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1
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Unal B, Celik MY, Gedik EO, Bassorgun CI, Elpek GO. Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers. World J Hepatol 2023; 15:775-785. [PMID: 37397937 PMCID: PMC10308291 DOI: 10.4254/wjh.v15.i6.775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/22/2023] [Accepted: 04/18/2023] [Indexed: 06/25/2023] Open
Abstract
Hepatocellular (HCC) and intrahepatic cholangiocarcinoma (ICC), the most common primary tumors of the liver, are among the most important causes of cancer deaths worldwide. Because patients with primary liver tumors are frequently diagnosed at an advanced stage and have high mortality, many efforts have been made to identify new markers to determine their behavior and treatment, similar to those in other solid organ tumors. Recently, morphological assessment of tumor budding (TB) has been revealed as a promising prognostic finding to predict tumor behavior and survival across several different tumor types. Currently, the TB score in colorectal cancer has been revealed as an important parameter in pathology report protocols to determine the course of the disease. Regarding the liver, despite enormous data showing that many mechanisms involved in TB are associated with tumor behavior in both HCC and ICC, studies focusing on the role of TB in predicting the behavior and prognosis of these tumors have started to be investigated very recently. The purpose of this review is to present data about TB in primary tumors of the liver, pointing out the potential role of this parameter in determining the course of the disease, and emphasize the need to increase the number of further studies focusing on the evaluation of this parameter with an overview of the mechanisms involved in TB.
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Affiliation(s)
- Betul Unal
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
| | | | - Elif Ocak Gedik
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
| | | | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey.
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2
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Gao Y, Zhang J, Pan J, Ying S, Lou B, Yang Q, Hong W, Yang G. F OF1-ATP synthase molecular motor biosensor for miRNA detection of colon cancer. Life Sci 2023; 319:121527. [PMID: 36841472 DOI: 10.1016/j.lfs.2023.121527] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/11/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
AIMS To establish a FOF1-ATP synthase molecular motor biosensor to accurately identify colon cancer miRNAs. MAIN METHODS The FOF1-ATP synthase molecular motor is extracted by fragmentation-centrifugation and connected to the colon cancer-specific miR-17 capture probe in the manner of the ε subunit-biotin-streptavidin-biotin system. Signal probes are designed for dual-signal characterization to increase detection accuracy. The FOF1-ATPase rotation rate decreases when the signaling and capture probes are combined with the target miRNA, resulting in a decrease in ATP synthesis. miR-17 concentrations are determined by changes in ATP-mediated chemiluminescence intensity and signal probe-mediated OD450nm. KEY FINDINGS The chemiluminescence intensity and OD450nm show a good linear relationship with the miR-17 concentration in the range of 5 to 200 nmol L-1 (R2 = 0.9985, 0.9989). The colon cancer mouse model is established for the blood samples, and miR-17 in serum and RNA extracts is quantitatively determined using the constructed sensor. SIGNIFICANCE The results are consistent with colon cancer progression, and the low concentration of miR-17 detecting accuracy is comparable to the PCR assay. In conclusion, the developed method is a direct, rapid, and promising method for miRNA detection of colon cancer.
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Affiliation(s)
- Ying Gao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China; Zhejiang Moda Biotech Co., Ltd, Hangzhou 310018, China
| | - Jie Zhang
- Taizhou Technician College, Taizhou 318000, China
| | - Jiexia Pan
- Criminal Investigation Corps of Zhejiang Provincial Public Security Department, Hangzhou 310009, China
| | - Sanjun Ying
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China
| | - Bang Lou
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China
| | - Qingliang Yang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China
| | - Weiyong Hong
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China; Department of Pharmacy, Municipal Hospital Affiliated to Taizhou University, Taizhou 318000, China.
| | - Gensheng Yang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China.
