. Accumulated evidence has supported its significant role in the metastasis of colorectal cancer, including epithelial-mesenchymal transition and angiogenesis. Dissecting microRNAome potentially identifies specific microRNAs as biomarkers of colorectal cancer metastasis. Better understanding of the complex network of microRNAs in colorectal cancer metastasis provide new insights in the biological process of metastasis and in the potential targets for colorectal cancer therapies and for diagnosis of recurrent and metastatic colorectal cancer.
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Plasma microRNA profiles: identification of miR-25 as a novel diagnostic and monitoring biomarker in oesophageal squamous cell carcinoma. Br J Cancer 2014; 111:1614-24. [PMID: 25117812 PMCID: PMC4200091 DOI: 10.1038/bjc.2014.451] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 07/07/2014] [Accepted: 07/17/2014] [Indexed: 12/11/2022] Open
Abstract
Background: Recent studies have demonstrated that microRNAs are stably detectable in plasma/serum because of their binding to specific proteins or being packaged in secretory particles. This study was designed to detect novel microRNAs in plasma for cancer detection and monitoring using microRNA array-based approaches in oesophageal squamous cell carcinoma (ESCC) patients. Methods: Through the integration of two Toray 3D-Gene microRNA array-based approaches to compare plasma microRNA levels between ESCC patients and healthy volunteers and between preoperative and postoperative ESCC patients, we identified a novel plasma biomarker in ESCC. Results: (1) Eight upregulated and common microRNAs (miR-15b, 16, 17, 25, 19b, 20a, 20b, and 106a) were selected using two high-resolution microRNA array approaches. (2) Test-scale analyses by quantitative RT–PCR validated a significant higher levels of plasma miR-19b (P=0.0020) and miR-25 (P=0.0030) in ESCC patients than controls. However, a significant correlation was observed between plasma miR-19b levels and concentrations of red blood cells (P=0.0073) and haemoglobin (P=0.0072). (3) miR-25 expression was found to be significantly higher in ESCC tissues (P=0.0157) and ESCC cell lines (P=0.0093) than in normal tissues and fibroblasts. (4) In a large-scale validation analysis, plasma miR-25 levels were significantly higher in 105 preoperative (P<0.0001) ESCC patients who underwent curative oesophagectomy and 20 superficial ESCC patients who underwent endoscopic resection (P<0.0001) than in 50 healthy volunteers. (5) Plasma miR-25 levels were significantly reduced in postoperative samples than in preoperative samples (P<0.0005) and were significantly increased during ESCC recurrences (P=0.0145). Conclusions: Plasma miR-25 might be a clinically useful biomarker for cancer detection and the monitoring of tumour dynamics in ESCC patients.
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Zhu X, Lv M, Wang H, Guan W. Identification of circulating microRNAs as novel potential biomarkers for gastric cancer detection: a systematic review and meta-analysis. Dig Dis Sci 2014; 59:911-9. [PMID: 24337687 DOI: 10.1007/s10620-013-2970-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 11/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recent studies show that microRNAs (miRNAs) in serum or plasma can be stably detected and used as potential biomarkers in cancer diagnosis. OBJECTIVES To systematically evaluate circulating miRNAs from numerous gastric cancer (GC) expression profiling studies and to determine miRNA biomarkers for GC detection. METHODS A systematic review and meta-analysis of published studies comparing the circulating miRNA expressions between GC patients and healthy controls were carried out. An miRNA ranking system that considered the number of comparisons in agreement, total number of samples, and average fold change was used. Then the receiver-operating characteristic curve (ROC) results of the top miRNAs were combined to further evaluate their diagnostic value by using Meta-disc 1.4. RESULTS A total of 35 miRNAs were reported in the 22 included studies, with 7 miRNAs reported in at least 2 studies. MiR-21 is the most consistently reported miRNA with upregulation. In further analysis, the sensitivity, specificity, and area under the curve of summary ROC for miR-21 in GC diagnosis are 0.78 (95 % CI 0.71-0.85), 0.89 (95 % CI 0.82-0.94), and 0.91, respectively. CONCLUSION Circulating miR-21 can serve as a potential biomarker for detection of GC.
