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Tashakori N, Armanfar M, Mashhadi A, Mohammed AT, Karim MM, Hussein AHA, Adil M, Azimi SA, Abedini F. Deciphering the Role of Exosomal Non-Coding RNA (ncRNA) in Drug Resistance of Gastrointestinal Tumors; an Updated Review. Cell Biochem Biophys 2024; 82:609-621. [PMID: 38878101 DOI: 10.1007/s12013-024-01290-0] [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] [Accepted: 04/20/2024] [Indexed: 08/25/2024]
Abstract
One of the most prevalent types of cancer worldwide today is gastric intestinal (GI) tumors. To guarantee their lives, people with a developed GI require palliative care. This covers the application of targeted medicines in addition to chemotherapy treatments including cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, and pemetrexed. Because of the evidence of drug resistance emerging in poor patient outcomes and prognoses, determining the exact process of medication resistance is motivated. Besides, it is noteworthy that exosomes and noncoding RNAs, like microRNAs and long non-coding RNAs (lncRNAs), produced from tumor cells are implicated in both GI medication resistance and the carcinogenesis and development of GI disease. Biochemical events related to the cell cycle, differentiation of cells, growth, and pluripotency, in addition to gene transcription, splicing, and epigenetics, are all regulated by noncoding RNAs (ncRNAs). Therefore, it should come as a wonder that several ncRNAs have been connected in recent years to drug susceptibility and resistance as well as tumorigenesis. Additionally, through communicating directly with medications, altering the transcriptome of tumor cells, and affecting the immune system, exosomes may govern treatment resistance. Because of this, exosomal lncRNAs often act as a competitive endogenous RNA (ceRNA) of miRNAs to carry out its role in modifying drug resistance. In light of this, we provide an overview of the roles and processes of ncRNA-enriched exosomes in GI medication resistance.
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Affiliation(s)
- Nafiseh Tashakori
- Department of Medicine, Faculty of Internal Medicine, Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Armanfar
- Department of Internal Medicine, Faculty of Internal Medicine, University of Shahid Beheshti Medical Science, Tehran, Iran
| | - Anahita Mashhadi
- Department of Medical Laboratory Science, Islamic Azad University, Arak branch, Arak, Iran
| | | | - Manal Morad Karim
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
| | - Sajad Ataei Azimi
- Hematology-Oncology, Mashhad University of Medical Science, Mashhad, Iran.
| | - Fatemeh Abedini
- Department of Biology, Science and Art University, Yazd, Iran.
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Chen W, Guo Q, Zhang H, Du Y, Zhou Y, Huang Z, Zhang M, Qin S. Differentially expressed microRNA in prognosis of gastric cancer with Lauren classification. Cancer Biomark 2024; 41:41-54. [PMID: 39177588 PMCID: PMC11492042 DOI: 10.3233/cbm-230303] [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: 08/07/2023] [Accepted: 07/19/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common tumors. There were several classifications of GC recently. The value of Lauren classification in evaluating the prognosis after radical gastrectomy was still unclear and the prognosis of gastric cancer remained relatively poor in the absence of prognostic biomarkers. This study aimed to explore microRNA (miRNA) in the prognosis of GC with different Lauren classification. METHODS A retrospective study of 1144 patients was performed in this study. Quantificational reverse transcription-PCR (qRT-PCR) was used to examine the expression of miRNAs. Univariate and multivariate analysis were performed to evaluate prognosis value of Lauren classification. RESULTS Total 1144 GC patients were recruited in this cohort, including 302 diffuse type (26.4%), 436 intestinal type (38.1%) and 406 mixed type (35.5%) GC. Multivariate analysis showed that Lauren classification, patients' age, tumor size, tumor infiltrating depth, vascular nerve infiltrating and metastatic lymph nodes ration were significantly correlated with GC patients' OS and DFS. The miR-141-3p, miR-200b-3p and miR-133a-5p were significantly down-regulated in diffuse type compared to intestinal type GC tissues, the miR-105-5p had significant lower expression in diffuse type compared with intestinal type and mixed type GC tissues. As a consequence of univariate analysis, low miR-141-3p in diffuse type GC showed significant worse OS and DFS than high miR-141-3p. CONCLUSIONS Lauren classification was an independent prognostic factor in GC. MiR-141-3p was an independent prognostic factor and a promising prognostic biomarker in Lauren classification GC.
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Affiliation(s)
- Wenjiao Chen
- Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Oncology, Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Qin Guo
- Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Clinical Laboratory, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Huo Zhang
- Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Medical Oncology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Yiping Du
- Department of Oncology, First People’s Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, China
| | - Yan Zhou
- Department of Oncology, Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Zebo Huang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Meiling Zhang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Songbing Qin
- Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
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Li Q. Bacterial infection and microbiota in carcinogenesis and tumor development. Front Cell Infect Microbiol 2023; 13:1294082. [PMID: 38035341 PMCID: PMC10684967 DOI: 10.3389/fcimb.2023.1294082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Microbiota colonize exposed body tissues (e.g., gastrointestinal tract, skin, lungs, female genital tract, and urogenital tracts) and unexposed sites (e.g., breast). Persistent bacterial infection in the host lead to the development of multiple disease. They are implicated in the pathogenesis of various complex diseases, including diabetes, atherosclerosis, autoimmune diseases, Alzheimer's disease, and malignant diseases. Amounting studies have demonstrated the role of bacterial infection in carcinogenesis. The study of microbiota in tumorigenesis is primarily focused on lung cancer, colorectal cancer (CRC), breast cancer, gastric cancer, and gynecologic tumors, and so on. Infection of Helicobacter pylori in gastric cancer carcinogenesis is recognized as class I carcinogen by the World Health Organization (WHO) decades ago. The role of Fusobacterium nucleatum in the development of colorectal cancer is extensively investigated. Variable bacteria have been cultured from the tumor tissues. The identification of microbiota in multiple tumor tissues reveal that bacterial infection and microbiota are associated with tumor development. The microbiota affects multiple aspects of carcinogenesis and tumor development, including favoring epithelial cells proliferation, establishing inflammatory microenvironment, promoting metastasis, and causing resistance to therapy. On the other hand, microbiota can shape a tumor surveillance environment by enhancing cell activity, and sensitize the tumor cells to immune therapy. In the present review, the roles of microbiota in multiple malignancies are summarized, and unraveling the mechanisms of host-microbiota interactions can contribute to a better understanding of the interaction between microbiota and host cells, also the development of potential anti-tumor therapeutic strategies.
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Affiliation(s)
- Qiao Li
- Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, Hubei, China
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Kazemi A, Goodarzi M, Daneshipour K, Sarabadani H, Shahpar Z, Hajiagha BS, Kheradjoo H, Mohammadzadehsaliani S. Unrevealing the vital role of ncRNAs in Gastric Cancer chemoresistance. Pathol Res Pract 2023; 250:154761. [PMID: 37689003 DOI: 10.1016/j.prp.2023.154761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 09/11/2023]
Abstract
The high incidence of gastric cancer in many nations and poor overall survival rates has remained a serious global health concern. Chemoresistance in gastric cancer is a significant issue that hinders the efficacy of available treatment options. In gastric cancer, non-coding RNAs like microRNAs, long non-coding RNAs, and circular RNAs have become effective regulators of chemoresistance. These non-coding RNAs can influence several mechanisms, including drug efflux transporters, drug metabolism, and detoxification, cancer stem cells and the epithelial-mesenchymal transition, autophagy and apoptosis, and the tumor microenvironment. In this article review, we summarize the key roles non-coding RNAs play in the chemoresistance of gastric cancer and consider how they might be used in clinical settings as markers for diagnosis and prognosis, as well as potential targets and treatment plans. We also emphasize the need for additional study and collaborations in this area and highlight the difficulties and opportunities in non-coding RNA research for gastric cancer chemoresistance. This review offers crucial insights into the intricate relationship between non-coding RNAs and chemoresistance in gastric cancer, with implications for precision oncology and personalized medicine.
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Affiliation(s)
- Aida Kazemi
- Department of Biomedical Science, Monash University, Melbourne, Australia
| | - Masomeh Goodarzi
- Department of Biology, Zabol University of Medical Sciences, Zabol, Iran
| | - Kosar Daneshipour
- Department of Biological Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Hoda Sarabadani
- Rajiv Gandhi Institute of Information Technology & Biotechnology, Bharati Vidyapeeth University, Pune, India
| | - Zahra Shahpar
- M.Sc, Technical Department, İstanbul University, İstanbul, Türkiye
| | - Bahareh Salmanian Hajiagha
- Department of Cellular and Molecular Biology, Faculty of Basic Science, East Tehran Branch, Islamic Azad University, Tehran, Iran
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Gupta J, Suliman M, Ali R, Margiana R, Hjazi A, Alsaab HO, Qasim MT, Hussien BM, Ahmed M. Double-edged sword role of miRNA-633 and miRNA-181 in human cancers. Pathol Res Pract 2023; 248:154701. [PMID: 37542859 DOI: 10.1016/j.prp.2023.154701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 08/07/2023]
Abstract
Understanding the function and mode of operation of microRNAs (miRNAs) in cancer is of growing interest. The short non-coding RNAs known as miRNAs, which target mRNA in multicellular organisms, are described as controlling essential cellular processes. The miR-181 family and miR-633 are well-known miRNAs that play a key role in the development and metastasis of tumor cells. They may facilitate either tumor-suppressive or oncogenic function in malignant cells, according to mounting evidence. Metastatic cells that are closely linked to cancer cell migration, invasion, and angiogenesis can be identified by abnormal levels of miR-181 and miR-633. Numerous studies have demonstrated their capacity to control drug resistance, cell growth, apoptosis, and the epithelial-mesenchymal transition (EMT) and metastasis process. Interestingly, the levels of miR-181 and miR-633 and their potential target genes in the basic cellular process can vary depending on the type of cancer cells and their gene expression profile. Such miRNAs' interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs can influence tumor behaviors. Herein, we concentrated on the multifaceted roles of miR-181 and miR-633 and potential targets in human tumorigenesis, ranging from cell growth and metastasis to drug resistance.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U. P., India.
