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Wang Y, Zhang P. Prediction of histone deacetylase inhibition by triazole compounds based on artificial intelligence. Front Pharmacol 2023; 14:1260349. [PMID: 38035010 PMCID: PMC10684768 DOI: 10.3389/fphar.2023.1260349] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
A quantitative structure-activity relationship (QSAR) study was conducted to predict the anti-colon cancer and HDAC inhibition of triazole-containing compounds. Four descriptors were selected from 579 descriptors which have the most obvious effect on the inhibition of histone deacetylase (HDAC). Four QSAR models were constructed using heuristic algorithm (HM), random forest (RF), radial basis kernel function support vector machine (RBF-SVM) and support vector machine optimized by particle swarm optimization (PSO-SVM). Furthermore, the robustness of four QSAR models were verified by K-fold cross-validation method, which was described by Q 2. In addition, the R 2 of the four models are greater than 0.8, which indicates that the four descriptors selected are reasonable. Among the four models, model based on PSO-SVM method has the best prediction ability and robustness with R 2 of 0.954, root mean squared error (RMSE) of 0.019 and Q 2 of 0.916 for the training set and R 2 of 0.965, RMSE of 0.017 and Q 2 of 0.907 for the test set. In this study, four key descriptors were discovered, which will help to screen effective new anti-colon cancer drugs in the future.
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Affiliation(s)
| | - Peijian Zhang
- College of Computer Science and Technology, Qingdao University, Qingdao, Shandong Province, China
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2
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B7-H3: A Useful Emerging Diagnostic Marker for Colon Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1523338. [PMID: 36605103 PMCID: PMC9810404 DOI: 10.1155/2022/1523338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/29/2022]
Abstract
Background Colon cancer is the second most common malignancy causing the majority of cancer-related deaths. B7-H3 concentrations have drawn major interest as possible diagnostic biomarkers of cancer. The aim of this study was to measure the preoperative serum B7-H3 levels and to determine those that are replaced in colon cancer. Method We measured preoperative serum B7-H3 concentrations of 90 patients aged 57-69 years diagnosed with colon cancer and 50 age-matched healthy individuals. B7-H3 levels were determined using the sandwich enzyme-linked immunosorbent assay (ELISA). Patients were categorized by stage based on the TNM staging system, and the serum levels of B7-H3 were compared between patients with different TNM stages. Result No statistically significant difference was found between the patient and control groups in terms of age and gender. Preoperative serum B7-H3 levels were statistically significantly higher in patients with colon cancer than in the healthy group (p < 0.001). Preoperative serum B7-H3 concentration of the stage IV patients was significantly higher than those of the patients with stage I and stage II disease. In addition, higher serum B7-H3 levels were associated with lymph node status and distant metastasis in colon cancer. Conclusion We showed that B7-H3 is highly expressed in colon cancer and can be used as a candidate diagnostic biomarker and a potential target in colon cancer in future.
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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Tan J, Lu T, Xu J, Hou Y, Chen Z, Zhou K, Ding Y, Jiang B, Zhu Y. MicroRNA-4463 facilitates the development of colon cancer by suppression of the expression of PPP1R12B. Clin Transl Oncol 2022; 24:1115-1123. [PMID: 35064454 DOI: 10.1007/s12094-021-02752-0] [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] [Received: 10/12/2021] [Accepted: 12/08/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE In the present work, we investigated the expression pattern of miR-4463 in the non-metastasis and metastasis colorectal cancer (CRC) patients and its regulation axis. METHODS RT-qPCR assay was performed to assess miR-4463 expression in the serum and tissues of patients with non-metastasis and metastasis, and in the CRC cell lines. MTT assay, colony formation assay, transwell assay, and flow cytometry assay were used to examine the role of miR-4463 in CRC cell viability, proliferation, and migration. Bioinformatic analysis was used to identify the potential target gene of miR-4463, and the targeting relationship between miR-4463 and PPP1R12B was verified in vitro using dual luciferase assay. Western blotting assay was used to determine the protein level of the target gene PPP1R12B in CRC cells under the transfections of miR-4463 mimic, inhibitor and vectors overexpressing PPP1R12B. RESULTS miR-4463 was markedly increased in the non-metastasis CRC tissues, and increased even higher in the metastasis CRC tissues, while miR-4463 expression had no significant difference in serum from non-metastasis and metastasis CRC samples. Besides, miR-4463 was upregulated in CRC cell lines. Functionally, miR-4463 promoted CRC cell proliferation, migration, and inhibiting cell apoptosis. Further analysis revealed that the miR-4463/PPP1R12B axis was responsible for the role of this miRNA. CONCLUSION We reported the roles of miR-4463 in CRC proliferation and migration, supporting that miR-4463 could be a potential predictive diagnostic marker for colon cancer.
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Affiliation(s)
- J Tan
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - T Lu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - J Xu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - Y Hou
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - Z Chen
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - K Zhou
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - Y Ding
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - B Jiang
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China
| | - Y Zhu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, Jiangsu Province, China.
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Kong D, Shen D, Liu Z, Zhang J, Zhang J, Geng C. Circ_0008500 Knockdown Improves Radiosensitivity and Inhibits Tumorigenesis in Breast Cancer Through the miR-758-3p/PFN2 Axis. J Mammary Gland Biol Neoplasia 2022; 27:37-52. [PMID: 35239064 DOI: 10.1007/s10911-022-09514-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 02/07/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is one of the most common malignancies worldwide. Circular RNAs (CircRNAs) were revealed to be implicated in the development of breast cancer. In this research, we aimed to investigate the role and underlying mechanism of circ_0008500 in the development and radiosensitivity of breast cancer. Using real-time quantitative PCR (RT-qPCR) and western blot, we found that hsa_circ_0008500 (circ_0008500) and profilin 2 (PFN2) were increased, while microRNA-758-3p (miR-758-3p) was decreased in breast cancer tissues and cells. Cell viability, the number of colonies, proliferation and apoptosis were detected using CCK-8, colony formation, EdU assays and flow cytometry, respectively. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were devoted to test the interaction between miR-758-3p and circ_0008500 or PFN2. The results showed that circ_0008500 knockdown inhibited cell growth, and facilitated cell apoptosis and radiosensitivity in breast cancer cells in vitro. Moreover, circ_0008500 regulated PFN2 expression by sponging miR-758-3p. Functionally, circ_0008500 knockdown regulated cell behaviors and radiosensitivity by targeting miR-758-3p to downregulate PFN2 expression in vitro. Additionally, in vivo tumor formation assay and immunohistochemistry (IHC) assay demonstrated that circ_0008500 knockdown enhanced the radiosensitivity and repressed tumor growth in vivo. In conclusion, circ_0008500 inhibition promoted the radiosensitivity and restrained the development of breast cancer by downregulating PFN2 expression via targeting miR-758-3p.