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3
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Farasati Far B, Vakili K, Fathi M, Yaghoobpoor S, Bhia M, Naimi-Jamal MR. The role of microRNA-21 (miR-21) in pathogenesis, diagnosis, and prognosis of gastrointestinal cancers: A review. Life Sci 2023; 316:121340. [PMID: 36586571 DOI: 10.1016/j.lfs.2022.121340] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/16/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs regulating the expression of several target genes. miRNAs play a significant role in cancer biology, as they can downregulate their corresponding target genes by impeding the translation of mRNA (at the mRNA level) as well as degrading mRNAs by binding to the 3'-untranslated (UTR) regions (at the protein level). miRNAs may be employed as cancer biomarkers. Therefore, miRNAs are widely investigated for early detection of cancers which can lead to improved survival rates and quality of life. This is particularly important in the case of gastrointestinal cancers, where early detection of the disease could substantially impact patients' survival. MicroRNA-21 (miR-21 or miRNA-21) is one of the most frequently researched miRNAs, where it is involved in the pathophysiology of cancer and the downregulation of several tumor suppressor genes. In gastrointestinal cancers, miR-21 regulates phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), mothers against decapentaplegic homolog 7 (SMAD7), phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT), matrix metalloproteinases (MMPs), β-catenin, tropomyosin 1, maspin, and ras homolog gene family member B (RHOB). In this review, we investigate the functions of miR-21 in pathogenesis and its applications as a diagnostic and prognostic cancer biomarker in four different gastrointestinal cancers, including colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and esophageal cancer (EC).
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammed Bhia
- Student Research Committee, Department of Pharmaceutics and Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - M Reza Naimi-Jamal
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.
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4
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Asim MN, Ibrahim MA, Imran Malik M, Dengel A, Ahmed S. Circ-LocNet: A Computational Framework for Circular RNA Sub-Cellular Localization Prediction. Int J Mol Sci 2022; 23:ijms23158221. [PMID: 35897818 PMCID: PMC9329987 DOI: 10.3390/ijms23158221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/15/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
Circular ribonucleic acids (circRNAs) are novel non-coding RNAs that emanate from alternative splicing of precursor mRNA in reversed order across exons. Despite the abundant presence of circRNAs in human genes and their involvement in diverse physiological processes, the functionality of most circRNAs remains a mystery. Like other non-coding RNAs, sub-cellular localization knowledge of circRNAs has the aptitude to demystify the influence of circRNAs on protein synthesis, degradation, destination, their association with different diseases, and potential for drug development. To date, wet experimental approaches are being used to detect sub-cellular locations of circular RNAs. These approaches help to elucidate the role of circRNAs as protein scaffolds, RNA-binding protein (RBP) sponges, micro-RNA (miRNA) sponges, parental gene expression modifiers, alternative splicing regulators, and transcription regulators. To complement wet-lab experiments, considering the progress made by machine learning approaches for the determination of sub-cellular localization of other non-coding RNAs, the paper in hand develops a computational framework, Circ-LocNet, to precisely detect circRNA sub-cellular localization. Circ-LocNet performs comprehensive extrinsic evaluation of 7 residue frequency-based, residue order and frequency-based, and physio-chemical property-based sequence descriptors using the five most widely used machine learning classifiers. Further, it explores the performance impact of K-order sequence descriptor fusion where it ensembles similar as well dissimilar genres of statistical representation learning approaches to reap the combined benefits. Considering the diversity of statistical representation learning schemes, it assesses the performance of second-order, third-order, and going all the way up to seventh-order sequence descriptor fusion. A comprehensive empirical evaluation of Circ-LocNet over a newly developed benchmark dataset using different settings reveals that standalone residue frequency-based sequence descriptors and tree-based classifiers are more suitable to predict sub-cellular localization of circular RNAs. Further, K-order heterogeneous sequence descriptors fusion in combination with tree-based classifiers most accurately predict sub-cellular localization of circular RNAs. We anticipate this study will act as a rich baseline and push the development of robust computational methodologies for the accurate sub-cellular localization determination of novel circRNAs.
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Affiliation(s)
- Muhammad Nabeel Asim
- German Research Center for Artificial Intelligence (DFKI), 67663 Kaiserslautern, Germany; (M.A.I.); (A.D.); (S.A.)