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Rida Ali
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhja Ahmed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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Ma H, Li N, Mo Z. Elevated Notch-1 expression promotes the lymph node metastasis of gastric cancer and the Notch-1-PTEN-ERK1/2 signalling axis promotes the progression of gastric cancer. Cytokine 2022; 159:156013. [PMID: 36067712 DOI: 10.1016/j.cyto.2022.156013] [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: 05/13/2022] [Revised: 08/02/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumours and has a high fatality rate worldwide. This study investigated the role of the Notch-1 signalling pathway in the pathogenesis and progression of GC. METHODS A total of 64 patients with GC were included in this study. Immunohistochemistry staining was used to detect Notch-1 expression in tumour tissues and adjacent non-tumour tissues, and Notch-1 knockdown in GC cells was identified using short hairpin RNA. A cell scratch assay, transwell assay and flow cytometry analysis were used to analyse the effect of Notch-1 knockdown on cell proliferation, migration and cell cycle distribution. The expression of Notch-1, PTEN, Akt, ERK1/2, E-cadherin and other proteins was detected using Western blotting. RESULTS The expression level of Notch-1 in GC tissues was higher than that in adjacent non-tumour tissues (P < 0.05). High levels of Notch-1 were also found to be associated with sex (male) and lymph node metastasis (P < 0.05). Notch-1 knockdown in the AGS and BGC-823 GC cell lines inhibited the migration and proliferation of GC cells, and Notch-1 knockdown arrested the cell cycle in the G0/G1 phase. PTEN protein expression was elevated in the presence of Notch-1 knockdown, resulting in the inhibition of phosphorylated Akt protein expression. In addition, phosphorylated ERK protein levels decreased in the presence of Notch-1 knockdown. Further inhibition of ERK1/2 signalling by the MEK1/2 inhibitor U0126 decreased the proliferation of AGS cells. The results of in vivo experiments with xenotransplantation in nude mice are consistent with these results. CONCLUSIONS Notch-1 plays a key role in the development of GC and was found to promote the lymph node metastasis of GC. Notch-1 knockdown can effectively attenuate the progression of GC cells, which may function in part through the Notch-1-PTEN-ERK1/2 signalling axis.
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Affiliation(s)
- Haining Ma
- Department of Gastrointestinal-pancreatic Surgery, Shanxi Province People's Hospital, Taiyuan, China.
| | - Ning Li
- Department of Gastrointestinal-pancreatic Surgery, Shanxi Province People's Hospital, Taiyuan, China
| | - Zhenzhou Mo
- Department of Gastrointestinal-pancreatic Surgery, Shanxi Province People's Hospital, Taiyuan, China
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Lin M, Lian NZ, Cao LL, Huang CM, Zheng CH, Li P, Xie JW, Wang JB, Lu J, Chen QY, Li YH, Peng ZH, Zhang XY, Mei YX, Lin JX. Down-regulated expression of CDK5RAP3 and UFM1 suggests a poor prognosis in gastric cancer patients. Front Oncol 2022; 12:927751. [PMID: 36387125 PMCID: PMC9647057 DOI: 10.3389/fonc.2022.927751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 10/10/2022] [Indexed: 11/12/2023] Open
Abstract
PURPOSE The relationship between the CDK5RAP3 and UFM1 expression and the prolonged outcomes of patients who underwent gastric cancer (GC) surgery was investigated. METHODS Single-sample gene set enrichment analysis (ssGSEA), unsupervised clustering and other methods were used to verify the relationship between CDK5RAP3 and UFM1 in GC through public databases. Additionally, CDK5RAP3 and UFM1 expression in cancerous and paracancerous tissues of GC was analysed in the context of patient prognosis. RESULTS CDK5RAP3 and UFM1 expression was downregulated synchronously, the interaction was observed between the two proteins, and UFM1 and CDK5RAP3 expression was found to be inversely associated to AKT pathway activation. Prognostic analysis showed that the prognosis is poorer for low CDK5RAP3 and UFM1 patients, than for high CDK5RAP3 and/or UFM1 (p<0.001) patients, and this expression pattern was an independent predictor for overall survival of GC. Coexpression of CDK5RAP3 and UFM1 combined with TNM staging can improve the accuracy of prognosis prediction for patients (p <0.001). CONCLUSIONS It is confirmed in our findings that a combination of CDK5RAP3 and UFM1 can produce a more precise prediction model for GC patients' survival.
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Affiliation(s)
- Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Ning-Zi Lian
- Department of Gynecology, Fujian Obstetrics and Gynecology Hospital, Fuzhou, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
| | - Ya-Han Li
- The Union Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhu-Huai Peng
- The Union Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiao-Yu Zhang
- The Union Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Yi-Xian Mei
- The Union Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China
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Kasaeian A, Roshanaei G, Kiumarsi A, Safari M, Abbasi M, Rahimi A. Influential factors on survival in gastric cancer: A single-center study. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2022; 27:19. [PMID: 35419060 PMCID: PMC8995304 DOI: 10.4103/jrms.jrms_1286_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/18/2021] [Accepted: 09/24/2021] [Indexed: 11/09/2022]
Abstract
Background: Gastric cancer (GC) is one of the conspicuous causes of cancer-related death worldwide. Considering the mounting incidence of this cancer in developing countries such as Iran, determining the influential factors on the survival of involved patients is noteworthy. Hence, we aimed to ascertain the survival rates and the prognostic factors in our GC patients. Materials and Methods: In this retrospective cohort study, data of 314 patients with GC in a referral cancer center in Hamadan province of Iran were studied. The outcome of our study was survival time and the influential factors were gender, age at diagnosis, tumor history, tumor grade, surgery history, radiotherapy history, stage of disease, metastasis history, and lymph node involvement. Kaplan − Meier method and log-rank test were used for the calculation and comparing the survival curves and Cox-proportional hazard model was used for the multivariable analysis of prognostic factors. Results: In a total of 314 GC patients, the median age at the diagnosis was 63 years (range: 21–92) with most patients (74.84%) being males. The median follow-up time was 2.42 years, and the median survival time was 2 years. The multivariable cox analysis of overall survival (OS) indicated that having distant metastasis increased the hazard of death by about 2.5 times (P < 0.0001, heart rates [HR]: 2.53, 95% confidence interval [CI]: [1.71, 3.75]), and receiving surgery as treatment, decreased the hazard of death up to 36% (P = 0.02, HR: 0.64, 95%CI: [0.46–0.89]). The other variables did not have any significant effects on the OS. Conclusion: The results of this study showed that lower survival (greater hazard of death) strongly and significantly associated with having distant metastasis in patients with GC and receiving surgery could significantly decrease the hazard of death in these patients instead.
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Wang J, Xu P, Hao Y, Yu T, Liu L, Song Y, Li Y. Interaction between DNMT3B and MYH11 via hypermethylation regulates gastric cancer progression. BMC Cancer 2021; 21:914. [PMID: 34380460 PMCID: PMC8359574 DOI: 10.1186/s12885-021-08653-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/05/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) has an unwelcoming prognosis when diagnosed at an advanced stage. The purpose of this study was to examine the expression of myosin heavy chain 11 (MYH11) in GC and mechanisms related. METHODS The MYH11 expression in GC was investigated via the SangerBox platform. MYH11 expression in GC tissues and cell lines was examined by immunohistochemistry, RT-qPCR, and western blot. The relationship between MYH11 expression and patients' prognosis was analyzed. The effects of MYH11 on the biological behaviors of GC cells were investigated by gain-of-function experiments. Bioinformatics analysis was used to find genes with relevance to MYH11 expression in GC. The relationship was verified by luciferase and ChIP-qPCR assays, followed by rescue assay validation. The causes of MYH11 downregulation in GC were verified by quantitative methylation-specific PCR. Finally, the effect of MYH11 on tumor growth was examined. RESULTS MYH11 was downregulated in GC and predicted poor prognoses. MYH11 reverted the malignant phenotype of GC cells. MYH11 repressed the TNFRSF14 expression by binding to the TNFRSF14 promoter. TNFRSF14 reversed the inhibitory effect of MYH11 on the malignant phenotype of GC cells. The methylation of the MYH11 promoter was elevated in GC, which was correlated with the elevated DNMT3B in GC. Overexpression of DNMT3B repressed transcription of MYH11 by promoting its methylation. Also, MYH11 upregulation inhibited tumor growth. CONCLUSION DNMT3B inhibits MYH11 expression by promoting its DNA methylation, thereby attenuating the repressive effect of MYH11 on the transcriptional of TNFRSF14 and promoting the progression of GC.
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Affiliation(s)
- Jianhua Wang
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Ping Xu
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Yanping Hao
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Tingting Yu
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Limin Liu
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Yan Song
- Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, People's Republic of China
| | - Yan Li
- Department of Obstetrics and Gynecology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, No. 66, Renmin South Road, Yancheng, 224001, Jiangsu, People's Republic of China.
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MiR-1299 functions as a tumor suppressor to inhibit the proliferation and metastasis of gastric cancer by targeting ARF6. Genes Genomics 2021; 44:237-245. [PMID: 34313969 DOI: 10.1007/s13258-021-01124-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 06/08/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND MiRNAs belong to non-coding RNAs that are involved in cancer development. Acting as a mediator, they could regulate the expression level of numerous gens. However, the expression and function of miR-1299 in gastric cancer (GC) are not clear. OBJECTIVE To explore the role of miR-1299 in the process of GC. METHODS We detected the levels of miR-1299 in clinical samples of GC and investigated the role of miR-1299 in the regulation of the GC cells proliferation, apoptosis and metastasis. Luciferase reporter assay was employed to verify the target of miR-1299. Additionally, the proliferation, apoptosis and metastasis of AGS and SGC7901 cells were analyzed after the overexpression of miR-1299. RESULTS Our study showed the expression of miR-1299 was decreased in GC tissues and cell lines. It indicated that the cell proliferation, migration and invasion was inhibited, while the cell apoptosis was promoted by the over-expressed miR-1299. Also, we found that miR-1299 could directly target the 3'-untranslated region (3'UTR) of ARF6 genes. In addition, rescue assay demonstrated that miR-1299 overexpression promoted the cell apoptosis and inhibited cell growth, which could be attenuated by the overexpression of ARF6. CONCLUSIONS These findings indicate that miR-1299 regulates cell progression in GC by targeting ARF6 genes, and suggest that miR-1299 may be a tumor suppressor in the GC progression.
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Battista S, Ambrosio MR, Limarzi F, Gallo G, Saragoni L. Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer. Int J Mol Sci 2021; 22:6652. [PMID: 34206291 PMCID: PMC8268370 DOI: 10.3390/ijms22136652] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022] Open
Abstract
Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.