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Affiliation(s)
- Deyou Kong
- Department of Radiotherapy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China
| | - Dongxing Shen
- Department of Radiotherapy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China
| | - Zhikun Liu
- Department of Radiotherapy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China
| | - Jun Zhang
- Department of Radiotherapy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China
| | - Jian Zhang
- Department of Radiotherapy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China
| | - Cuizhi Geng
- Breast Center, the Fourth Hospital of Hebei Medical University, Yuhua District, No. 169 Tianshan Street, Shijiazhuang, 050035, China.
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Gao C, Zhang Y, Tian Y, Han C, Wang L, Ding B, Tian H, Zhou C, Ju Y, Peng A, Yu Q. Circ_0055625 knockdown inhibits tumorigenesis and improves radiosensitivity by regulating miR-338-3p/MSI1 axis in colon cancer. World J Surg Oncol 2021; 19:131. [PMID: 33882945 PMCID: PMC8061229 DOI: 10.1186/s12957-021-02234-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/06/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Radiotherapy is a main therapeutic method for cancers, including colon cancer. In the current study, we aim to explore the effects of circular RNA (circRNA) circ_0055625 in the progression and radiosensitivity of colon cancer and the underlying mechanism. METHODS The expression of circ_0055625 and musashi homolog 1 (MSI1) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). MSI1 protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and colony formation assays. Cell survival fraction, apoptosis, and invasion were investigated by colony formation assay, flow cytometry analysis, and transwell invasion assay, respectively. Cell migration was detected by wound-healing and transwell migration assays. The binding relationship between microRNA-338-3p (miR-338-3p) and circ_0055625 or MSI1 was predicted by online databases and identified by Dual-Luciferase Reporter Assay. The effects of circ_0055625 silencing on the tumor formation and radiosensitivity of colon cancer in vivo were explored by in vivo tumor formation assay. RESULTS Circ_0055625 and MSI1 were upregulated in colon cancer tissues and cells relative to control groups. Radiation treatment apparently increased the expression of circ_0055625 and MSI1 in colon cancer cells. Circ_0055625 knockdown or MSI1 silencing repressed cell proliferation, migration, and invasion and promoted cell apoptosis and radiosensitivity in colon cancer. Also, circ_0055625 silencing-mediated effects were attenuated by MSI1 overexpression. Additionally, circ_0055625 silencing reduced MSI1 expression, which could be attenuated by miR-338-3p inhibitor. Mechanically, circ_0055625 acted as a sponge for miR-338-3p to regulate MSI1. Furthermore, circ_0055625 knockdown hindered tumor growth and improved radiosensitivity in vivo. CONCLUSION Circ_0055625 repression inhibited the progression and radioresistance of colon cancer by downregulating MSI1 through sponging miR-338-3p. This result might provide a theoretical basis for improving the therapy of colon cancer with radiation.
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Affiliation(s)
- Chao Gao
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yi Zhang
- Department of Physiology, Hebei Medical University, Shijiazhuang, 050011, Hebei Province, China
| | - Yanming Tian
- Department of Physiology, Hebei Medical University, Shijiazhuang, 050011, Hebei Province, China
| | - Chun Han
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lan Wang
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Boyue Ding
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hua Tian
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yingchao Ju
- Department of Experimental Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ale Peng
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qiyao Yu
- Department of Research, The Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang, 050011, Hebei Province, China.
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Fawzy MS, Ibrahiem AT, AlSel BTA, Alghamdi SA, Toraih EA. Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: a pilot study. Sci Rep 2020; 10:16940. [PMID: 33037254 PMCID: PMC7547073 DOI: 10.1038/s41598-020-73951-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 09/23/2020] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are implicated in every stage of carcinogenesis and play an essential role as genetic biomarkers of cancer. We aimed to evaluate microRNA-34a gene (MIR34A) expression in colorectal cancer (CRC) tissues compared with non-cancer one and to preliminarily explore the association of one related variant to CRC risk. A total of 116 paraffin-embedded colon specimens were enrolled. MiR-34a was quantified by qPCR, and rs2666433 (A/G) genotyping was performed by TaqMan Real-Time PCR. Also, the somatic mutation burden was assessed. MIR34A expression in the CRC specimens was significantly upregulated (median = 21.50, IQR: 7.0-209.2; P = 0.001) relative to the non-cancer tissues. Allele (A) was highly prevalent in CRC tissues represented 0.56 (P < 0.001). AA/AG genotype carriers were 5.7 and 2.8 more likely to develop cancer than GG carriers. Tumor-normal tissue paired analysis revealed genotype concordance in 33 out of 58 tissue samples. Approximately 43% of the specimens showed a tendency for G to A shift. Additionally, a higher frequency of somatic mutation (92%) was observed in adenocarcinoma (P = 0.006). MIR34A expression and gene variant did not show associations with the clinicopathological data. However, G > A somatic mutation carriers had more prolonged DFS and OS. Bioinformatics analysis revealed miR-34a could target 30 genes that are implied in all steps of CRC tumorigenesis. In conclusion, this study confirms MIR34A upregulation in CRC tissues, and its rs2666433 (A/G) variant showed association with CRC and a high somatic mutation rate in cancer tissues. MiR-34a could provide a novel targeted therapy after validation in large-scale studies.
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Affiliation(s)
- Manal S Fawzy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia.