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Affiliation(s)
- Xingya Zhu
- First Clinical Medical College, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China,
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Zhu C, Ren C, Han J, Ding Y, Du J, Dai N, Dai J, Ma H, Hu Z, Shen H, Xu Y, Jin G. A five-microRNA panel in plasma was identified as potential biomarker for early detection of gastric cancer. Br J Cancer 2014; 110:2291-9. [PMID: 24595006 PMCID: PMC4007222 DOI: 10.1038/bjc.2014.119] [Citation(s) in RCA: 185] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/22/2014] [Accepted: 02/10/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Circulating microRNAs (miRNAs) have been implicated as novel biomarkers for gastric cancer (GC) diagnosis. However, the mixture of GC subtypes may have led to the inconsistent circulating miRNA profiles, and the clinical performance of circulating miRNAs has not yet been evaluated independently on early detection of GC. METHODS A four-phase study was designed with a total of 160 cancer-free controls, 124 patients with gastric non-cardia adenocarcinoma (GNCA) and 36 patients diagnosed gastric cardia adenocarcinoma (GCA). In the discovery phase, we screened the miRNA expression profile in plasma of 40 GNCA patients (stage I) and 40 matched controls by TaqMan low density array (TLDA) chips with pooled samples. Differentially expressed miRNAs were further validated in individual sample using quantitative reverse-transcriptase PCR (qRT-PCR) in the training phase. Subsequently, in an independent validation phase, the identified miRNAs were evaluated in 48 GNCA patients (stage I) and 102 matched controls. Finally, the identified miRNAs were further assessed in an external validation phase including advanced GNCA and GCA patients. Additionally, the expression levels of identified miRNAs were measured in the media of BGC823 and MGC803 cell lines. RESULTS Five miRNAs (miR-16, miR-25, miR-92a, miR-451 and miR-486-5p) showed consistently elevated levels in plasma of the GC patients as compared with controls, and were identified to be potential markers for GNCA with area under the receiver operating characteristic (ROC) curves (AUCs) ranging from 0.850 to 0.925 and 0.694 to 0.790 in the training and validation phases, respectively. The five-miRNA panel presented a high diagnostic accuracy for the early-stage GNCA (AUCs=0.989 and 0.812 for the training and validation phases, respectively). Three miRNAs (miR-16, miR-25 and miR-92a) were excreted into the culture media of GC cell lines. CONCLUSIONS The five-miRNA panel in plasma may serve as a potential non-invasive biomarker in detecting the early-stage GC.
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Affiliation(s)
- C Zhu
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
| | - C Ren
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Clinical Laboratory, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - J Han
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
| | - Y Ding
- Department of Gastroenterology, Yangzhou First People's Hospital, Yangzhou 225001, China
| | - J Du
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - N Dai
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - J Dai
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - H Ma
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Z Hu
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
| | - H Shen
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
| | - Y Xu
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- E-mail:
| | - G Jin
- Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 211166, China
- E-mail:
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Tsujiura M, Ichikawa D, Konishi H, Komatsu S, Shiozaki A, Otsuji E. Liquid biopsy of gastric cancer patients: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2014; 20:3265-3286. [PMID: 24696609 PMCID: PMC3964398 DOI: 10.3748/wjg.v20.i12.3265] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/27/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
To improve the clinical outcomes of cancer patients, early detection and accurate monitoring of diseases are necessary. Numerous genetic and epigenetic alterations contribute to oncogenesis and cancer progression, and analyses of these changes have been increasingly utilized for diagnostic, prognostic and therapeutic purposes in malignant diseases including gastric cancer (GC). Surgical and/or biopsy specimens are generally used to understand the tumor-associated alterations; however, those approaches cannot always be performed because of their invasive characteristics and may fail to reflect current tumor dynamics and drug sensitivities, which may change during the therapeutic process. Therefore, the importance of developing a non-invasive biomarker with the ability to monitor real-time tumor dynamics should be emphasized. This concept, so called “liquid biopsy”, would provide an ideal therapeutic strategy for an individual cancer patient and would facilitate the development of “tailor-made” cancer management programs. In the blood of cancer patients, the presence and potent utilities of circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) such as DNA, mRNA and microRNA have been recognized, and their clinical relevance is attracting considerable attention. In this review, we discuss recent developments in this research field as well as the relevance and future perspectives of CTCs and cfNAs in cancer patients, especially focusing on GC.