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Affiliation(s)
- Serena Battista
- Pathology Department, “S. Maria della Misericordia Hospital”, Friuli-Venezia Giulia, 33100 Udine, Italy
| | | | - Francesco Limarzi
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
| | - Graziana Gallo
- Pathology Department, “M. Bufalini Hospital”, Emilia Romagna, 47521 Cesena, Italy;
| | - Luca Saragoni
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
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12
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Swaminathan G, Shigna A, Kumar A, Byroju VV, Durgempudi VR, Dinesh Kumar L. RNA Interference and Nanotechnology: A Promising Alliance for Next Generation Cancer Therapeutics. FRONTIERS IN NANOTECHNOLOGY 2021. [DOI: 10.3389/fnano.2021.694838] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cancer is a significant health hazard of the 21st century, and GLOBOCAN predicts increasing cancer incidence in the coming decades. Though several conventional treatment modalities exist, most of them end up causing off-target and debilitating effects, and drug resistance acquisition. Advances in our understanding of tumor molecular biology offer alternative strategies for precise, robust, and potentially less toxic treatment paradigms for circumventing the disease at the cellular and molecular level. Several deregulated molecules associated with tumorigenesis have been developed as targets in RNA interference (RNAi) based cancer therapeutics. RNAi, a post-transcriptional gene regulation mechanism, has significantly gained attention because of its precise multi-targeted gene silencing. Although the RNAi approach is favorable, the direct administration of small oligonucleotides has not been fruitful because of their inherent lower half-lives and instability in the biological systems. Moreover, the lack of an appropriate delivery system to the primary site of the tumor that helps determine the potency of the drug and its reach, has limited the effective medical utilization of these bio-drugs. Nanotechnology, with its unique characteristics of enhanced permeation and better tumor-targeting efficiency, offers promising solutions owing to the various possibilities and amenability for modifications of the nanoparticles to augment cancer therapeutics. Nanoparticles could be made multimodal, by designing and synthesizing multiple desired functionalities, often resulting in unique and potentially applicable biological structures. A small number of Phase I clinical trials with systemically administered siRNA molecules conjugated with nanoparticles have been completed and the results are promising, indicating that, these new combinatorial therapies can successfully and safely be used to inhibit target genes in cancer patients to alleviate some of the disease burden. In this review, we highlight different types of nano-based delivery strategies for engineering Nano-RNAi-based bio drugs. Furthermore, we have highlighted the insights gained from current research that are entering the preclinical evaluation and information about initial clinical developments, shaping the future for next generation cancer therapeutics.
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13
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Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 22:791-802. [PMID: 33230476 PMCID: PMC7644579 DOI: 10.1016/j.omtn.2020.10.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023]
Abstract
Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.
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14
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Zeinali T, Karimi L, Hosseinahli N, Shanehbandi D, Mansoori B, Mohammadi A, Hajiasgharzadeh K, Babaloo Z, Majidi-Zolbanin J, Baradaran B. Overexpression of miRNA-145 induces apoptosis and prevents proliferation and migration of MKN-45 gastric cancer cells. EXCLI JOURNAL 2020; 19:1446-1458. [PMID: 33250681 PMCID: PMC7689247 DOI: 10.17179/excli2020-2777] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022]
Abstract
MiR-145 is a tumor suppressor miRNA that its ubiquitously expressed in the body but in numerous types of cancers such as GC, its expression became reduced or sometimes ceased in many subjects. This study aimed at restoring the function of the miR-145 in MKN-45 cells and investigating the function of this miRNA in proliferation, apoptosis, and migration of GC cells. MKN-45 cells were transfected using the PCMV-miR-145 plasmid vector. The MTT, DAPI staining, and wound healing assays were applied to estimate the impacts of ectopic expression of miR-145 in vitro. Moreover, alterations in the expression levels of K-Ras, c-Myc, caspase-3, caspase-9, Bax, Bcl-2, and MMP-9 mRNA were measured by qRT-PCR analysis. The findings designated that high expression of miR-145 reduced the proliferation and migration and increased the apoptosis of the MKN-45 cells. These effects occur with concurrent suppression of c-Myc, K-Ras, Bcl-2, and MMP-9 as well as induction of caspase-3, caspase-9, and Bax expression. Exogenous miR-145 influences multiple oncogenic pathways and can be regarded as a promising avenue of future therapeutic interventions for GC therapy.
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Affiliation(s)
- Tahereh Zeinali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Leila Karimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nayer Hosseinahli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zohreh Babaloo
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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MicroRNA-1297 inhibits proliferation and promotes apoptosis in gastric cancer cells by downregulating CDC6 expression. Anticancer Drugs 2020; 30:803-811. [PMID: 31419217 DOI: 10.1097/cad.0000000000000776] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Gastric cancer (GC), one of the most common malignant tumors and the second most common leading cause of cancer-related death worldwide, is a biologically heterogeneous disease accompanied by various genetic and epigenetic alterations. However, the molecular mechanisms underlying this disease are complex and not completely understood. Increasing studies have shown that aberrant microRNA (miRNA) expression is associated with GC tumorigenesis and growth. MiR-1297 has been confirmed to be a cancer suppressor in diverse tumors in humans. However, to date, the function and mechanism of miR-1297 in GC have not been determined. Here, we found that the expression of miR-1297 was significantly reduced in GC tissues or GC cell lines compared with paracarcinoma normal tissue or normal cell lines. Exogenic overexpression of miR-1297 in GC cell lines can inhibit cell proliferation and colony formation and induce apoptosis, and inhibition of miR-1297 in GC cell lines can promote cell proliferation and colony formation, and reduce apoptosis in vitro. We further confirmed that miR-1297 acted as a tumor suppressor through targeting cell division control protein 6 (CDC6) in GC. Moreover, the inverse relationship between miR-1297 and CDC6 was verified in GC cell lines. Our results indicated that miR-1297 is a potent tumor suppressor in GC, and its antiproliferative and gene-regulatory effects are, in part, mediated through its downstream target gene, CDC6. These findings implied that miR-1297 might be used as a novel therapeutic target of GC.
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16
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Sánchez Y, Vaca-Paniagua F, Herrera L, Oñate L, Herrera-Goepfert R, Navarro-Martínez G, Cerrato D, Díaz-Velázquez C, Quezada EM, García-Cuellar C, Prada D. Nutritional Indexes as Predictors of Survival and Their Genomic Implications in Gastric Cancer Patients. Nutr Cancer 2020; 73:1429-1439. [PMID: 32715775 DOI: 10.1080/01635581.2020.1797833] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric cancer is an aggressive malignancy with poor prognosis. Although obesity is a risk factor, an association between overweight and better survival has been reported. We explored the genomic implications of such association. Data from 940 patients were analyzed using Cox regression models and ROC curves to assess body mass index (BMI) and prognostic nutritional index (PNI) as predictors of survival. The exome sequencing of a random subset was analyzed to determine copy number variation (CNV) and single nucleotide variation (SNV), using Kruskal-Wallis and chi-square tests to evaluate their clinical implications. Overall survival was lower in patients with BMI ≤ 24.9 and PNI ≤ 29 (p < 0.001). BMI and survival were directly correlated (HR: 0.972, 95% CI: 0.953, 0.992; p-value < 0.007). A higher PNI correlated with improved survival (HR: 0.586, 95% CI: 0.429, 0.801; p-value <0.001). We found a PNI cutoff point of 41.00 for overall survival. Genomic analysis showed an association between lower BMI, less CNV events (p-value = 0.040) and loss of tumor suppressor genes (p-value = 0.021). BMI and PNI are independent factors for overall survival in gastric cancer, probably linked to variations in genomic intratumoral alterations.
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Affiliation(s)
- Yesennia Sánchez
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Felipe Vaca-Paniagua
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
| | - Luis Herrera
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Luis Oñate
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | - Guiselle Navarro-Martínez
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Dennis Cerrato
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Clara Díaz-Velázquez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
| | - Ericka Marel Quezada
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Claudia García-Cuellar
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Diddier Prada
- Unit of Biomedical Research in Cancer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Department of Biomedical Informatics, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Department of Environmental Health Science, Mailman School of Public Health, Columbia University, New York City, USA
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17
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Dongol S, Zhang Q, Qiu C, Sun C, Zhang Z, Wu H, Kong B. IQGAP3 promotes cancer proliferation and metastasis in high-grade serous ovarian cancer. Oncol Lett 2020; 20:1179-1192. [PMID: 32724358 PMCID: PMC7377165 DOI: 10.3892/ol.2020.11664] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 04/22/2020] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer is a type of gynecological cancer with the highest mortality rate worldwide. Due to a lack of effective screening methods, most cases are diagnosed at later stages where the survival rates are poor. Thus, it is termed a ‘silent killer’ and is the most lethal of all the malignancies in women. IQ motif containing GTPase Activating Protein 3 (IQGAP3) is a member of the Rho family of GTPases, and plays a crucial role in the development and progression of several types of cancer. The aim of the present study was to investigate the oncogenic functions and mechanisms of IQGAP3 on the proliferation and metastasis of high-grade serous ovarian cancer (HGSOC). Therefore, the expression levels of IQGAP3 in HGSOC and normal tissue samples were compared, and IQGAP3 knockdown was performed to examine its functional role using various in vitro and in vivo experiments. It was demonstrated that the expression of IQGAP3 was upregulated in HGSOC tissues compared with the healthy tissues; this differential expression was also observed in the ovarian cancer cell lines. Functional experimental results suggested that IQGAP3 silencing significantly reduced proliferation, migration and invasion in ovarian cancer cell lines. Moreover, in vivo experimental findings validated the in vitro results, where the tumorigenic and metastatic capacities of IQGAP3-silenced cells were significantly lower in the nude mice compared with the mice implanted with the control cells. Furthermore, knockdown of IQGAP3 resulted in increased apoptosis, and the effects of IQGAP3 expression on various epithelial-mesenchymal transition markers were identified, suggesting a possible mechanism associated with the role of IQGAP3 in metastasis. The effect of IQGAP3 silencing on chemosensitivity towards olaparib was also assessed. Collectively, the present results indicated that IQGAP3 is a potential diagnostic and prognostic marker, and a putative therapeutic target of HGSOC.
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Affiliation(s)
- Samina Dongol
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Qing Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Chunping Qiu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Zhiwei Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Huan Wu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.,Key Laboratory of Gynecologic Oncology of Shandong, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
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18
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Liu B, Li G, Zhang Z, Wu H. Influence of miR-376c-3p/SYF2 Axis on the Progression of Gastric Cancer. Technol Cancer Res Treat 2020; 18:1533033819874808. [PMID: 31522605 PMCID: PMC6747844 DOI: 10.1177/1533033819874808] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
MicroRNA-376c-3p was previous reported to have a crucial role in the progression of human cancer. This study was aimed to investigate the influence of microRNA-376c-3p on the proliferation and migration of human gastric cancer cells and the associated mechanism. We explored the expression of microRNA-376c-3p in gastric cancer cells using reverse transcription-quantitative polymerase chain reaction. Also, we analyzed the association and biological significance of microRNA-376c-3p and SYF2 pre-mRNA-splicing factor in gastric cancer. MicroRNA-376c-3p expression was found downregulated in gastric cancer cell lines compared to the normal cell line. MicroRNA-376c-3p directly targeted SYF2 and reduced SYF2 expression. Overexpression of microRNA-376c-3p inhibits gastric cancer cell proliferation and migration. Besides that, overexpression of SYF2 abrogates the inhibitory influences on gastric cancer cell behaviors caused by microRNA-376c-3p mimic. These results showed that microRNA-376c-3p inhibits the proliferation and migration of gastric cancer cells via targeting SYF2.