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.
| | - Afaf T Ibrahiem
- Department of Pathology, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Baraah T Abu AlSel
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, 1321, Saudi Arabia
| | - Saleh A Alghamdi
- Medical Genetics, Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, Taif, 21944,, Saudi Arabia
| | - Eman A Toraih
- Department of Surgery, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
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8
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Jafari D, Noorbakhsh F, Delavari A, Tavakkoli-Bazzaz J, Farashi-Bonab S, Abdollahzadeh R, Rezaei N. Expression level of long noncoding RNA NKILAmiR103-miR107 inflammatory axis and its clinical significance as potential biomarker in patients with colorectal cancer. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:41. [PMID: 32582347 PMCID: PMC7306231 DOI: 10.4103/jrms.jrms_943_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/07/2020] [Accepted: 02/23/2020] [Indexed: 12/13/2022]
Abstract
Background: Inflammatory cytokines have been observed in colorectal cancer (CRC) tissues and can promote the susceptibility to metastasis of CRC cells. Diverse regulatory mechanisms of long ncRNAs (lncRNAs) and microRNAs (miRNAs) involved in the inflammatory responses are associated with tumor progression. The aim of this research was to investigate the expression level of the nuclear factor-kappa B interacting lncRNA (NKILA)‐miR103-miR107 regulatory axis and its clinical significance as a potential biomarker in patients with CRC. Materials and Methods: In the present study, we investigated the expression levels of miR103, miR107, and NKILA in 21 paired CRC tissues and corresponding adjacent tissues, using real‐time polymerase chain reaction technique. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of biomarkers and to compare their predictive value. Results: It was found that the expression level of miR103 was significantly increased with the development of CRC (cancerous vs. corresponding normal tissues; 2.29 ± 1.65 vs. 1.16 ± 0.64, P = 0.003). Moreover, miR107 was upregulated in CRC tissues compared with paired normal tissues (2.1 ± 1.4 vs. 1.25 ± 0.83, P = 0.005), while NKILA displayed an opposite expression pattern versus miR103/107, but it was not statistically significant (3.69 ± 5.2 vs. 4.35 ± 5.99, P > 0.05). The ROC analysis demonstrated that miR103 had the best diagnostic ability performance with area under curve of 0.723 (0.545–0.901). Conclusion: We identified miR103/107 as tumor-promoting miRNAs with diagnostic value in cancer patients and presumptive negative regulators of NKILA, a potential cancer metastatic suppressor. Strategies that disrupt this regulatory axis might block CRC progression.
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Affiliation(s)
- Davood Jafari
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Delavari
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoli-Bazzaz
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samad Farashi-Bonab
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Rasoul Abdollahzadeh
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran
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Mao Z, Zhao H, Qin Y, Wei J, Sun J, Zhang W, Kang Y. Post-Transcriptional Dysregulation of microRNA and Alternative Polyadenylation in Colorectal Cancer. Front Genet 2020; 11:64. [PMID: 32153636 PMCID: PMC7047281 DOI: 10.3389/fgene.2020.00064] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 01/20/2020] [Indexed: 01/08/2023] Open
Abstract
Background Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. microRNAs (miRNAs) repress gene expression by binding to complementary sequences in the 3' untranslated region (3'UTR) of target mRNAs. Alternative polyadenylation (APA) are relevant to the variability of the 3'UTR of mRNA. However, the posttranscriptional dysregulation of miRNAs and APA in CRC are poorly understood. Method In this study, we conducted small RNA sequencing to identify differentially expressed miRNAs (DERs) and their target genes. Function analysis on DER-target genes can explain the regulation roles of miRNAs in CRC. The mutual regulation of miRNAs and APA was analyzed by combining miRNA data to 3'UTR alteration using 3' termini of polyadenylated RNAs sequencing (3T-seq) technique, and this was validated using TCGA gene expression data. Results Our results showed 64 significant differentially expressed miRNAs (DERs) in CRC patients. Their target genes were related to cell adhesion and transcription regulation and were prevailingly involved in the CRC-related pathway. Integrative analysis of the miRNA and APA profile revealed 16 DERs were correlated with 12 polyadenylation factors, and six of them were significantly differently expressed in CRC. We also found four DERs that lost binding sites due to APA and showed a positive correlation between the miRNA and gene expression. Conclusion Our study found that miRNAs regulated APA by modulating key polyadenylation factors, and several miRNAs lost their suppression on mRNA due to APA. Associating this with gene expression may provide some important clues for a deeper study of posttranscriptional cellular regulation and biomarker research in CRC. Our data provided the first evidence that the interaction between miRNAs and APA associated with gene expression could serve as biomarkers for CRC, suggesting that hsa-miR-133a-3p and MLEC, hsa-miR-145-5p and SET, hsa-miR-1-3p and PPIA, and hsa-miR-378d and YY1 might be novel and potential biomarkers in improving the diagnosis of CRC.
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Affiliation(s)
- Zhanrui Mao
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Zhao
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
| | - Yulan Qin
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
| | - Jianming Wei
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Jielin Sun
- Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Weiwei Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yani Kang
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China
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10
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Dai X, Kaushik AC, Zhang J. The Emerging Role of Major Regulatory RNAs in Cancer Control. Front Oncol 2019; 9:920. [PMID: 31608229 PMCID: PMC6771296 DOI: 10.3389/fonc.2019.00920] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022] Open
Abstract
Alterations and personal variations of RNA interactions have been mechanistically coupled with disease etiology and phenotypical variations. RNA biomarkers, RNA mimics, and RNA antagonists have been developed for diagnostic, prognostic, and therapeutic uses. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are two major types of RNA molecules with regulatory roles, deregulation of which has been implicated in the initiation and progression of many human malignancies. Accumulating evidence indicated the clinical roles of regulatory RNAs in cancer control, stimulating a surge in exploring the functionalities of regulatory RNAs for improved understanding on disease pathogenesis and management. In this review, we highlight the critical roles of lncRNAs and miRNAs played in tumorigenesis, scrutinize their potential functionalities as diagnostic/prognostic biomarkers and/or therapeutic targets in clinics, outline opportunities that ncRNAs may bring to complement current clinical practice for improved cancer management and identify challenges faced by translating frontier knowledge on non-coding RNAs (ncRNAs) to bedside clinics as well as possible solutions.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Aman Chandra Kaushik
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.,School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Jianying Zhang
- Henan Key Laboratory of Tumor Epidemiology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
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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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Fang Z, Li C, Li S. MicroRNA-193b acts as a tumor suppressor in colon cancer progression via targeting RAB22A. Exp Ther Med 2019; 17:3921-3928. [PMID: 31007734 PMCID: PMC6468329 DOI: 10.3892/etm.2019.7435] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 02/04/2019] [Indexed: 01/08/2023] Open
Abstract
To explore microRNA (miR)-193b expression and its potential role in colon cancer, reverse transcription-quantitative polymerase chain reaction was performed to detect the miR-193b expression levels in 62 colon cancer tissues and normal adjacent tissues. The miR-193b-overexpressed cell line SW620 was used to study the role of miR-193b in colon cancer. Subsequently, a Transwell assay and cell cycle assay were performed to observe the functional cell changes in the in vitro expression levels of miR-193b. Results indicated that miR-193b expression levels were significantly decreased in colon cancer tissues compared with adjacent normal tissue (P<0.001) and the expression of miR-193b was significantly correlated with TNM staging (P=0.03) and lymph node invasion (P=0.007). Furthermore, overexpression of miR-193b significantly decreased colon cancer cell cycle progression and its migration ability. In addition, the present findings suggested that the increased expression of miR-193b by RAB22A, inhibited downstream proteins involved in the Ras signaling pathway, including the Ras and extracellular signal-related kinase which may inhibit cancer proliferation and migration. In conclusion, the aim was to clarify the association of miR-193b expression with colon cancer, and to explore the mechanism of miR-193b in colon cancer proliferation and cell migration. The preliminary findings revealed that miR-193b may have an important role in the process in colon cancer cell cycle and migration by the RAB22A-Ras signaling pathway, thus providing a theoretical basis for miR-193b as a potential molecular target for colon cancer treatment.