- Department of Computer Science, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
- Correspondence:
| | - Muhammad Ali Ibrahim
- German Research Center for Artificial Intelligence (DFKI), 67663 Kaiserslautern, Germany; (M.A.I.); (A.D.); (S.A.)
- Department of Computer Science, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Muhammad Imran Malik
- School of Computer Science & Electrical Engineering, National University of Sciences and Technology, Islamabad 44000, Pakistan;
| | - Andreas Dengel
- German Research Center for Artificial Intelligence (DFKI), 67663 Kaiserslautern, Germany; (M.A.I.); (A.D.); (S.A.)
- Department of Computer Science, Technical University of Kaiserslautern, 67663 Kaiserslautern, Germany
| | - Sheraz Ahmed
- German Research Center for Artificial Intelligence (DFKI), 67663 Kaiserslautern, Germany; (M.A.I.); (A.D.); (S.A.)
- DeepReader GmbH, Trippstadter Str. 122, 67663 Kaiserslautern, Germany
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5
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Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer. Clin Sci (Lond) 2022; 136:521-535. [PMID: 35445707 DOI: 10.1042/cs20210886] [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: 01/25/2022] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Poor survival of CRC associated with the development of tumour metastasis led to the investigation of the potential biomarkers to predict outcomes in CRC patients. Tumour budding (TB) is a well-known independent prognostic marker for poor survival and disease metastasis. Therefore, it has been suggested that TB status is included in routine clinicopathological factors for risk assessment in CRC. In contrast with a vast majority of studies regarding the prognostic power of TB, there is no clear evidence pertaining to the underlying molecular mechanism driving this phenotype, or an understanding of TB relationship with the tumour microenvironment (TME). The aim of the present study is to present a comprehensive review of TB and tumour cell signalling pathways together with the cross-talk of immune cells that could drive TB formation in CRC.
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6
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Monocyte Infiltration and Differentiation in 3D Multicellular Spheroid Cancer Models. Pathogens 2021; 10:pathogens10080969. [PMID: 34451433 PMCID: PMC8399809 DOI: 10.3390/pathogens10080969] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 01/01/2023] Open
Abstract
Tumor-associated macrophages often correlate with tumor progression, and therapies targeting immune cells in tumors have emerged as promising treatments. To select effective therapies, we established an in vitro 3D multicellular spheroid model including cancer cells, fibroblasts, and monocytes. We analyzed monocyte infiltration and differentiation in spheroids generated from fibroblasts and either of the cancer cell lines MCF-7, HT-29, PANC-1, or MIA PaCa-2. Monocytes rapidly infiltrated spheroids and differentiated into mature macrophages with diverse phenotypes in a cancer cell line-dependent manner. MIA PaCa-2 spheroids polarized infiltrating monocytes to M2-like macrophages with high CD206 and CD14 expression, whereas monocytes polarized by MCF-7 spheroids displayed an M1-like phenotype. Monocytes in HT-29 and PANC-1 primarily obtained an M2-like phenotype but also showed upregulation of M1 markers. Analysis of the secretion of 43 soluble factors demonstrated that the cytokine profile between spheroid cultures differed considerably depending on the cancer cell line. Secretion of most of the cytokines increased upon the addition of monocytes resulting in a more inflammatory and pro-tumorigenic environment. These multicellular spheroids can be used to recapitulate the tumor microenvironment and the phenotype of tumor-associated macrophages in vitro and provide more realistic 3D cancer models allowing the in vitro screening of immunotherapeutic compounds.