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Affiliation(s)
- Bin Liu
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, China
| | - Guangchun Li
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, China
| | - Zhen Zhang
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, China
| | - Honglei Wu
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan, China
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19
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Ye DM, Xu G, Ma W, Li Y, Luo W, Xiao Y, Liu Y, Zhang Z. Significant function and research progress of biomarkers in gastric cancer. Oncol Lett 2020; 19:17-29. [PMID: 31897111 PMCID: PMC6924079 DOI: 10.3892/ol.2019.11078] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 09/26/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is one of the most common gastrointestinal tumor types, and the incidence and mortality rates are higher in men compared with women. Various studies have revealed that gastric cancer is a spectrum of tumor types, which have biological and genetic diversity. It has proven to be difficult to improve the overall survival and disease-free survival of patients with gastric cancer through the use of traditional surgery and chemoradiation, as gastric cancer is usually identified at an advanced stage. In consequence, the outcome is frequently poor. Thus, novel biomarkers and anticancer targets are required to improve the outcome. As the identification of biomarkers has increased due to advances in research and the greater availability of bioinformatics and functional genomics, the potential therapeutic regimens available have also increased concurrently. These advances have also improved the ability to predict responses to chemotherapy, targeted therapy and immunotherapy, whilst other biomarkers predict post-treatment survival and recurrence based on their expression. This review focuses closely on the important functions of biomarkers in the timely diagnosis and treatment of gastric cancer, in addition to the advances in the study of certain novel markers in gastric cancer.
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Affiliation(s)
- Dong Mei Ye
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Gaosheng Xu
- Department of Surgery, Yueyang Maternal and Child Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Wei Ma
- Department of Surgery, Yueyang Maternal and Child Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Yuxuan Li
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Weiru Luo
- Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yiyang Xiao
- Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yong Liu
- Department of Pathology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiwei Zhang
- Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
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20
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Hevia MJ, Castro P, Pinto K, Reyna-Jeldes M, Rodríguez-Tirado F, Robles-Planells C, Ramírez-Rivera S, Madariaga JA, Gutierrez F, López J, Barra M, De la Fuente-Ortega E, Bernal G, Coddou C. Differential Effects of Purinergic Signaling in Gastric Cancer-Derived Cells Through P2Y and P2X Receptors. Front Pharmacol 2019; 10:612. [PMID: 31249523 PMCID: PMC6584115 DOI: 10.3389/fphar.2019.00612] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/15/2019] [Indexed: 01/04/2023] Open
Abstract
Gastric cancer (GC) is the one of the most prevalent cancers and one of the leading causes of cancer-induced deaths. Previously, we found that the expression of purinergic P2Y2 receptor (P2Y2R) is increased in GC samples as compared to adjacent healthy mucosa taken from GC-diagnosed patients. In this work, we studied in detail purinergic signaling in the gastric adenocarcinoma-derived cell lines: AGS, MKN-45, and MKN-74, and compared them to a nontumoral epithelial cell line: GES-1. In GC-derived cells, we detected the expression of several purinergic receptors, and found important differences as compared to GES-1 cells. Functional studies revealed a strong contribution of P2Y2Rs in intracellular calcium increases, elicited by adenosine-triphosphate (ATP), uridine-triphosphate (UTP), and the P2Y2R agonist MRS2768. Responses were preserved in the absence of extracellular calcium and inhibited by P2Y2R antagonists. In GES-1 cells, ATP and UTP induced similar responses and the combination of P2X and P2Y receptor antagonists was able to block them. Proliferation studies showed that ATP regulates AGS and MKN-74 cells in a biphasic manner, increasing cell proliferation at 10–100 μM, but inhibiting at 300 μM ATP. On the other hand, 1–300 μM UTP, a P2Y2R agonist, increased concentration-dependent cell proliferation. The effects of UTP and ATP were prevented by both wide-range and specific purinergic antagonists. In contrast, in GES-1 cells ATP only decreased cell proliferation in a concentration-dependent manner, and UTP had no effect. Notably, the isolated application of purinergic antagonists was sufficient to change the basal proliferation of AGS cells, indicating that nucleotides released by the cells can act as paracrine/autocrine signals. Finally, in tumor-derived biopsies, we found an increase of P2Y2R and a decrease in P2X4R expression; however, we found high variability between seven different biopsies and their respective adjacent healthy gastric mucosa. Even so, we found a correlation between the expression levels of P2Y2R and P2X4R and survival rates of GC patients. Taken together, these results demonstrate the involvement of different purinergic receptors and signaling in GC, and the pattern of expression changes in tumoral cells, and this change likely directs ATP and nucleotide signaling from antiproliferative effects in healthy tissues to proliferative effects in cancer.
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Affiliation(s)
- María José Hevia
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Patricio Castro
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.,Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Katherine Pinto
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Mauricio Reyna-Jeldes
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | | | | | - Sebastián Ramírez-Rivera
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Juan Andrés Madariaga
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.,Hospital San Pablo, Coquimbo, Chile
| | | | - Javier López
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.,Hospital San Pablo, Coquimbo, Chile
| | - Marcelo Barra
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile.,Hospital San Pablo, Coquimbo, Chile
| | - Erwin De la Fuente-Ortega
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Giuliano Bernal
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
| | - Claudio Coddou
- Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
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21
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Kim E, Ahn B, Oh H, Lee YJ, Lee JH, Lee Y, Kim CH, Chae YS, Kim JY. High Yes-associated protein 1 with concomitant negative LATS1/2 expression is associated with poor prognosis of advanced gastric cancer. Pathology 2019; 51:261-267. [DOI: 10.1016/j.pathol.2019.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/25/2018] [Accepted: 01/05/2019] [Indexed: 02/07/2023]
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22
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Guo H, Ji F, Zhao X, Yang X, He J, Huang L, Zhang Y. MicroRNA-371a-3p promotes progression of gastric cancer by targeting TOB1. Cancer Lett 2019; 443:179-188. [DOI: 10.1016/j.canlet.2018.11.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 11/19/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
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23
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Hattori Y, Sentani K, Shinmei S, Oo HZ, Hattori T, Imai T, Sekino Y, Sakamoto N, Oue N, Niitsu H, Hinoi T, Ohdan H, Yasui W. Clinicopathological significance of RCAN2 production in gastric carcinoma. Histopathology 2019; 74:430-442. [DOI: 10.1111/his.13764] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/29/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Yui Hattori
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Shunsuke Shinmei
- Department of Urology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Htoo Zarni Oo
- Department of Urologic Sciences; University of British Columbia; Vancouver Prostate Centre; Vancouver British Columbia Canada
| | - Takuya Hattori
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Takeharu Imai
- Department of Surgical Oncology; Gifu University Graduate School of Medicine; Gifu Japan
| | - Yohei Sekino
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Department of Urology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Naohide Oue
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Hiroaki Niitsu
- Department of Gastroenterological Transplant Surgery; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Takao Hinoi
- Department of Gastroenterological Transplant Surgery; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Department of Surgery; National Hospital Organisation Kure Medical Centre; Kure Japan
| | - Hideki Ohdan
- Department of Gastroenterological Transplant Surgery; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
| | - Wataru Yasui
- Department of Molecular Pathology; Graduate School of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
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24
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Maleki Kakelar H, Barzegari A, Dehghani J, Hanifian S, Saeedi N, Barar J, Omidi Y. Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination. Gastric Cancer 2019; 22:23-36. [PMID: 30145749 DOI: 10.1007/s10120-018-0867-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori affect around 50% of the population worldwide. More importantly, the gastric infection induced by this bacterium is deemed to be associated with the progression of distal gastric carcinoma and gastric mucosal lymphoma in the human. H. pylori infection and its prevalent genotype significantly differ across various geographical regions. Based on numerous virulence factors, H. pylori can target different cellular proteins to modulate the variety of inflammatory responses and initiate numerous "hits" on the gastric mucosa. Such reactions lead to serious complications, including gastritis and peptic ulceration, gastric cancer and gastric mucosa-associated lymphoid structure lymphoma. Therefore, H. pylori have been considered as the type I carcinogen by the Global Firm for Research on Cancer. During the two past decades, different reports revealed that H. pylori possess oncogenic potentials in the gastric mucosa through a complicated interplay between the bacterial factors, various facets, and the environmental factors. Accordingly, numerous signaling pathways could be triggered in the development of gastrointestinal diseases (e.g., gastric cancer). Therefore, the main strategy for the treatment of gastric cancer is controlling the disease far before its onset using preventive/curative vaccination. Increasing the efficiency of vaccines may be achieved by new trials of vaccine modalities, which is used to optimize the cellular immunity. Taken all, H. pylori infection may impose severe complications, for resolving of which extensive researches are essential in terms of immune responses to H. pylori. We envision that H. pylori-mediated diseases can be controlled by advanced vaccines and immunotherapies.
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Affiliation(s)
- Hadi Maleki Kakelar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Barzegari
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaber Dehghani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Hanifian
- Department of Food Science and Technology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Nazli Saeedi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran.
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25
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Raj N, Verma D, Kumar A, Rai P, Rao RN. HER2 Oncogene Amplification and Immunohistochemical Profiling in Gastric Adenocarcinoma. Discoveries (Craiova) 2018; 6:e83. [PMID: 32309603 PMCID: PMC7086066 DOI: 10.15190/d.2018.6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives: Gastric adenocarcinoma is one of the most common malignant tumors and a major cause of cancer death worldwide, especially in developing countries. Her2/neu gene amplification and protein overexpression in breast cancer is a golden criterion for the targeted therapy with trastuzumab. However, the role of Her2 as a prognostic factor in gastric cancer is still controversial. The purpose of this study was to evaluate the frequency of Her2 oncogene overexpression and concordance between the results for Her2 protein expression and gene amplification. Materials and Methods: A total of 65 retroprospective cases with gastric adenocarcinoma, including biopsy and resected specimens obtained between July 2015 to December 2017, were analyzed. Her2/neu expression was determined by Immuno-histochemistry (IHC). Equivocal and some selected cases were submitted for FISH to detect Her2/neu gene amplification. Results: In the present study, out of 65 patients of gastric adenocarcinoma, there were 50 males and 15 females, with mean age of 54.52 years. The majority of tumors were located within the antropyloric region. We found 27 (41.4%) positivity, scored as IHC 3+ and IHC 2+, and 38 (58.3%) negativity, scored as IHC 1+ and IHC 0. We also evidentiated a significant difference between Her2/neu expression with age (p=0.010) and depth of invasion (p=0.020).Her2/neu gene was amplified only in 13 cases, 4 cases were of Her2/neu (3+) positive, 11 cases (39.3%) Her2/neu (2+) with IHC staining. The concordance rate between the results of IHC and FISH in all 18 cases was 83.3%. Conclusion: IHC detection can be carried out to guide the treatment when FISH detection cannot be performed. Overexpression of Her 2/neu in gastric adenocarcinoma could potentially be used in selecting the patients who can get benefit from the anti-Her2/neu targeted therapy.