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Affiliation(s)
- Zhiming Fang
- Department of Anus and Intestine Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Chengren Li
- Department of Anus and Intestine Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Shouchao Li
- Department of Anus and Intestine Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
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13
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Chen Z, Li K, Yin X, Li H, Li Y, Zhang Q, Wang H, Qiu Y. Lower Expression of Gelsolin in Colon Cancer and Its Diagnostic Value in Colon Cancer Patients. J Cancer 2019; 10:1288-1296. [PMID: 30854138 PMCID: PMC6400693 DOI: 10.7150/jca.28529] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 01/04/2019] [Indexed: 12/26/2022] Open
Abstract
Colon cancer is one of the most common malignancies causing the majority of cancer-related deaths. Gelsolin (GSN) has been found to be dysregulated in various cancers. However, the secreted GSN in colon cancer remains largely unknown. In the present study, we explored the expression profile of GSN in colon cancer tissues and the diagnostic value of serum GSN in colon cancer. In addition, the effects of secreted GSN in colon cancer cells were studied. We thus found that immunoreactive GSN levels were significantly lower in colon cancer tissues than those in non-tumor colon tissues. Functional studies demonstrated that secreted GSN could restrain cell invasion and migration in vitro. Mechanistically, dose dependent recombinant GSN down-regulated the expression of MMP2 and MMP9, which might restrain the process of cell invasion and migration. Furthermore, serum levels of GSN were significantly lower in colon cancer patients than those in healthy volunteers, and ROC curves showed serum level of GSN had a better diagnostic value for colon cancer (AUC=0.932) than the traditional tumor biomarker Carcinoembryonic Antigen (CEA) or Carbohydrate Antigen 19-9 (CA199). In conclusion, our results suggest that the secreted GSN restrains the invasion and migration of colon cancer cells. Meanwhile, the serum GSN may be a new biomarker for the diagnosis of colon cancer.
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Affiliation(s)
- Zhuoyu Chen
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Clinical Laboratory, Beijing University of Chinese Medicine Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Kaifei Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaofeng Yin
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Haixia Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yao Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Zhang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Haifang Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yurong Qiu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Biochip Technology, Southern Medical University, Guangzhou, Guangdong, China.,Huayin Medical Laboratory Center Co., Ltd., Guangzhou, Guangdong, China
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14
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Jiang M, Xu B, Li X, Shang Y, Chu Y, Wang W, Chen D, Wu N, Hu S, Zhang S, Li M, Wu K, Yang X, Liang J, Nie Y, Fan D. O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit. Oncogene 2019; 38:301-316. [PMID: 30093632 PMCID: PMC6336687 DOI: 10.1038/s41388-018-0435-5] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 07/14/2018] [Accepted: 07/17/2018] [Indexed: 12/21/2022]
Abstract
Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.
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Affiliation(s)
- Mingzuo Jiang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Bing Xu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China
| | - Xiaowei Li
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yulong Shang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yi Chu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Weijie Wang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Di Chen
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Nan Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
- Lab of Tissue Engineering, Faculty of Life Science, Northwest University, Xi'an, China
| | - Sijun Hu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Song Zhang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Mengbin Li
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Xiaoyong Yang
- Department of molecular cellular and developmental biology, Yale University, New Haven, USA
| | - Jie Liang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
| | - Daiming Fan
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
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15
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To KKW, Tong CWS, Wu M, Cho WCS. MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J Gastroenterol 2018; 24:2949-2973. [PMID: 30038463 PMCID: PMC6054943 DOI: 10.3748/wjg.v24.i27.2949] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/28/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that can post-transcriptionally regulate the expression of various oncogenes and tumor suppressor genes. Dysregulated expression of many miRNAs have been shown to mediate the signaling pathways critical in the multistep carcinogenesis of colorectal cancer (CRC). MiRNAs are stable and protected from RNase-mediated degradation, thereby enabling its detection in biological fluids and archival tissues for biomarker studies. This review focuses on the role and application of miRNAs in the prognosis and therapy of CRC. While stage II CRC is potentially curable by surgical resection, a significant percentage of stage II CRC patients do develop recurrence. MiRNA biomarkers may be used to stratify such high-risk population for adjuvant chemotherapy to provide better prognoses. Growing evidence also suggests that miRNAs are involved in the metastatic process of CRC. Certain of these miRNAs may thus be used as prognostic biomarkers to identify patients more likely to have micro-metastasis, who could be monitored more closely after surgery and/or given more aggressive adjuvant chemotherapy. Intrinsic and acquired resistance to chemotherapy severely hinders successful chemotherapy in CRC treatment. Predictive miRNA biomarkers for response to chemotherapy may identify patients who will benefit the most from a particular regimen and also spare the patients from unnecessary side effects. Selection of patients to receive the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Lastly, forced expression of tumor suppressor miRNA or silencing of oncogenic miRNA in tumors by gene therapy can also be adopted to treat CRC alone or in combination with other chemotherapeutic drugs.
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Affiliation(s)
- Kenneth KW To
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Christy WS Tong
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Mingxia Wu
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - William CS Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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16
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Gao SJ, Chen L, Lu W, Zhang L, Wang L, Zhu HH. miR-888 functions as an oncogene and predicts poor prognosis in colorectal cancer. Oncol Lett 2018; 15:9101-9109. [PMID: 29928331 PMCID: PMC6004656 DOI: 10.3892/ol.2018.8461] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 06/06/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of tumor formation, progression and metastasis. The present study characterized a novel miRNA (miR)-888, as a potent oncomiR in human colorectal cancer (CRC). The clinicopathological investigation on 126 cases of CRC patients demonstrated that the expression level of miR-888 was significantly upregulated in tumors compared with adjacent healthy tissue, and was associated with tumor stage and histological differentiation. A Kaplan-Meier analysis and log-rank test demonstrated that CRC patients with increased miR-888 expression exhibited a decreased overall survival (OS) and disease-free survival (DFS) compared with patients with low miR-888 expression. Further univariate and multivariate analyses identified miR-888 as an independent prognostic factor for poor survival outcome in CRC patients. To determine the biological role of miR-888 in human CRC, in vitro Cell Counting kit-8, wound healing and transwell assays were performed and demonstrated that miR-888 contributed greatly to CRC cell proliferation, invasion and metastasis. Furthermore, potential targets of miR-888 were investigated using a luciferase reporter assay, followed by polymerase chain reaction and western blot analysis. The findings revealed that miR-888 directly bound to the 3′-untranslated region of mothers against decapentaplegic-4 and thus inhibited its expression and promoted the tumor growth factor-1-induced cancer metastasis signaling. The results of the present study identified miR-888 as an oncogenic miRNA in CRC and provide a foundation for promising research in the future regarding this predictive and prognostic biomarker.