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7
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Malham M, James JP, Jakobsen C, Hoegdall E, Holmstroem K, Wewer V, Nielsen BS, Riis LB. Mucosal microRNAs relate to age and severity of disease in ulcerative colitis. Aging (Albany NY) 2021; 13:6359-6374. [PMID: 33647883 PMCID: PMC7993741 DOI: 10.18632/aging.202715] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/25/2021] [Indexed: 12/12/2022]
Abstract
Despite significant evidence that the expression of several microRNAs (miRNAs) impacts disease activity in patients with ulcerative colitis (UC), it remains unknown if the more severe disease phenotype seen in pediatric onset UC can be explained by an altered miRNA expression. In this study, we assessed the relationship between miRNA expression, age, and disease severity in pediatric and adult patients with UC. Using RT-qPCR, we analyzed the expression of miR-21, miR-31, miR-126, miR-142 and miR-155 in paraffin embedded rectum biopsies from 30 pediatric and 30 adult-onset UC patients. We found that lesions from adult patients had significantly higher expression levels of miR-21 compared to pediatric patients and that the expression levels of miR-31 (all patients) and miR-155 (pediatric patients only) correlated inversely with histological assessed disease severity. Using in situ hybridization followed by image analysis, the expression level estimates of miR-21 and miR-126 correlated with histological assessed disease severity. In conclusion, we found that the expression of miRNAs depends on the age of the patient and/or the severity of the disease, suggesting that miRNAs may contribute to the regulation of inflammation in UC and could be useful biomarkers in the surveillance of disease severity.
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Affiliation(s)
- Mikkel Malham
- The Pediatric Department, Copenhagen University Hospital, Hvidovre 2650, Denmark.,The Pediatric Department, Holbaek Hospital, Holbaek 4300, Denmark
| | - Jaslin P James
- Department of Pathology, Copenhagen University Hospital, Herlev 2730, Denmark.,Biomedical Technology, Bioneer A/S, Hoersholm 2970, Denmark
| | - Christian Jakobsen
- The Pediatric Department, Copenhagen University Hospital, Hvidovre 2650, Denmark
| | - Estrid Hoegdall
- Department of Pathology, Copenhagen University Hospital, Herlev 2730, Denmark
| | - Kim Holmstroem
- Biomedical Technology, Bioneer A/S, Hoersholm 2970, Denmark
| | - Vibeke Wewer
- The Pediatric Department, Copenhagen University Hospital, Hvidovre 2650, Denmark
| | - Boye S Nielsen
- Biomedical Technology, Bioneer A/S, Hoersholm 2970, Denmark
| | - Lene B Riis
- Department of Pathology, Copenhagen University Hospital, Herlev 2730, Denmark
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8
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9
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Nielsen BS, Larsen J, Høffding J, Nhat SL, Madsen NH, Møller T, Holst B, Holmstrøm K. Detection of lncRNA by LNA-Based In Situ Hybridization in Paraffin-Embedded Cancer Cell Spheroids. Methods Mol Biol 2021; 2348:123-137. [PMID: 34160803 DOI: 10.1007/978-1-0716-1581-2_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cancer cell spheroids are considered important preclinical tools to evaluate the efficacy of new drugs. In cancer cell spheroids, the cells assemble and grow in 3D structures with cell contact interactions that are partly impermeable, which leads to central hypoxia and necrosis. The cell spheroids thus possess several features identified in clinical tumors. Not only will the effect and behavior of therapeutic drugs in 3D cell spheroids be affected more similarly than in cells grown on culture plates, but molecular interactions and signaling pathways in cells are also more likely to mimic the in vivo situation. The monitoring of various biomarkers including lncRNAs in 3D cell spheroids is important to assess a potentially induced phenotype in the cells and the effects of drugs. Specifically, for lncRNAs, in situ localization can be done using locked nucleic acid (LNA) probe technology. Here we present a protocol for preparation of cell spheroids for use in LNA probe-based in situ hybridization to study lncRNA expression in paraffin embedded 3D cancer cell spheroids.
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Affiliation(s)
| | | | - Jakob Høffding
- Bioneer A/S, Hørsholm, Denmark.,Københavns Professionshøjskole, København, Denmark
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10
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Abstract
Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the invasive tumour front. The prognostic value of tumour budding is now supported by a large body of evidence, whereas the utility of this phenotype as a predictive biomarker remains under investigation. The application of tumour budding indices in clinical practice requires a standardized scoring system that can be tailored to specific tumour types and clinical scenarios. In the context of CRC, tumour budding can be assessed according to the method agreed at the International Tumour Budding Consensus Conference (ITBCC) in 2016. Using the ITBCC scoring system, tumour budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and of unfavourable survival in patients with stage II colon cancer. Regardless of the clinical scenario or tumour type, the assertion that 'the more tumour buds, the worse the clinical outcome' applies. In this Review, we provide an overview of tumour budding in solid cancers, highlighting the molecular and biological aspects of this phenomenon, including its associations with epithelial-mesenchymal transition and features of the tumour microenvironment. We also describe the available evidence demonstrating the value of tumour budding as a biomarker across various solid cancers.