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Affiliation(s)
- Nisha Raj
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Divya Verma
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Praveer Rai
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ram Nawal Rao
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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26
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Fang CL, Lin CC, Chen HK, Hseu YC, Hung ST, Sun DP, Uen YH, Lin KY. Ubiquitin-specific protease 3 overexpression promotes gastric carcinogenesis and is predictive of poor patient prognosis. Cancer Sci 2018; 109:3438-3449. [PMID: 30168892 PMCID: PMC6215897 DOI: 10.1111/cas.13789] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 08/24/2018] [Accepted: 08/26/2018] [Indexed: 12/31/2022] Open
Abstract
Although gastric cancer (GC) is one of the most common cancers, knowledge of its development and carcinogenesis is limited. To date, expression of ubiquitin-specific protease 3 (USP3) in all types of cancer, including GC, is still unknown. The present study explored the involvement of USP3 in the carcinogenesis and prognosis of GC. We measured USP3 expression in normal and GC tissues and cell lines. Correlations between USP3 protein level and clinicopathological parameters, as well as the significance of USP3 protein level for disease-free survival were assessed. Small hairpin RNA technology and transfection were used to investigate the effect of USP3 manipulation on cell proliferation and spreading. Moreover, xenograft proliferation and metastasis were used to explore the influence of USP3 on tumor growth and metastasis in animals. An increase in USP3 expression was observed in GC cells and tissues. The overexpression of USP3 was significantly correlated with several clinicopathological parameters and poor disease-free survival. Multivariate Cox regression analysis showed that the overexpression of USP3 was an independent prognostic biomarker. Silencing of USP3 suppressed GC cell proliferation and spreading in vitro as well as xenograft proliferation and metastasis in vivo; however, opposite results were obtained when USP3 was overexpressed. Further studies showed that USP3 influenced cell proliferation and spreading by regulating the cell cycle control- and epithelial-mesenchymal transition-related molecules. This study suggests that USP3 overexpression can be a useful biomarker for predicting the outcomes of GC patients and that USP3 targeting represents a potential modality for treating GC.
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Affiliation(s)
- Chia-Lang Fang
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chih-Chan Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Han-Kun Chen
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics, China Medical University, Taichung, Taiwan.,Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
| | - Shih-Ting Hung
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Ding-Ping Sun
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.,Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yih-Huei Uen
- Department of Surgery, Asia University Hospital, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan.,Department of Surgery, Tainan Municipal An-Nan Hospital, Tainan, Taiwan
| | - Kai-Yuan Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.,Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
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27
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Uen YH, Fang CL, Lin CC, Hseu YC, Hung ST, Sun DP, Lin KY. Ceramide synthase 6 predicts the prognosis of human gastric cancer: It functions as an oncoprotein by dysregulating the SOCS2/JAK2/STAT3 pathway. Mol Carcinog 2018; 57:1675-1689. [DOI: 10.1002/mc.22888] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 08/15/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Yih-Huei Uen
- Department of Surgery; Asia University Hospital; Taichung Taiwan
- Department of Biotechnology; Asia University; Taichung Taiwan
- Department of Surgery; Tainan Municipal An-Nan Hospital; Tainan Taiwan
| | - Chia-Lang Fang
- Department of Pathology, School of Medicine, College of Medicine; Taipei Medical University; Taipei Taiwan
- Department of Pathology; Wan Fang Hospital; Taipei Medical University; Taipei Taiwan
| | - Chih-Chan Lin
- Department of Medical Research; Chi Mei Medical Center; Tainan Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics; China Medical University; Taichung Taiwan
- Department of Health and Nutrition Biotechnology; Asia University; Taichung Taiwan
| | - Shih-Ting Hung
- Department of Medical Research; Chi Mei Medical Center; Tainan Taiwan
| | - Ding-Ping Sun
- Department of Surgery; Chi Mei Medical Center; Tainan Taiwan
- Department of Food Science and Technology; Chia Nan University of Pharmacy and Science; Tainan Taiwan
| | - Kai-Yuan Lin
- Department of Medical Research; Chi Mei Medical Center; Tainan Taiwan
- Department of Biotechnology; Chia Nan University of Pharmacy and Science; Tainan Taiwan
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28
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Zhu C, Ma J, Li Y, Zhang Y, Da M. Low expression of long noncoding RNA MT1JP is associated with poor overall survival in gastric cancer patients: Protocol for meta-analysis. Medicine (Baltimore) 2018; 97:e10394. [PMID: 29794726 PMCID: PMC6392895 DOI: 10.1097/md.0000000000010394] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Accepted: 03/21/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Although several researches have investigated the association between development and metastasis of gastric cancer (GC) and the expression level of MT1JP, there are no consensuses about whether its expression is associated with overall survival (OS) and clinical feature for GC patients. METHODS The databases including PubMed, EMBase databases, and the Cochrane Library were searched from inception to January 30, 2016, to identify the eligible studies. The quality of included studies was assessed according to reporting recommendations for tumor marker prognostic studies (REMARK). The association between expression level of LncRNA HOTAIR with OS for GC patients was assessed by calculating the pooled hazard ratio (HR) and 95% confidence interval (95% CI) using STATA version 12.0. Heterogeneity among studies will be assessed using the I statistic. RESULTS Randomized controlled trials (RCTs), prospective cohort studies, and case-control studies will be used for the qualitative and quantitative synthesis of the meta-analysis to explore the association between MT1JP expression levels with OS for gastric cancer patients. CONCLUSION We aim to draw an objective conclusion of the association between MT1JP expression levels with OS for gastric cancer patients.
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Affiliation(s)
- Chenglou Zhu
- College of Clinical Medicine, Gansu University of Chinese Medicine
| | - Jichun Ma
- Department of General Surgery Intensive Care Unit, Lanzhou University Second Hospital, Lanzhou
| | - Yaoqi Li
- College of Clinical Medicine, Ningxia Medical University, Yinchuan
| | - Yongbin Zhang
- Department of Surgical Oncology, Gansu Provincial People's Hospital, Lanzhou, China
| | - Mingxu Da
- Department of Surgical Oncology, Gansu Provincial People's Hospital, Lanzhou, China
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29
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Hedayatizadeh-Omran A, Alizadeh-Navaei R, Janbabaei G, Omrani-Nava V, Hasheminasab Y, Amjadi O, Tehrani M. Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high-risk region. Biomed Rep 2018; 8:433-438. [PMID: 29616139 PMCID: PMC5876468 DOI: 10.3892/br.2018.1070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/30/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer has the fourth highest morbidity rate of all cancers worldwide. Genetic factors including alterations in oncogenes and tumor suppressor genes serve an important role in gastric cancer development and progression. The P53 gene acts as a tumor suppressor gene by regulating the cell cycle, DNA transcription and repair, apoptosis, senescence and genome stability. In addition to somatic P53 mutations in cancer development, germline polymorphisms are also involved in different malignancies. The polymorphism of P53 at codon 72 (Arg72Pro) is established as a common variant that increases susceptibility to various cancers. The present case-control study was conducted to evaluate the possible association between this P53 polymorphism and gastric cancer in the Iranian population. A total of 59 patients with gastric cancer and 59 healthy controls were enrolled in the present study. Genomic DNA was extracted from peripheral blood mononuclear cells and genotype analysis was performed using a polymerase chain reaction-based restriction fragment length polymorphism assay. Genotype frequencies did not differ significantly between the patients and controls (P=0.4); the frequencies of the three genotypes Arg/Arg, Arg/Pro and Pro/Pro in gastric cancer patients were 28.8, 49.2 and 22.0%, and in controls were 37.3, 49.2 and 13.6%. Additionally, there were no differences in genotype frequencies based on tumor location, histological differentiation or tumor stage. Based on these findings, it may be concluded that the P53 codon 72 polymorphism does not contribute to gastric cancer susceptibility in Northern Iran.
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Affiliation(s)
- Akbar Hedayatizadeh-Omran
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
| | - Reza Alizadeh-Navaei
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
- Correspondence to: Dr Reza Alizadeh-Navaei, Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran, E-mail:
| | - Ghasem Janbabaei
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
| | - Versa Omrani-Nava
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
| | - Yahya Hasheminasab
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
| | - Omolbanin Amjadi
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
| | - Mohsen Tehrani
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran 48166-33131, Iran
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30
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Mohsenzadeh M, Sadeghi RN, Vahedi M, Kamani F, Hashemi M, Asadzadeh H, Zali MR. Promoter hypermethylation of RAR-β tumor suppressor gene in gastric carcinoma: Association with histological type and clinical outcomes. Cancer Biomark 2018; 20:7-15. [PMID: 28759951 DOI: 10.3233/cbm-160331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND While gastric cancer is a common cancer in the world and Iran, its molecular mechanisms are not fully understood as yet. Epigenetic modifications can lead to alteration of gene expression and development of tumorigenesis mechanisms. METHODS To clarify the difference in DNA methylation pattern of histological types in gastric carcinoma, CpG islands in the promoters of retinoic acid receptor β gene (RAR-β) was studied using methylation-specific PCR. RESULTS In gastric cancer tissues, hypermethylation frequency of RAR-β gene was respectively 61 and 33% for diffuse and intestinal type. In diffuse type, hypermethylation of RAR-β has been significantly associated with invasion (P= 0.007), differentiation (P= 0.033) and location (P= 0.012) of the tumor. However, hypermethylation of RAR-β correlated only with tumor size (P= 0.029) in intestinal type. For adjacent non-tumor samples, hypermethylation of RAR-β was not detected and there was no significant association between age of diagnosis and hypermethylation of RAR-β in both types of gastric cancer. CONCLUSIONS These results support previous findings denoting a distinct profile of promoter hypermethylation status in the development of the intestinal and diffuse type of gastric carcinoma and the process of the tumorigenesis in these subtypes of gastric cancer is different from each other.