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Affiliation(s)
- Su-Jun Gao
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Lei Chen
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Wei Lu
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Li Zhang
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Lu Wang
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
| | - Hai-Hang Zhu
- Digestive Department of Subei People's Hospital, Clinical College of Yangzhou University, Yangzhou 225001, P.R. China
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17
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miR-15a-5p, A Novel Prognostic Biomarker, Predicting Recurrent Colorectal Adenocarcinoma. Mol Diagn Ther 2018; 21:453-464. [PMID: 28405803 DOI: 10.1007/s40291-017-0270-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Colorectal cancer is one of the most common gastrointestinal diseases and the second leading cause of cancer-associated deaths among adults. miR-15a-5p is a post-transcriptional regulator of the proto-oncogene MYB, a transcription factor essential for prolonged cancer cell proliferation and survival. In the current study, we assessed the potential diagnostic and prognostic utility of miR-15a-5p expression in colorectal adenocarcinoma. METHODS To accomplish this goal, total RNA was extracted from 182 colorectal adenocarcinoma specimens and 86 non-cancerous colorectal mucosae. After polyadenylation by poly(A) polymerase and subsequent reverse transcription with an oligo-dT adapter primer, miR-15a-5p expression was analyzed using an in-house developed reverse transcription quantitative real-time PCR method, based on SYBR Green chemistry. SNORD43 (RNU43) was used as an internal control gene. RESULTS miR-15a-5p was significantly upregulated in colorectal tumors compared to non-cancerous colorectal mucosae, while ROC analysis suggested its potential use for diagnostic purposes. Moreover, miR-15a-5p overexpression predicts poor disease-free survival (DFS) and overall survival (OS). Multivariate Cox regression analysis confirmed that miR-15a-5p overexpression is a significant unfavorable prognosticator of DFS in colorectal adenocarcinoma, independent of other established prognostic factors plus treatment of patients. Importantly, miR-15a-5p overexpression retains its unfavorable prognostic value in patients with T3 colorectal adenocarcinoma and in those without distant metastasis (M0). More importantly, the cumulative DFS probability of patients with early stage disease was significantly lower for those with colorectal adenocarcinoma overexpressing miR-15a-5p. DISCUSSION In conclusion, elevated expression of the cancer-associated miR-15a-5p predicts poor DFS and OS of colorectal adenocarcinoma patients. The prognostic value of miR-15a-5p expression regarding DFS is independent of clinicopathological factors currently used for colorectal adenocarcinoma prognosis.
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18
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Heublein S, Albertsmeier M, Pfeifer D, Loehrs L, Bazhin AV, Kirchner T, Werner J, Neumann J, Angele MK. Association of differential miRNA expression with hepatic vs. peritoneal metastatic spread in colorectal cancer. BMC Cancer 2018; 18:201. [PMID: 29463215 PMCID: PMC5819695 DOI: 10.1186/s12885-018-4043-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 01/24/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Though peritoneal carcinomatosis reflects a late stage of colorectal cancer (CRC), only few patients present with synchronous or metachronous liver metastases alongside their peritoneal carcinomatosis. It is hypothesized that this phenomenon may be causally linked to molecular characteristics of the primary CRC. This study used miRNA profiling of primary CRC tissue either metastasized to the liver, to the peritoneum or not metastasized at all thus to identify miRNAs potentially associated with defining the site of metastatic spread in CRC. METHODS Tissue of the primary tumor stemming from CRC patients diagnosed for either liver metastasis (LM; n = 10) or peritoneal carcinomatosis (PER; n = 10) was analyzed in this study. Advanced CRC cases without metastasis (M0; n = 3) were also included thus to select on those miRNAs most potentially associated with determining metastatic spread in general. miRNA profiling of 754 different miRNAs was performed in each group. MiRNAs being either differentially expressed comparing PER and LM or even triple differentially expressed (PER vs. LM vs. M0) were identified. Differentially expressed miRNAs were further validated by in silico and functional analysis. RESULTS Comparative analysis identified 41 miRNAs to be differentially expressed comparing primary tumors metastasized to the liver as opposed to those spread to the peritoneum. A set of 31 miRNAs was significantly induced in primary tumors that spread to the peritoneum (PER), while the remaining 10 miRNAs were found to be repressed. Out of these 41 miRNAs a number of 25 miRNAs was triple-differentially expressed (i.e. differentially expressed comparing LM vs. PER vs. M0). The latter underwent in silico analysis. Finally, we demonstrated that miR-31 down-regulated c-MET in DLD-1 colon cancer cells. CONCLUSIONS This study demonstrates that CRC primary tumors spread to the peritoneum vs. metastasized to the liver display significantly different miRNA profiles. Larger patient cohorts will be needed to validate whether determination of e.g. miR-31 may aid to predict the course of disease and whether this may help to create individualized follow up or treatment protocols. To determine whether certain miRNAs may be involved in regulating the metastatic potential of CRC, functional studies will be essential.