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11
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Liu C, Yang J, Wu H, Li J. Downregulated miR-585-3p promotes cell growth and proliferation in colon cancer by upregulating PSME3. Onco Targets Ther 2019; 12:6525-6534. [PMID: 31616162 PMCID: PMC6698586 DOI: 10.2147/ott.s203175] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/16/2019] [Indexed: 12/18/2022] Open
Abstract
Background Upregulation of PSME3 and its oncogenic roles have been reported in colon cancer recently. However, the underlying mechanism of PSME3 upregulation remains unknown. Here, we explored the expression of PSME3 and subsequently uncovered its mechanism in colon cancer. Materials and methods The expression of PSME3 was analyzed by using online databases, Oncomine and UALCAN. qPCR was carried out to detect the expression of PSME3 in collected colon cancer tissues and cell lines. Moreover, the promoter methylation and the hnRNA level of PSME3 were also analyzed by online database and qPCR, respectively. The candidate miRNAs targeting PSME3 were predicted by Starbase 3.0 and validated by luciferase reporter system. CCK-8, plate colon formation, and Edu incorporation were applied to study the functions of miRNA in colon cancer. The expression of miRNA and its correlation with PSME3 were detected in colon cancer tissues. Results Oncomine and UALCAN data indicate PSME3 is obviously upregulated in colon cancer tissue samples which is further confirmed in collected colon cancer tissues and cells by qPCR. No significant difference in methylation status promoter of PSME3 was observed between colon and colon cancer tissues. The hnRNA level of PSME3 was comparable between colon epithelial cell and colon cancer cells. miR-585-3p is predicted to directly target PSME3 and is validated by luciferase reporter assay. Then, miR-585-3p downregulation is confirmed and miR-585-3p restoration can suppress cell growth and proliferation by inhibiting PSME3 in colon cancer indicating by CCK-8, plate colon formation, and Edu incorporation. Moreover, negative correlation in expression between miR-585-3p and PSME3 was observed in our collected tissues samples. Conclusion We reveal for the first time that miR-585-3p downregulation accounts for the overexpression of PSME3 in colon cancer. Moreover, miR-585-3p, serving as a tumor suppressor, can inhibit cell growth and proliferation in colon cancer by targeting PSME3.
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Affiliation(s)
- Chunmei Liu
- Department of Pathology, Luohe Central Hospital, Luohe 462000, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Luohe Medical College, Luohe 462000, People's Republic of China
| | - Juan Yang
- Department of Pathology, Luohe Central Hospital, Luohe 462000, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Luohe Medical College, Luohe 462000, People's Republic of China
| | - Han Wu
- Department of Pathology, Luohe Central Hospital, Luohe 462000, People's Republic of China.,Department of Pathology, The First Affiliated Hospital of Luohe Medical College, Luohe 462000, People's Republic of China
| | - Jun Li
- Nursing Department, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China
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12
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Dehghan F, Boozarpour S, Torabizadeh Z, Alijanpour S. miR-21: a promising biomarker for the early detection of colon cancer. Onco Targets Ther 2019; 12:5601-5607. [PMID: 31371997 PMCID: PMC6628966 DOI: 10.2147/ott.s199508] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 05/18/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose The aim of this study was to compare the expression of miR-21 gene in stages II-IV of formalin-fixed paraffin-embedded (FFPE) tissue in patients with colon cancer and introduce miR-21 as a potential molecular marker for detection of colon cancer in the early stages. Introduction Currently, identification of key molecules involved in the pathogenesis of cancer is one of the areas under consideration. miRNAs, are small RNAs which have been identified in many cancers. In this study, we investigated the expression of miR-21 in three pathologic stages in patients with colon cancer in the north of Iran. Patients and methods A total of 40 FFPE samples were obtained from patients with stages II, III, and IV from hospitals in Mazandaran and Golestan provinces. After extraction of RNA, treatment with DNase I and cDNA synthesis was performed and miR-21 expression was assessed by qPCR. Then, the data were analyzed using statistical software R (3.4.3). Results The expression of miR-21 in stage II was significantly different from stage IV. However, no significant difference was observed between the other stages. In stage II, the level of miR-21 expression was higher in men than women. Moreover, in the second pathological stage, miR-21 expression was reduced in patients with adjacent lymphoid tissue engagement. In addition, the expression of miR-21 in grade I was significantly higher than grade II. Conclusion The results of this study suggest that miR-21 can be a diagnostic marker for early stages of colon cancer, especially in men. It can also be considered as a good candidate for targeted treatment of colon cancer in the early stages of the disease. Furthermore, for the first time, we suggested that miR-21 can be a good molecular marker for classification of the stages of colon cancer.