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Affiliation(s)
- Maedeh Mohsenzadeh
- Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Rouhallah Najjar Sadeghi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Faculty of Medicine, Department of Clinical Biochemistry, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohsen Vahedi
- Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Fereshteh Kamani
- Department of Surgery, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Hamid Asadzadeh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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31
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Jiang Y, Li W, Lu J, Zhao X, Li L. Association between PRKAA1 rs13361707 T>C polymorphism and gastric cancer risk: Evidence based on a meta-analysis. Medicine (Baltimore) 2018; 97:e0302. [PMID: 29620653 PMCID: PMC5902272 DOI: 10.1097/md.0000000000010302] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recently, several published studies investigating the relationship between protein kinase catalytic subunit alpha-1 gene (PRKAA1) rs13361707 T>C polymorphism and gastric cancer (GC) susceptibility reported controversial results. The purpose of this meta-analysis was to estimate the strength of the relationship. METHODS Qualified studies were identified form a comprehensive search conducted in the Embase, Pubmed, Wangfang, and China National Knowledge Infrastructure (CNKI) databases for studies published before February 12, 2018. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the relationship between the PRKAA1 rs13361707 T>C polymorphism and GC risk. RESULTS Fifteen independent case-control studies, which included 14,615 GC patients and 18,143 control subjects, were included in this present meta-analysis. The overall analysis of the 15 studies indicated that the PRKAA1 rs13361707 T>C polymorphism significantly increased susceptibility for GC in all genetic models. When stratified analysis was carried out by country and source of controls, similar results were found in each subgroup, except for the Hispanic Americans. There was no publication bias in our study. Omitting each study 1 at a time in the sensitivity analysis of the PRKAA1 rs13361707 T>C polymorphism and GC risk had no noticeable influence on the pooled OR, which identified the reliability of the meta-analysis. False-positive report probability analysis and trial sequential analysis demonstrated that such relationship was confirmed in the present study. CONCLUSIONS The meta-analysis reveals that the PRKAA1 rs13361707 T>C polymorphism has a significant relationship with increased GC risk. To confirm the risk identified in the present meta-analysis, well-designed and large-scale case-control studies are warranted to investigate the relationship, especially among non-Asian ethnicity.
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Affiliation(s)
- You Jiang
- Department of General Surgery, Hefei Second People's Hospital
| | - Wenbo Li
- Department of General Surgery, Hefei Second People's Hospital
| | - Jun Lu
- Department of General Surgery, Hefei Second People's Hospital
| | - Xin Zhao
- Department of Emergency, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Liang Li
- Department of General Surgery, Hefei Second People's Hospital
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32
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Li R, Zhang H, Liu H, Lin C, Cao Y, Zhang W, Shen Z, Xu J. High expression of C-C chemokine receptor 2 associates with poor overall survival in gastric cancer patients after surgical resection. Oncotarget 2018; 7:23909-18. [PMID: 26992207 PMCID: PMC5029673 DOI: 10.18632/oncotarget.8069] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 02/28/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Being a critical chemokine receptor in chemoattracting myeloid cells into tumor tissues, C-C chemokine receptor 2 (CCR2) has been detected in many malignant tumors. This study aims to evaluate the prognostic value of CCR2 expression in patients with gastric cancer after surgery. RESULTS CCR2 expression was detected in the accessory cells around gastric cancer cells in a diffused manner. CCR2 high expression was correlated with tumor invasion depth (P=0.006 and P=0.004, respectively), lymph node metastasis (P=0.038 and P=0.011, respectively) and TNM stage (P=0.003 and P=0.001, respectively) in the two independent sets. Multivariate Cox regression analysis identifies CCR2 high expression was an independent poor prognostic factor for OS of patients with gastric cancer in the two sets (P=0.013 and P=0.006, respectively). Integration of CCR2 expression and TNM stage could provide additional prognostic value for OS than TNM stage alone in the two sets (P=0.038 and P=0.002, respectively). METHODS Two independent sets comprising a total of 474 patients who received standard gastrectomy were enrolled in the study. The expression level of CCR2 was detected by immunohistochemistry. The correlations between CCR2 expression and clinicopathological factors were explored, and the prognostic significance for overall survival (OS) was determined by Kaplan-Meier analysis. CONCLUSIONS CCR2 high expression in the tumor microenvironment is a novel independent unfavorable prognostic factor for patients with gastric cancer. Combination of CCR2 expression and TNM stage could provide a better prognostic model for OS of gastric cancer patients.
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Affiliation(s)
- Ruochen Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Heng Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chao Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yifan Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Weijuan Zhang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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33
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Szász AM, Lánczky A, Nagy Á, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A, Győrffy B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget 2018; 7:49322-49333. [PMID: 27384994 PMCID: PMC5226511 DOI: 10.18632/oncotarget.10337] [Citation(s) in RCA: 753] [Impact Index Per Article: 107.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/13/2016] [Indexed: 02/07/2023] Open
Abstract
Introduction Multiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates. Results The entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS. MATERIALS AND METHODS We integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012–2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis. Conclusions The major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.
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Affiliation(s)
- A Marcell Szász
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - András Lánczky
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Ádám Nagy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Susann Förster
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Kim Hark
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jeffrey E Green
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Alex Boussioutas
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - Rita Busuttil
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - András Szabó
- 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Balázs Győrffy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
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Cao C, Sun D, Zhang L, Song L. miR-186 affects the proliferation, invasion and migration of human gastric cancer by inhibition of Twist1. Oncotarget 2018; 7:79956-79963. [PMID: 27835599 PMCID: PMC5346763 DOI: 10.18632/oncotarget.13182] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 10/17/2016] [Indexed: 01/06/2023] Open
Abstract
Recent evidence shows that miRNAs are dysregulated in a variety of cancers including gastric cancer (GC), and emerging as key oncogenes or tumor suppressors. In this study, qRT-PCR was used to analyze the expression of miR-186 in GC tissues and adjacent non-cancerous tissues, and then more in-vitro experiments were used to investigate the role of miR-186 in GC cells. Here, we identified miR-186 was generally down-regulated in GC tissues; however, Twist1 was generally up-regulated in GC tissues. Moreover, miR-186 and Twist1 were associated with larger tumor size and advanced clinical stage of GC. In-vitro experiments demonstrated that ectopic overexpression of miR-186 inhibited GC cell proliferation, invasion and migration; however, inhibited expression of miR-186 enhanced cell proliferation, invasion and migration. Furthermore, the luciferase reporter assay demonstrated Twist1 as a direct target of miR-186. Finally, over-expression of Twist1 abrogated inhibitory impact of miR-186 on cell proliferation, invasion and migration. In conclusion, miR-186 affects the proliferation, invasion and migration of human gastric cancer by inhibition of Twist1, and could be a tumor suppressor in GC development. Thus, miR-186 may be served as a candidate prognostic biomarker and target for new therapies in human gastric cancer.
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Affiliation(s)
- Chunhong Cao
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027 Liaoning, China
| | - Deguang Sun
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027 Liaoning, China
| | - Liang Zhang
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027 Liaoning, China
| | - Lei Song
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027 Liaoning, China
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Cao Y, Tan S, Tu Y, Zhang G, Liu Y, Li D, Xu S, Le Z, Xiong J, Zou W, Gong P, Li Z, Jie Z. MicroRNA-125a-5p inhibits invasion and metastasis of gastric cancer cells by targeting BRMS1 expression. Oncol Lett 2018; 15:5119-5130. [PMID: 29552146 DOI: 10.3892/ol.2018.7983] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 09/07/2017] [Indexed: 12/12/2022] Open
Abstract
Accumulating studies have demonstrated microRNAs (miRNAs/miRs) have an important role in multiple processes of human malignant tumor development and progression. Decreased expression of miR-125a-5p has been observed in several types of cancer, including gastric cancer (GC). However, the mechanism and exact function of miR-125a-5p in GC have not been largely elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction indicated that the expression of miR-125a-5p was downregulated in GC tissues and cell lines compared with matched normal tissues (P<0.01) and normal gastric mucosa cell lines (P<0.01), respectively. Moreover, clinical pathological characteristics and Kaplan-Meier analysis indicated that a low expression of miR-125a-5p was not only associated with lymph metastasis, peritoneal dissemination and advanced tumor-node metastasis stage but also affected the prognosis of GC patients. Compared with miR-control-transfected GC cells, markedly decreased migration and invasion was observed in GC cells that overexpress miR-125a-5p. By contrast, increased metastasis and invasion were observed in miR-125a-5p-knocked down cells compared with the control. Furthermore, luciferase reporter assays indicated that breast cancer metastasis suppressor 1 (BRMS1) was a direct target of miR-125a-5p. Notably, a positive correlation between the levels of BRMS1 and miR-125a-5p in GC tissues was observed, and BRMS1 expression was indicated to be regulated by miR-125a-5p in GC cells. In conclusion, miR-125a-5p may act as a tumor suppressor by targeting the metastasis-inhibitory gene, BRMS1. The data suggesting that BRMS1 is a potential target gene of miR-125a-5p, may provide novel insight into miRNA regulation of human gene expression, and a useful target for gene therapy of GC.
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Affiliation(s)
- Yi Cao
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shengxing Tan
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Tu
- Department of Pathology, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Guoyang Zhang
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Liu
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Daojiang Li
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shan Xu
- Department of Pathology, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhibiao Le
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jianbo Xiong
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wenyu Zou
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Peitao Gong
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhengrong Li
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhigang Jie
- Department of General Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Oue N, Yamamoto Y, Oshima T, Asai R, Ishikawa A, Uraoka N, Sakamoto N, Sentani K, Yasui W. Overexpression of the Transmembrane Protein IQGAP3 Is Associated with Poor Survival of Patients with Gastric Cancer. Pathobiology 2017; 85:192-200. [DOI: 10.1159/000481890] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/02/2017] [Indexed: 01/04/2023] Open
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Hong SA, Son MW, Cho J, Jang SH, Lee HJ, Lee JH, Cho HD, Oh MH, Lee MS. Low angiomotin-p130 with concomitant high Yes-associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer. APMIS 2017; 125:996-1006. [PMID: 28885730 DOI: 10.1111/apm.12750] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 07/14/2017] [Indexed: 11/26/2022]
Abstract
Angiomotin (AMOT) promotes angiogenesis and plays a role in neovascularization during tumorigenesis. Recently, the AMOT isoform, AMOT-p130, was shown to exert a regulatory effect on Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway. The specific roles of AMOT-p130 and YAP1 in advanced gastric cancer (AGC) are yet to be established. In this study, a total of 166 patients with AGC were enrolled, and AMOT-p130 and YAP1 levels were analyzed by immunohistochemistry using tissue microarrays. Low AMOT-p130 together with high YAP1 expression (n = 30, 18.1%) was associated with high T stage (p = 0.042), high TNM stage (p = 0.025), and venous invasion (p = 0.048). A Kaplan-Meier survival analysis with log-rank test revealed a significant correlation with decreased AMOT-p130 coupled with high nuclear YAP1 expression with shorter overall survival (p = 0.0045) and disease-free survival (p = 0.0028). Furthermore, multivariate analyses showed that the low AMOT-p130/high YAP1 expression profile was an independent prognostic factor for disease-free survival (p = 0.008, HR = 1.874, CI, 1.177-2.986) and overall survival (p = 0.012, HR = 1.903, CI, 1.152-3.143). Our findings collectively demonstrate that low AMOT-p130 combined with high YAP1 expression is correlated with an unfavorable AGC prognosis.