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Affiliation(s)
- Sabine Heublein
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
- Department of Obstetrics and Gynaecology, Heidelberg University Hospital, Heidelberg, Germany
| | - Markus Albertsmeier
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
| | - David Pfeifer
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
| | - Lisa Loehrs
- Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Alexandr V. Bazhin
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Thomas Kirchner
- Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jens Werner
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Jens Neumann
- Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Kurt Angele
- Department of General, Visceral, Transplantation and Vascular Surgery, University Hospital LMU Munich, Marachioninistrasse 15, 81377 Munich, Germany
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19
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Liu J, Chen Z, Xiang J, Gu X. MicroRNA-155 acts as a tumor suppressor in colorectal cancer by targeting CTHRC1 in vitro. Oncol Lett 2018; 15:5561-5568. [PMID: 29556299 PMCID: PMC5844014 DOI: 10.3892/ol.2018.8069] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is one of the most common malignancies. Aberrant expressed microRNAs (miRNAs) have been demonstrated to have strong associations with colorectal cancer by repressing their targets. Therefore, miRNAs are thought to have significant promise in the diagnosis and prognosis of colorectal cancer. Previous studies indicated that miR-155 and collagen triple helix repeat containing 1 (CTHRC1) were both involved in pathogenesis of colorectal cancer, but the underlying mechanisms of miR-155 and CTHRC1 are still unknown. The present study aimed to investigate the biological functions of miR-155 and CTHRC1 in colorectal cancer. Reverse transcription-quantitative polymerase chain reaction was used to examine miR-155 and CTHRC1 expression levels. A dual-luciferase reporter assay was applied to verify the target interaction between miR-155 and CTHRC1. Proliferation, cell cycle, apoptosis, cell migration and invasion were measured using the MTT assay, flow cytometry and Transwell assays, respectively. Results showed that miR-155 expression was decreased, but CTHRC1 expression was increased in colorectal cancer tissue and cell lines. Furthermore, it was demonstrated that miR-155 negatively regulated CTHRC1. Additionally, miR-155 overexpression suppressed cell proliferation, induced cell cycle arrest and promoted cell apoptosis, while an inhibitor of miR-155 facilitated cell proliferation and cell cycle and repressed apoptosis. Transwell experiments indicated that miR-155 inhibited the cell migratory and invasive abilities of HT-29 cells, but miR-155 inhibitor enhanced these abilities of HT-29 cells. These results suggested that miR-155 prevented colorectal cancer progression and metastasis via silencing CTHRC1 in vitro, which provides evidence for miR-155 and CTHRC1 as a novel anti-onco molecular target for the treatment of colorectal cancer in the future.
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Affiliation(s)
- Jingtian Liu
- Department of Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.,Department of Surgery, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, P.R. China
| | - Zongyou Chen
- Department of Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
| | - Jianbin Xiang
- Department of Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
| | - Xiaodong Gu
- Department of Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
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20
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Lü Y, Han B, Yu H, Cui Z, Li Z, Wang J. Berberine regulates the microRNA-21-ITGΒ4-PDCD4 axis and inhibits colon cancer viability. Oncol Lett 2018; 15:5971-5976. [PMID: 29564000 DOI: 10.3892/ol.2018.7997] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 05/16/2017] [Indexed: 12/12/2022] Open
Abstract
Berberine is sourced from multiple medicinal herb resources and is easy to extract. With the advantages of low price, safety and convenience, berberine may have potential for wide clinical use. The present study aimed to investigate whether berberine inhibited the viability of colon cancer and whether it regulated the three-gene network microRNA (miR)-21-integrin β4 (ITGβ4)-programmed cell death 4 (PDCD4). It was demonstrated that berberine treatment suppressed colon cancer cell viability, and induced apoptosis and activated caspase-3 activity in the human colon carcinoma HCT116 cell line. Berberine inhibited miR-21 expression and promoted ITGβ4 and PDCD4 protein expression in the HCT116 cell line. Overexpression of miR-21 reduced the anti-cancer effects of berberine on cell viability, apoptosis rate and caspase-3 activity of the HCT116 cell line. However, it was revealed that the overexpression of miR-21 also suppressed ITGβ4 and PDCD4 protein expression in the HCT116 cell line. In conclusion, miR-21, ITGβ4 and PDCD4 are involved in the anti-cancer effects of berberine on cell viability and apoptosis in the HCT116 cell line.
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Affiliation(s)
- Yanfeng Lü
- Department of Anoproctology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Bingbing Han
- Microcirculation Laboratory, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Hualong Yu
- Department of Anoproctology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhenghua Cui
- Department of Anoproctology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhiwen Li
- Department of Anoproctology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jianxin Wang
- Department of Anoproctology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Gong H, Fang L, Li Y, Du J, Zhou B, Wang X, Zhou H, Gao L, Wang K, Zhang J. miR‑873 inhibits colorectal cancer cell proliferation by targeting TRAF5 and TAB1. Oncol Rep 2018; 39:1090-1098. [PMID: 29328486 PMCID: PMC5802030 DOI: 10.3892/or.2018.6199] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/20/2017] [Indexed: 12/17/2022] Open
Abstract
MicroRNA-873 (miR-873) has been reported to be dysregulated in a variety of malignancies, however, the biological function and underlying molecular mechanism of miR-873 in colorectal cancer (CRC) remain unclear. In the present study we found that the expression levels of miR-873 were markedly decreased in CRC cell lines and tissues from patients. Statistical analysis revealed that miR-873 expression was inversely correlated with the disease stage of CRC. Kaplan-Meier survival analysis revealed that patients with CRC with lower miR-873 expression had shorter overall survival rates. Additionally, downregulation of miR-873 enhanced the proliferation of CRC cells, while upregulation of miR-873 reduced this proliferation. Furthermore, we found that tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1) were direct targets of miR-873 in CRC cells. A luciferase assay revealed that ectopic expression of miR-873 significantly reduced nuclear factor κB (NF-κB) luciferase activity, while ectopic expression of miR-873 inhibitor enhanced luciferase activity, suggesting that downregulation of miR-873 can activate NF-κB signaling. Therefore, our findings established a tumor-suppressive role for miR-873 in the inhibition of CRC progression, which may be employed as a novel prognostic marker and as an effective therapeutic target for CRC.
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Affiliation(s)
- Hui Gong
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Lishan Fang
- Central Laboratory, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518033, P.R. China
| | - Yifan Li
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Jihui Du
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Bei Zhou
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Xiu Wang
- Clinical Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Hekai Zhou
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Lingli Gao
- Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Kaixin Wang
- Department of Pathology, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
| | - Juan Zhang
- Department of Pathology, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518033, P.R. China
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22
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Chen Z, Yin X, Li K, Chen S, Li H, Li Y, Zhang Q, Wang H, Qiu Y. Serum Levels of TRIM72 Are Lower among Patients with Colon Cancer: Identification of a Potential Diagnostic Marker. TOHOKU J EXP MED 2018; 245:61-68. [DOI: 10.1620/tjem.245.61] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Zhuoyu Chen
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Xiaofeng Yin
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Kaifei Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Shuyu Chen
- Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, The State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University
| | - Haixia Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Yao Li
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Qiong Zhang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Haifang Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
| | - Yurong Qiu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University
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Abstract
The accuracy and efficiency of tumor treatment depends mainly on early and precise diagnosis. Although histopathology is always the gold standard for cancer diagnosis, noninvasive biomarkers represent an opportunity for early detection and molecular staging of cancer. Besides the classical tumor markers, noncoding RNAs (ncRNAs) emerge to be a novel category of biomarker for cancer diagnosis since the dysregulation of ncRNAs is closely associated with the development and progression of human cancers such as liver, lung, breast, gastric, and other kinds of cancers. In this chapter, we will summarize the different types of ncRNAs in the diagnosis of major human cancers. In addition, we will introduce the recent advances in the detection and applications of circulating serum or plasma ncRNAs and non-blood fluid ncRNAs because the noninvasive body fluid-based assays are easy to examine for cancer diagnosis and monitoring.