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Lee LS, Szafranska-Schwarzbach AE, Wylie D, Doyle LA, Bellizzi AM, Kadiyala V, Suleiman S, Banks PA, Andruss BF, Conwell DL. Investigating MicroRNA Expression Profiles in Pancreatic Cystic Neoplasms. Clin Transl Gastroenterol 2014; 5:e47. [PMID: 24476997 PMCID: PMC3912316 DOI: 10.1038/ctg.2013.18] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/23/2013] [Accepted: 10/08/2013] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES: Current diagnostic tools for pancreatic cysts fail to reliably differentiate mucinous from nonmucinous cysts. Reliable biomarkers are needed. MicroRNAs (miRNA) may offer insights into pancreatic cysts. Our aims were to (1) identify miRNAs that distinguish benign from both premalignant cysts and malignant pancreatic lesions using formalin-fixed, paraffin-embedded (FFPE) pathology specimens; (2) identify miRNAs that distinguish mucinous cystic neoplasm (MCN) from branch duct-intraductal papillary mucinous neoplasm (BD-IPMN). METHODS: A total of 69 FFPE pancreatic specimens were identified: (1) benign (20 serous cystadenoma (SCA)), (2) premalignant (10 MCN, 10 BD-IPMN, 10 main duct IPMN (MD-IPMN)), and (3) malignant (19 pancreatic ductal adenocarcinoma (PDAC)). Total nucleic acid extraction was performed followed by miRNA expression profiling of 378 miRNAs interrogated using TaqMan MicroRNA Arrays Pool A and verification of candidate miRNAs. Bioinformatics was used to generate classifiers. RESULTS: MiRNA profiling of 69 FFPE specimens yielded 35 differentially expressed miRNA candidates. Four different 4-miRNA panels differentiated among the lesions: one panel separated SCA from MCN, BD-IPMN, MD-IPMN, and PDAC with sensitivity 85% (62, 97), specificity 100% (93, 100), a second panel distinguished MCN from SCA, BD-IPMN, MD-IPMN, and PDAC with sensitivity and specificity 100% (100, 100), a third panel differentiated PDAC from IPMN with sensitivity 95% (76, 100) and specificity 85% (72, 96), and the final panel diagnosed MCN from BD-IPMN with sensitivity and specificity approaching 100%. CONCLUSIONS: MiRNA profiling of surgical pathology specimens differentiates serous cystadenoma from both premalignant pancreatic cystic neoplasms and PDAC and MCN from BD-IPMN.