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Affiliation(s)
- Soon Auck Hong
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Myoung Won Son
- Department of General Surgery, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Junhun Cho
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Si-Hyong Jang
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Hyun Ju Lee
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Ji-Hye Lee
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Hyun Deuk Cho
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Mee-Hye Oh
- Department of Pathology, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Moon Soo Lee
- Department of General Surgery, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
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Lin J, Chen Z, Huang Z, Chen F, Ye Z, Lin S, Wang W. Upregulation of T-cadherin suppresses cell proliferation, migration and invasion of gastric cancer in vitro. Exp Ther Med 2017; 14:4194-4200. [PMID: 29104635 PMCID: PMC5658734 DOI: 10.3892/etm.2017.5090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 05/31/2017] [Indexed: 12/12/2022] Open
Abstract
As a unique member of the cadherin superfamily, T-cadherin (T-cad) has been demonstrated to be associated with gastric cancer (GC) prognosis. To elucidate the function of T-cad in GC in vitro, the present study firstly examined T-cad protein expression in normal and gastric cancer tissues and cell lines, and it was demonstrated to be significantly downregulated in gastric cancer samples compared with normal samples. Control and T-cad expression vectors were then transfected into the MGC8-03 and AGS GC cell lines. Utilizing MTT, clonogenic, flow cytometry, wound healing and Transwell invasion assays in addition to Western blotting, the present study demonstrated that the overexpression of T-cad suppressed GC cell growth and colony formation via cell cycle arrest at the G0/G1 phase via downregulating the expression of cyclin dependent kinase 4 and Cyclin D1. In addition, overexpression of T-cad significantly inhibited GC cell migration and invasion by increasing E-cadherin and decreasing Vimentin expression. These findings suggest T-cad may be important in GC cell proliferation and metastasis and serve as a promising target for the treatment of GC in the future.
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Affiliation(s)
- Jianqing Lin
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Zhiyao Chen
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Zhijun Huang
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Feng Chen
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Zeyi Ye
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Shaoze Lin
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Weidong Wang
- Department of Surgical Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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Ni J, Shen N, Tang J, Ren K. Correlation between protein kinase catalytic subunit alpha-1 gene rs13361707 polymorphism and gastric cancer susceptibility in asian populations. Oncotarget 2017; 8:68354-68364. [PMID: 28978122 PMCID: PMC5620262 DOI: 10.18632/oncotarget.19355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 06/18/2017] [Indexed: 12/20/2022] Open
Abstract
A single nucleotide polymorphism (SNP) of the protein kinase catalytic subunit alpha-1 gene (PRKAA1) that confers susceptibility to gastric cancer (GC) was identified by genome-wide association in several case-control studies. However, the results remained controversial and ambiguous. Therefore, we performed a larger meta-analysis to confirm this association. We searched the PubMed, Embase, WanFang, and CNKI databases, without any restriction on language, covering all papers published until Feb 22, 2017. Overall, 14 case-control studies with 14,485 cases and 14,792 controls were retrieved based on the search criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to quantify the strength of the association. Publication bias was assessed by Egger’s and Begg’s tests. We found that the PRKAA1 rs13361707 C/T polymorphism had no association with GC risk in any of the pooled genetic models (for example, the T-allele vs. C-allele allelic contrast model yielded the following estimates: OR = 0.87, 95% CI = 0.73–1.05, Pheterogeneity = 0.000). Furthermore, in analyses stratified by either source of control or geographical origin of subjects, a statistically significant inverse relationship was detected between PRKAA1 rs13361707 C/T polymorphism and GC risk. No obvious evidence of publication bias was detected in the pooled meta-analysis. Furthermore, we observed that individuals carrying T-allele (TT or TC) genotypes had a lower expression of PRKAA1. Our present study indicated that PRKAA1 rs13361707 C/T was not significantly associated with GC risk, despite few positive results in the subgroups.
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Affiliation(s)
- Jianfeng Ni
- Department of Gastroenterology, Tongzhou People's Hospital of Nantong, Nantong 226300, China
| | - Nan Shen
- Department of Clinical Pharmacy, The Affiliated Jiangyin Hospital of Southeast University Medical School, Jiangyin 214400, China
| | - Jilei Tang
- Department of Orthopedics, Qidong People's Hospital, Nantong 226200, China
| | - Kewei Ren
- Department of Orthopedics, The Affiliated Jiangyin Hospital of Southeast University Medical School, Jiangyin 214400, China
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Xiong J, Jiang XM, Mao SS, Yu XN, Huang XX. Heat shock protein 70 downregulation inhibits proliferation, migration and tumorigenicity in hepatocellular carcinoma cells. Oncol Lett 2017; 14:2703-2708. [PMID: 28928813 PMCID: PMC5588163 DOI: 10.3892/ol.2017.6531] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 05/11/2017] [Indexed: 12/14/2022] Open
Abstract
The overexpression of heat shock protein 70 (HSP70), a major stress-inducible heat shock protein, has been identified to enhance the proliferation, survival, invasion and metastasis of diverse types of human cancer. However, its role in hepatocellular carcinoma (HCC) remains poorly understood. The present study demonstrated that HSP70 expression was higher in tested HCC cell lines, compared with the normal hepatocyte LO2, and the suppression of HSP70 significantly inhibited the proliferation of SMMC-7721 and Hep3B cells. The growth inhibitory effect was mediated by cell cycle arrest at the G1/S phase with reduced cyclin D1 and increased p27Kip1 expression. Furthermore, HSP70 knockdown significantly inhibited the migration and invasion abilities of HCC cells. In conclusion, HSP70 is a key regulator involved in the proliferation, migration and invasion of HCC, and it may be used as a potential therapeutic target for HCC.
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Affiliation(s)
- Ju Xiong
- Department of General Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China
| | - Xue-Mei Jiang
- Department of Gastroenterology, Haikou People's Hospital, Haikou, Hainan 570028, P.R. China
| | - Shan-Shan Mao
- Department of Oncology, Haikou People's Hospital, Haikou, Hainan 570028, P.R. China
| | - Xiang-Nan Yu
- Department of Gastroenterology, Haikou People's Hospital, Haikou, Hainan 570028, P.R. China
| | - Xiao-Xi Huang
- Department of Gastroenterology, Haikou People's Hospital, Haikou, Hainan 570028, P.R. China
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Assessment of the association between ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility: a meta-analysis. Int J Biol Markers 2017; 32:e96-e101. [PMID: 27646774 DOI: 10.5301/jbm.5000231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2016] [Indexed: 01/29/2023]
Abstract
BACKGROUND The protein encoded by ZBTB20 is a member of the POK family, whose members function as transcriptional repressors through interactions mediated by their conserved C2H2 Krüppel-type zinc finger and BTB/POZ domains. Polymorphisms in ZBTB20 appeared to be associated with gastric and esophageal cancer susceptibility in biological models, but the results of these studies were inconclusive. Therefore, we conducted a meta-analysis by pooling all available data to assess the exact association between the ZBTB20 rs9841504 polymorphism and gastric and esophageal cancer susceptibility. METHOD The meta-analysis was performed for homozygote comparison, heterozygote comparison, and dominant and recessive models by applying a fixed- or random-effects model. The pooled odds ratios (ORs) with the corresponding confidence intervals (CIs) were calculated. Moreover, the data were analyzed using the Stata 12.0 software(StataCorp). RESULT A total of 8 independent case-control studies comprising 9,994 cases and 10,258 controls were included. We found a significant association between the rs9841504 polymorphism and decreased gastric cancer susceptibility in the allelic, homozygous, dominant and recessive models (B vs. A:OR = 0.797, 95% CI 0.644-0.986, p = 0.036; BB vs. AA:OR = 0.601, 95% CI 0.366-0.988, p = 0.045; BA + BB vs. AA:OR = 0.789, 95% CI 0.627-0.992, p = 0.043; BB vs. BA + AA:OR = 0.635, 95% CI 0.405-0.997, p = 0.049). Conversely, no association between the rs9841504 polymorphism and esophageal cancer susceptibility was found. In subgroup analysis by ethnicity, we observed a significantly decreased susceptibility to gastric cancer in Asian populations in the allele contrast, homozygous and recessive models (B vs. A:OR = 0.791, 95% CI 0.628-0.996, p = 0.046; BB vs. AA:OR = 0.559, 95% CI 0.323-0.966, p = 0.037; BB vs. BA + AA:OR = 0.593, 95% CI 0.361-0.972, p = 0.038). CONCLUSIONS In summary, our work suggests that the ZBTB20 rs9841504 polymorphism is a protective factor for gastric cancer rather than esophageal cancer.
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Lin F, Li Y, Yan S, Liu S, Qian W, Shen D, Lin Q, Mao W. MicroRNA-181a inhibits tumor proliferation, invasiveness, and metastasis and is downregulated in gastric cancer. Oncol Res 2017; 22:75-84. [PMID: 25706394 PMCID: PMC7838452 DOI: 10.3727/096504014x14024160459203] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer. The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of gastric cancer. Here we show that miR-181a levels were significantly downregulated in gastric cancer tissues compared with the adjacent normal regions in 80 paired samples. Moreover, the lower levels of miR-181a were associated with the pM or pTNM stage in clinical gastric cancer patients. In addition, the ectopic expression of miR-181a in the gastric cancer cell line HGC-27 inhibited cell proliferation, cell migration, and invasion by directly interacting with the mRNA encoding the oncogenic factor Prox1. Taken together, our results indicate that miR-181a might act as a tumor suppressor in gastric cancer, which may provide a novel diagnostic and therapeutic option for human gastric cancer in the near future.
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Affiliation(s)
- Feng Lin
- Department of Oncology, the Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu, PR China
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Pham TT, Oue N, Yamamoto M, Fujihara M, Ishida T, Mukai S, Sakamoto N, Sentani K, Yasui W. Characteristic expression of fukutin in gastric cancer among atomic bomb survivors. Oncol Lett 2017; 13:937-941. [PMID: 28356981 PMCID: PMC5351402 DOI: 10.3892/ol.2016.5520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 10/25/2016] [Indexed: 12/29/2022] Open
Abstract
Approximately 70 years have passed since the atomic bombs were dropped on Nagasaki and Hiroshima. To elucidate potential biomarkers and possible mechanisms of radiation-induced cancer, the expression of FKTN, which encodes fukutin protein and causes Fukuyama-type congenital muscular dystrophy, was analyzed in gastric cancer (GC) tissue samples from atomic bomb survivors. Expression of cluster of differentiation (CD) 10 was also evaluated, as it has previously been observed that positive fukutin expression was frequently noted in CD10-positive GC cases. In the first cohort from Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital (Hiroshima, Japan; n=92), 102 (53%) of the GC cases were positive for fukutin. Expression of fukutin was not associated with exposure status, but was associated with CD10 expression (P=0.0001). The second cohort was from Hiroshima University Hospital (Hiroshima, Japan; n=86), and these patients were also in the Life Span Study cohort, in which atomic bomb radiation doses were precisely estimated using the DS02 system. Expression of fukutin was detected in 58 (67%) of GC cases. GC cases positive for fukutin were observed more frequently in the low dose-exposed group than in the high dose-exposed group (P=0.0001). Further studies with a larger cohort, including precise radiation dose estimation, may aid in clarifying whether fukutin could serve as a potential biomarker to define radiation-induced GC in atomic-bomb survivors.