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Regulatory miRNAs in Colorectal Carcinogenesis and Metastasis. Int J Mol Sci 2017; 18:ijms18040890. [PMID: 28441730 PMCID: PMC5412469 DOI: 10.3390/ijms18040890] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 04/15/2017] [Accepted: 04/20/2017] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in carcinogenesis and progression through regulating of oncogenic signaling pathways, stem cells, epithelial-mesenchymal transition, and metastasis. This review summarizes the roles of microRNAs in the regulating of Wnt, Ras, TGF-β, and inflammatory signaling pathways, stemness, and epithelial-mesenchymal transition, for carcinogenesis and metastasis in colorectal cancer. Improving our understanding of the mechanisms of regulatory interactions of microRNAs with signaling pathways in colorectal cancer formation and progression will aid in determining the genes responsible for colorectal cancer initiation, progression, metastasis, and recurrence and, finally, in developing personalized approaches for cancer prevention and therapy.
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Negative Correlation between miR-200c and Decorin Plays an Important Role in the Pathogenesis of Colorectal Carcinoma. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1038984. [PMID: 28567416 PMCID: PMC5439253 DOI: 10.1155/2017/1038984] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 03/16/2017] [Indexed: 12/19/2022]
Abstract
Aim. To demonstrate the regulatory role of miRNA in colorectal carcinoma (CRC) and reveal the transcript markers that may be associated with CRC clinical outcomes. Method. Herein, we analyzed both mRNA and miRNA gene expression profiles of 255 CRC tumor samples from The Cancer Genome Atlas project to reveal the regulatory association between miRNA and mRNA. Also, the potential role of gene coexpression network in CRC has been explored. Results. The negative correlation between miR-200c and DCN (Decorin) was calculated in CRC, indicating that DCN could be a potential target of miR-200c. Clinical features indicated that colon polyp history and overall survival were significantly related to the expression level of miR-200c. Three coexpression networks have been constructed, and genes involved in the networks are related to cell cycle, NOTCH, and mTOR signaling pathways. Conclusion. Our result provides a new insight into cancer related mRNA coexpression network in CRC research.
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26
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Xu B, Yu L, Zhao LZ. Curcumin up regulates T helper 1 cells in patients with colon cancer. Am J Transl Res 2017; 9:1866-1875. [PMID: 28469791 PMCID: PMC5411934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 12/15/2016] [Indexed: 06/07/2023]
Abstract
The therapy for the advanced colon cancer (Cca) is unsatisfactory currently. To regulate the immune effector cell function has shown a positive effect on the treatment of advanced cancers. This study tests a hypothesis that administration with curcumin converts the Cca patient-derived regulatory T cells (Treg) to T helper (Th) 1 cells. In this study, a group of patients with advanced Cca was recruited into this study. The patients were treated with curcumin. The peripheral Tregs and Th1 cells were assessed by flow cytometry. The results showed that, after the curcumin therapy, the forkhead box protein (Foxp) 3 positive Treg frequency was markedly reduced, the frequency of Th1 cells was significantly increased in Cca patients. Treating with curcumin repressed the Foxp3 gene transcription in Tregs; the Tregs were then converted into Th1 cells. The results also revealed that Foxp3 bound T-bet to prevent IFN-γ expression in CD4+ T cells, which was abolished by treating with curcumin. In conclusion, the administration of curcumin can convert Tregs to Th1 cells via repressing Foxp3 expression and enhancing IFN-γ production.
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Affiliation(s)
- Bin Xu
- Department of Colorectal Surgery, Tianjin Union Medical CenterTianjin, China
| | - Lin Yu
- Department of Colorectal Surgery, Tianjin Union Medical CenterTianjin, China
| | - Li-Zhong Zhao
- Research Institute of Anal and Colorectal Disease of Tianjin CityJie-Yuan Road, Tianjin 300191, China
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27
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MicroR-545 mediates colorectal cancer cells proliferation through up-regulating epidermal growth factor receptor expression in HOTAIR long non-coding RNA dependent. Mol Cell Biochem 2017; 431:45-54. [PMID: 28364379 DOI: 10.1007/s11010-017-2974-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 02/07/2017] [Indexed: 01/01/2023]
Abstract
The functional impact of recently discovered miRNAs in human cancer remains to be clarified. One miRNA in colorectal cancer which has attracted attention is miR-545. In this study, we examined the function of miR-545 in proliferation of colorectal cancer cells. Expressions of HOTAIR, miRNA-545, and epidermal growth factor receptor (EGFR) mRNA were measured in 100 paired cancerous and non-cancerous tissues as well as in SW480 and LOVO colorectal cancer cell (CRC) lines by quantitative RT-PCR. The relative protein level of EGFR was measured using western blotting. Effects of miRNA-545 and HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches. Insight of mechanism of promotion cancer by miR-545 was gained from luciferase reporter assay and gene expression analysis. CRC proliferation was evaluated using clone formation and MTT assay. Differential expressions of HOTAIR, miR-545, and EGFR were observed in cancerous tissues in comparison to non-cancerous tissues. By expressional management of miR-545, we observed that miR-545 negatively regulated cell proliferation. Also luciferase reporter assay revealed that miR-545 inhibited regulated EGFR expression by affecting its 3'-UTR activity. In addition, miR-545 expression was suppressed by HOTAIR overexpression whereas enhanced by HOTAIR silence. Suppression of EGFR expression by miR-545 mimic was abrogated by HOTAIR overexpression. Monitoring of tumor growth in mice showed that miR-545 overexpression suppressed LOVO tumor growth. Our data suggested that HOTAIR long non-coding RNA mediates microR-545 regulating colorectal cancer cells proliferation.