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Affiliation(s)
- Linda S Lee
- 1] Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA [2] Interdisciplinary Management of Pancreatic Cystic Tumors (IMPACT) Clinic, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | | | - Leona A Doyle
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Andrew M Bellizzi
- Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Vivek Kadiyala
- Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Shadeah Suleiman
- Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Peter A Banks
- Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Darwin L Conwell
- 1] Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts, USA [2] Interdisciplinary Management of Pancreatic Cystic Tumors (IMPACT) Clinic, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Abstract
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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Affiliation(s)
- Roopma Wadhwa
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, 77030
| | - Yixin Yao
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
| | - Qingyi Wei
- Department of Epidemiology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas, 77030
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas, 77030
- Department of Epidemiology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas, 77030
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Abstract
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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Yang B, Jing C, Wang J, Guo X, Chen Y, Xu R, Peng L, Liu J, Li L. Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol 2013; 16:374-9. [PMID: 23881463 DOI: 10.1007/s12094-013-1081-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 07/15/2013] [Indexed: 02/08/2023]
Abstract
PURPOSE Lymphatic metastasis is a primary cause of gastric cancer-related death, yet factors governing tumor cell lymphatic metastasis have not been fully elucidated. MicroRNAs (miRNAs) are a recently discovered class of regulatory, non-coding RNAs, some of which are involved in gastric cancer progression. However, little is known about which miRNA contributes to the lymphatic metastasis in human gastric cancer. This prompted us to find the significant miRNAs associated with lymphangiogenesis in human gastric cancer. METHODS We screened vascular endothelial growth factor C (VEGF-C) expression in several gastric cancer cell lines as well as in the immortalized human gastric mucosal cell line GES-1, by real-time reverse transcriptase PCR (qRT-PCR). The gastric cancer cell lines MKN-45 and SGC-7901, which have commonly been cultured with human lymphatic endothelial cells (HLECs) in vitro, promoted tube formation of HLECs following transformation with a VEGF-C expression vector. Using microarrays, we identified a panel of differentially expressed miRNAs in HLECs that had been co-cultured with VEGF-C-transformed gastric cancer cells compared with non-transformed gastric cancer cells. A subset of miRNAs was further validated using qRT-PCR. RESULTS We found altered expression of miRNAs in HLECs co-cultured with lymphangiogenesis-inducing VEGF-C-transformed gastric cancer cells, with 47 up-regulated and 42 down-regulated miRNAs. These findings were confirmed by qRT-PCR of selected miRNAs. Furthermore, several miRNAs were differentially expressed in patients with positive lymphatic metastasis of the primary gastric tumor. Up-regulated miRNAs included miR-648, miR-5002-3p, miR-4754, miR-4760-5p, miR-4491, miR-4252, miR-5007-3p, and miR-647; and down-regulated miRNAs included miR-3178, miR-593-5p, miR-4485, miR-135a-3p, miR-17, miR-1469, and miR-124-5p. CONCLUSIONS Several lymphangiogenesis-related miRNAs are significantly altered during lymphatic metastasis of gastric cancer.
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Affiliation(s)
- B Yang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
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Chen YJ, Zhu JM, Wu H, Fan J, Zhou J, Hu J, Yu Q, Liu TT, Yang L, Wu CL, Guo XL, Huang XW, Shen XZ. Circulating microRNAs as a Fingerprint for Liver Cirrhosis. PLoS One 2013; 8:e66577. [PMID: 23805240 PMCID: PMC3689750 DOI: 10.1371/journal.pone.0066577] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 05/07/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Sensitive and specific detection of liver cirrhosis is an urgent need for optimal individualized management of disease activity. Substantial studies have identified circulation miRNAs as biomarkers for diverse diseases including chronic liver diseases. In this study, we investigated the plasma miRNA signature to serve as a potential diagnostic biomarker for silent liver cirrhosis. METHODS A genome-wide miRNA microarray was first performed in 80 plasma specimens. Six candidate miRNAs were selected and then trained in CHB-related cirrhosis and controls by qPCR. A classifier, miR-106b and miR-181b, was validated finally in two independent cohorts including CHB-related silent cirrhosis and controls, as well as non-CHB-related cirrhosis and controls as validation sets, respectively. RESULTS A profile of 2 miRNAs (miR-106b and miR-181b) was identified as liver cirrhosis biomarkers irrespective of etiology. The classifier constructed by the two miRNAs provided a high diagnostic accuracy for cirrhosis (AUC = 0.882 for CHB-related cirrhosis in the training set, 0.774 for CHB-related silent cirrhosis in one validation set, and 0.915 for non-CHB-related cirrhosis in another validation set). CONCLUSION Our study demonstrated that the combined detection of miR-106b and miR-181b has a considerable clinical value to diagnose patients with liver cirrhosis, especially those at early stage.