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Affiliation(s)
- Trang T.B. Pham
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Manabu Yamamoto
- Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka 811-1395, Japan
| | - Megumu Fujihara
- Department of Pathology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Teruyoshi Ishida
- Department of Surgery, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima 730-8619, Japan
| | - Shoichiro Mukai
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Naoya Sakamoto
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734-8551, Japan
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44
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MicroRNA-1225-5p inhibits proliferation and metastasis of gastric carcinoma through repressing insulin receptor substrate-1 and activation of β-catenin signaling. Oncotarget 2016; 7:4647-63. [PMID: 26684358 PMCID: PMC4826233 DOI: 10.18632/oncotarget.6615] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 12/02/2015] [Indexed: 12/29/2022] Open
Abstract
Emerging evidence has linked aberrantly expressed microRNAs (miRNAs) with oncogenesis and malignant development in various human cancers. However, their specific roles and functions in gastric carcinoma (GC) remain largely undefined. In this study we identify and report a novel miRNA, miR-1225-5p, as tumor suppressor in GC development and progression. Microarray analysis revealed that there were fifty-six differentially expressed miRNAs (thirty-two upregulated and twenty-four downregulated) in GC tumor samples compared to their corresponding nontumorous tissues. Downregulation of miR-1225-5p was frequently detected in GC and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays demonstrated that ectopic overexpression of miR-1225-5p could inhibit cell proliferation, colony formation, migration and invasion in vitro, as well as suppress tumor growth and metastasis in nude mice. Further integrative and functional studies suggested insulin receptor substrate 1 (IRS1) as a downstream effector of miR-1225-5p which acted through β-catenin signaling pathway. These results demonstrate that miR-1225-5p serves to constrain GC growth and metastatic potential via inhibition of IRS1 and β-catenin signaling. Therefore, downregulation of miR-1225-5p is likely to be one of major molecular mechanisms accounting for the development and progression of GC.
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45
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Wang JB, Wang ZW, Li Y, Huang CQ, Zheng CH, Li P, Xie JW, Lin JX, Lu J, Chen QY, Cao LL, Lin M, Tu RH, Lin Y, Huang CM. CDK5RAP3 acts as a tumor suppressor in gastric cancer through inhibition of β-catenin signaling. Cancer Lett 2016; 385:188-197. [PMID: 27793695 DOI: 10.1016/j.canlet.2016.10.024] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/13/2016] [Accepted: 10/18/2016] [Indexed: 12/18/2022]
Abstract
CDK5RAP3 was isolated as a binding protein of the Cdk5 activator p35. Although CDK5RAP3 has been implicated in cancer progression, its expression and function have not been investigated in gastric cancer. Our study demonstrated that the mRNA and protein levels of CDK5RAP3 were markedly decreased in gastric tumor tissues when compared with respective adjacent non-tumor tissues. CDK5RAP3 in gastric cancer cells significantly reduced cell proliferation, migration, invasion and tumor xenograft growth through inhibition of β-catenin. Secondly, CDK5RAP3 was found to suppress the phosphorylation of GSK-3β (Ser9), leading to the phosphorylation (Ser37/Thr41) and subsequent degradation of β-catenin. Lastly, the prognostic value of CDK5RAP3 for overall survival was found to be dependent on β-catenin cytoplasm/nucleus localization in human gastric cancer samples. Collectively, our results demonstrated that CDK5RAP3 negatively regulates the β-catenin signaling pathway by repressing GSK-3β phosphorylation and could be a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Zu-Wei Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Yun Li
- Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People's Republic of China
| | - Chao-Qun Huang
- College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, People's Republic of China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Yao Lin
- College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, People's Republic of China.
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou 350001, Fujian Province, People's Republic of China.
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46
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Kanda M, Shimizu D, Sueoka S, Nomoto S, Oya H, Takami H, Ezaka K, Hashimoto R, Tanaka Y, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y. Prognostic relevance of SAMSN1 expression in gastric cancer. Oncol Lett 2016; 12:4708-4716. [PMID: 28105178 DOI: 10.3892/ol.2016.5233] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 07/21/2016] [Indexed: 12/26/2022] Open
Abstract
The prognosis for patients with advanced gastric cancer (GC) remains poor. The identification of biomarkers relevant to the recurrence and metastasis of GC is advantageous for stratifying patients and proposing novel molecular targets. In the present study the oncological roles of SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1), a mediator of B-cell function, were elucidated in GC. The expression and methylation status of SAMSN1 were investigated in a panel of 11 GC cell lines. Immunohistochemical staining was performed to determine the pattern of SAMSN1 protein expression in gastric tissues. The prognostic impact of SAMSN1 expression was determined by analyzing 175 pairs of surgically resected gastric tissues. A marked decrease in the level of SAMSN1 mRNA was detected in 8/11 GC cell lines as compared with that in a non-transformed intestinal epithelium cell line (FHs 74) without promoter methylation. The mean expression level of SAMSN1 mRNA was reduced in GC tissues compared with normal adjacent tissues, an observation that was independent of tumor differentiation. The pattern of SAMSN1 protein expression was significantly correlated with that of SAMSN1 mRNA. Low SAMSN1 mRNA expression was significantly associated with tumor size (>60 mm; P=0.026) and shorter overall survival times (P=0.004). Multivariate analysis identified low SAMSN1 mRNA expression as an independent prognostic factor for poor overall survival (hazard ratio, 1.80; 95% confidence interval, 1.07-3.05; P=0.025). The difference in survival between the low and high SAMSN1 expression groups was more marked in patients with stage II/III GC compared to those with stage IV GC. In patients with stage II/III GC who underwent curative surgery, low SAMSN1 expression was associated with reduced disease free survival times. The results of the present study indicate that downregulation of SAMSN1 transcription may affect the progression and recurrence of GC, and therefore may represent a novel biomarker of GC.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Satoshi Sueoka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi 464-8651, Japan
| | - Hisaharu Oya
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Kazuhiro Ezaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Ryoji Hashimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yuri Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
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47
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Kanda M, Kodera Y. Molecular mechanisms of peritoneal dissemination in gastric cancer. World J Gastroenterol 2016; 22:6829-6840. [PMID: 27570420 PMCID: PMC4974582 DOI: 10.3748/wjg.v22.i30.6829] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets.
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48
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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49
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Li Y, Nie Y, Tu S, Wang H, Zhou Y, Du Y, Cao J, Ye M. Epigenetically deregulated miR-200c is involved in a negative feedback loop with DNMT3a in gastric cancer cells. Oncol Rep 2016; 36:2108-16. [PMID: 27498672 DOI: 10.3892/or.2016.4996] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 03/28/2016] [Indexed: 11/05/2022] Open
Abstract
Aberrant methylation of miRNAs is commonly observed in cancers. In the present study, we investigated the regulation of the miR-200 family and its role in regulating DNA methylation events in gastric cancer (GC). We demonstrated that miR‑200c was aberrantly expressed in GC and associated with histologic type and tumor progression. Hypermethylation of the promoter region was found to be responsible for the loss of miR-200c in GC cells. Demethylation agents led to recovery of miR-200c expression in GC cell lines. Moreover, DNMT3a knockdown abolished the hypermethylation of the miR-200c gene and induced upregulation of miR-200c expression, whereas ectopic DNMT3a expression increased miR-200c promoter methylation and decreased miR-200c expression. Conversely, transfection of miR-200c led to downregulation of DNMT3a protein and induced endogenous pre-miR-200c and pri-miR‑200c re-expression. Luciferase assays confirmed miR‑200c binding to the DNMT3a 3'UTR. Finally, ectopic expression of miR-200c or knockdown of DNMT3a expression impeded GC cell growth, migration and invasion. Taken together, these observations demonstrates a novel epigenetic feedback loop between miR-200c and DNMT3a in the carcinogenesis and progression of GC.
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Affiliation(s)
- Yingfei Li
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yuqiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Sanfang Tu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Hong Wang
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yongjian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Yanlei Du
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Jie Cao
- Department of General Surgery, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
| | - Min Ye
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China
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50
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Alpízar-Alpízar W, Laerum OD, Christensen IJ, Ovrebo K, Skarstein A, Høyer-Hansen G, Ploug M, Illemann M. Tissue Inhibitor of Metalloproteinase-1 Is Confined to Tumor-Associated Myofibroblasts and Is Increased With Progression in Gastric Adenocarcinoma. J Histochem Cytochem 2016; 64:483-94. [PMID: 27370797 DOI: 10.1369/0022155416656173] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 05/31/2016] [Indexed: 12/20/2022] Open
Abstract
The tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the extracellular matrix-degrading activity of several matrix metalloproteinases, thereby regulating cancer cell invasion and metastasis. Studies describing the expression pattern and cellular localization of TIMP-1 in gastric cancer are, however, highly discordant. We addressed these inconsistencies by performing immunohistochemistry and in situ hybridization analyses in a set of 49 gastric cancer lesions to reexamine the TIMP-1 localization. In addition, we correlated these findings to clinicopathological parameters. We show that strong expression of TIMP-1 protein and mRNA was observed in a subpopulation of stromal fibroblast-like cells at the periphery of the cancer lesions. In a few cases, a small fraction of cancer cells showed weak expression of TIMP-1 protein and mRNA. The stromal TIMP-1-expressing cells were mainly tumor-associated myofibroblasts. In the normal-appearing mucosa, scattered TIMP-1 protein was only found in chromogranin A positive cells. TIMP-1-positive myofibroblasts at the invasive front of the tumors were more frequently seen in intestinal than in diffuse histological subtype cases (p=0.009). A significant trend to a higher number of cases showing TIMP-1 staining in myofibroblasts with increasing tumor, node, metastasis (TNM) stage was also revealed (p=0.041). In conclusion, tumor-associated myofibroblasts are the main source of increased TIMP-1 expression in gastric cancer.
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Affiliation(s)
- Warner Alpízar-Alpízar
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Center for Research in Microscopic Structures (CIEMIC) and Cancer Research Program, Health Research Institute (INISA), University of Costa Rica, San José, Costa Rica (WA-A)
| | - Ole Didrik Laerum
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Department of Clinical Medicine, The Gade Laboratory for Pathology, University of Bergen, Bergen, Norway (ODL),Departments of Pathology, Haukeland University Hospital, Bergen, Norway (ODL)
| | - Ib J Christensen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
| | - Kjell Ovrebo
- Department of Surgical Sciences, University of Bergen, Bergen, Norway (KO),Surgery, Haukeland University Hospital, Bergen, Norway (KO, AS)
| | - Arne Skarstein
- Department of Clinical Medicine, University of Bergen, Bergen, Norway (AS),Surgery, Haukeland University Hospital, Bergen, Norway (KO, AS)
| | - Gunilla Høyer-Hansen
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
| | - Michael Ploug
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI),Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
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