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Affiliation(s)
- Farnaz Dehghan
- Department of Biology, Faculty of Basic Sciences, Gonbad kavous University, Gonbad kavous, Golestan, Iran
| | - Sohrab Boozarpour
- Department of Biology, Faculty of Basic Sciences, Gonbad kavous University, Gonbad kavous, Golestan, Iran
| | - Zhila Torabizadeh
- Department of Medical Pathology, Faculty of Medicine, Sari University of Medical Sciences, Sari, Mazandaran, Iran
| | - Sakineh Alijanpour
- Department of Biology, Faculty of Basic Sciences, Gonbad kavous University, Gonbad kavous, Golestan, Iran
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13
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Møller T, James JP, Holmstrøm K, Sørensen FB, Lindebjerg J, Nielsen BS. Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer. Int J Mol Sci 2019; 20:E1907. [PMID: 30999696 PMCID: PMC6515373 DOI: 10.3390/ijms20081907] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/09/2019] [Accepted: 04/15/2019] [Indexed: 12/17/2022] Open
Abstract
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (n = 4) with evident cancer cell budding. In all four cases, TNF-α mRNA was seen in a small subset of cancer cells at the invasive front. Evaluation of miR-21 and TNF-α mRNA expression was performed on digital slides obtained by confocal slide scanning microscopy. Both co-expression and lack of co-expression with miR-21 in the budding cancer cells was noted, suggesting non-correlated expression. miR-21 was more often seen in cancer cells than TNF-α mRNA. In conclusion, we report that miR-21 is not linked to expression of the pro-inflammatory cytokine TNF-α mRNA, but that miR-21 and TNF-α both take part in the cancer expansion at the invasive front of colon cancers. We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity.
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Affiliation(s)
- Trine Møller
- Bioneer A/S, Hørsholm, Kogle Allé 2, 2970 Hørsholm, Denmark.
| | - Jaslin P James
- Bioneer A/S, Hørsholm, Kogle Allé 2, 2970 Hørsholm, Denmark.
| | - Kim Holmstrøm
- Bioneer A/S, Hørsholm, Kogle Allé 2, 2970 Hørsholm, Denmark.
| | - Flemming B Sørensen
- Danish Colorectal Cancer Center South, Vejle Hospital, Part of Lillebaelt Hospital, Beriderbakken 4, 7100 Vejle, Denmark.
- University Institute of Pathology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
| | - Jan Lindebjerg
- Danish Colorectal Cancer Center South, Vejle Hospital, Part of Lillebaelt Hospital, Beriderbakken 4, 7100 Vejle, Denmark.
- Department of Pathology, Vejle Hospital, Part of Lillebaelt Hospital, Beriderbakken 4, 7100 Vejle, Denmark.
- Institute of Regional Health Research, University of Southern Denmark, Winsløwparken 19,3, 5000 Odense C, Denmark.
| | - Boye S Nielsen
- Bioneer A/S, Hørsholm, Kogle Allé 2, 2970 Hørsholm, Denmark.
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