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Affiliation(s)
- Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hao Wu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jie Hu
- Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Qian Yu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lei Yang
- Department of Statistics, School of Public Health of Fudan University, Shanghai, China
| | - Chun-Lei Wu
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Xiao-Ling Guo
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xiao-Wu Huang
- Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China
- * E-mail: (XWH); (XZS)
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
- * E-mail: (XWH); (XZS)
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Coté GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology 2013; 144:1262-71.e1. [PMID: 23622136 DOI: 10.1053/j.gastro.2013.01.076] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 12/27/2012] [Accepted: 01/03/2013] [Indexed: 02/06/2023]
Abstract
The prognosis is poor for most patients with pancreatic cancer, chronic pancreatitis, or other pancreatic diseases. Advances in pancreatic imaging could help identify these diseases at earlier stages, when they are easier to treat. Radiographic imaging and endoscopic imaging of the pancreas have progressed from the abdominal roentogram and endoscopic retrograde pancreatography to multi-detector computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasonography, and pancreatoscopy. These technologies have improved the diagnosis and treatment of benign disease but have not significantly increased our ability to detect early-stage disease or affect outcomes of patients with pancreatic cancer or chronic pancreatitis. Advances in endoscopic imaging and molecular-based radiographic tests could allow physicians to identify pancreatic lesions and their precursors at earlier stages. Furthermore, research studies that include these tools could improve our understanding of disease pathogenesis and identify diagnostic markers and therapeutic targets. We review endoscopic imaging modalities, focusing on new endoscopic and molecular-based radiographic imaging tests that have the potential to substantially improve diagnosis and treatment of pancreatic disease.
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Affiliation(s)
- Gregory A Coté
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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Clinical impact of circulating miR-18a in plasma of patients with oesophageal squamous cell carcinoma. Br J Cancer 2013; 108:1822-9. [PMID: 23579215 PMCID: PMC3658511 DOI: 10.1038/bjc.2013.148] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background: Several recent studies demonstrated that microRNAs are stably detectable in plasma/serum. We tested whether miR-18a, which is located in the miR-17-92 cluster and reported to be highly expressed in tissues of oesophageal squamous cell carcinoma (ESCC), served as a plasma biomarker in patients with ESCC. Methods: This study was divided into three steps: (1) confirmation of higher miR-18a levels in primary ESCC tissues and cell lines than normal ESCC tissues and a human fibroblast cell line. (2) Evaluation of the plasma miR-18a assay using quantitative RT–PCR by comparing results from 106 consecutive patients with ESCC and 54 healthy volunteers. (3) Evaluation of the assay for monitoring tumour dynamics in patients with ESCC. Results: (1) Expression of miR-18a was significantly higher in ESCC tissues (P=0.0020) and ESCC cell lines (P=0.0121) than normal tissues and fibroblasts. (2) Plasma concentrations of miR-18a were significantly higher in ESCC patients than healthy volunteers (P<0.0001; ESCC patients vs healthy volunteers (mean±s.d.): 11.77±13.45 vs 0.73±0.54 amol μl−1). The value of the area under the receiver-operating characteristic (ROC) curve (AUC) was 0.9449. Furthermore, the ROC curves to detect early ESCC such as pTis-1 and pStage0-I showed AUCs of 0.9479 and 0.9642, respectively. (3) Plasma levels of miR-18a were significantly lower in postoperative samples than preoperative samples (P=0.0076). Conclusion: Plasma miR-18a may be a very useful biomarker for cancer detection and the monitoring of tumour dynamics in patients with ESCC.
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