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Zeng JH, Liang L, He RQ, Tang RX, Cai XY, Chen JQ, Luo DZ, Chen G. Comprehensive investigation of a novel differentially expressed lncRNA expression profile signature to assess the survival of patients with colorectal adenocarcinoma. Oncotarget 2017; 8:16811-16828. [PMID: 28187432 PMCID: PMC5370003 DOI: 10.18632/oncotarget.15161] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 01/24/2017] [Indexed: 02/06/2023] Open
Abstract
Growing evidence has shown that long non-coding RNAs (lncRNAs) can serve as prospective markers for survival in patients with colorectal adenocarcinoma. However, most studies have explored a limited number of lncRNAs in a small number of cases. The objective of this study is to identify a panel of lncRNA signature that could evaluate the prognosis in colorectal adenocarcinoma based on the data from The Cancer Genome Atlas (TCGA). Altogether, 371 colon adenocarcinoma (COAD) patients with complete clinical data were included in our study as the test cohort. A total of 578 differentially expressed lncRNAs (DELs) were observed, among which 20 lncRNAs closely related to overall survival (OS) in COAD patients were identified using a Cox proportional regression model. A risk score formula was developed to assess the prognostic value of the lncRNA signature in COAD with four lncRNAs (LINC01555, RP11-610P16.1, RP11-108K3.1 and LINC01207), which were identified to possess the most remarkable correlation with OS in COAD patients. COAD patients with a high-risk score had poorer OS than those with a low-risk score. The multivariate Cox regression analyses confirmed that the four-lncRNA signature could function as an independent prognostic indicator for COAD patients, which was largely mirrored in the validating cohort with rectal adenocarcinoma (READ) containing 158 cases. In addition, the correlative genes of LINC01555 and LINC01207 were enriched in the cAMP signaling and mucin type O-Glycan biosynthesis pathways. With further validation in the future, our study indicates that the four-lncRNA signature could serve as an independent biomarker for survival of colorectal adenocarcinoma.
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Affiliation(s)
- Jiang-Hui Zeng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Liang Liang
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University (West Branch), Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Rui-Xue Tang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Xiao-Yong Cai
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University (West Branch), Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Jun-Qiang Chen
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Dian-Zhong Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
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Hanisch C, Sharbati J, Kutz-Lohroff B, Huber O, Einspanier R, Sharbati S. TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS. Cell Death Discov 2017; 3:16106. [PMID: 28149533 PMCID: PMC5279457 DOI: 10.1038/cddiscovery.2016.106] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 12/17/2016] [Indexed: 12/21/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) is a double-edged cytokine associated with pathogenesis of inflammatory-related cancers being also able to induce cancer cell death. In the process of tumour development or metastasis, cancer cells can become resistant to TNF-α. In trefoil factor 3 (TFF3) overexpressing colorectal adenocarcinoma cells (HT-29/B6), we observed enhanced resistance against TNF-α/interferon gamma-induced apoptosis. TFF3 is a secreted small peptide that supports intestinal tissue repair but is also involved in intestinal tumour progression and scattering. We hypothesised that TFF3 rescues intestinal epithelial cancer cells from TNF-α-induced apoptosis by involving regulatory RNA networks. In silico-based expression analysis revealed TFF3-mediated regulation of selected microRNAs as well as long non-coding RNAs (lncRNAs), whereas miR-491-5p was identified to target the lncRNA ‘psoriasis susceptibility-related RNA gene induced by stress’ (PRINS). RNA interference-based gain- and loss-of-function experiments examined miR-491-PRINS axis to exert the TFF3-mediated phenotype. Chemical inhibition of selected pathways showed that phosphatidylinositol 3-kinase/AKT accounts for TFF3-mediated downregulation of miR-491-5p and accumulation of PRINS. Moreover, we showed that PRINS colocalises with PMAIP1 (NOXA) in nuclei of HT-29/B6 possessing inhibitory effects. Immunoprecipitation experiments proved molecular interaction of PMAIP1 with PRINS. Our study provides an insight into RNA regulatory networks that determine resistance of colorectal cancer cells to apoptosis.
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Affiliation(s)
- Carlos Hanisch
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Jutta Sharbati
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin, Berlin, Germany; Lise Meitner School of Science, Berlin, Germany
| | - Barbara Kutz-Lohroff
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Otmar Huber
- Institute of Biochemistry II, Jena University Hospital , Jena, Germany
| | - Ralf Einspanier
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Soroush Sharbati
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
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Kuroda K, Fukuda T, Krstic-Demonacos M, Demonacos C, Okumura K, Isogai H, Hayashi M, Saito K, Isogai E. miR-663a regulates growth of colon cancer cells, after administration of antimicrobial peptides, by targeting CXCR4-p21 pathway. BMC Cancer 2017; 17:33. [PMID: 28061765 PMCID: PMC5219750 DOI: 10.1186/s12885-016-3003-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 12/15/2016] [Indexed: 01/18/2023] Open
Abstract
Background Antimicrobial peptides (AMPs) play important roles in the innate immune system of all life forms and recently have been characterized as multifunctional peptides that have a variety of biological roles such as anticancer agents. However, detailed mechanism of antimicrobial peptides on cancer cells is still largely unknown. Methods miRNA array and real-time qPCR were performed to reveal the behavior of miRNA in colon cancer HCT116 cells during the growth suppression induced by the AMPs. Establishment of miR-663a over-expressing HCT116 cells was carried out for the evaluation of growth both in vitro and in vivo. To identify the molecular mechanisms, we used western blotting analysis. Results miR-663a is upregulated by administration of the human cathelicidin AMP, LL-37, and its analogue peptide, FF/CAP18, in the colon cancer cell line HCT116. Over-expression of miR-663a caused anti-proliferative effects both in vitro and in vivo. We also provide evidence supporting the view that these effects are attributed to suppression of the expression of the chemokine receptor CXCR4, resulting in the abrogation of phosphorylation of Akt and cell cycle arrest in G2/M via p21 activation. Conclusions This study contributes to the understanding of the AMPs’ mediated anti-cancer mechanisms in colon cancer cells and highlights the possibility of using AMPs and miRNAs towards developing future strategies for cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-3003-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kengo Kuroda
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan
| | - Tomokazu Fukuda
- United Graduate School of Agricultural Sciences, Graduate School of Agricultural Science, Iwate University, Morioka, Iwate, Japan
| | | | - Constantinos Demonacos
- Division of Pharmacy and Optometry, Faculty of Biology Medicine and Health, School of Health Sciences, University of Manchester, Manchester, UK
| | - Kazuhiko Okumura
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Hiroshi Isogai
- Animal Research Center, Sapporo Medical University, Sapporo, Japan
| | - Miwa Hayashi
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan
| | - Kazuki Saito
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan
| | - Emiko Isogai
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University, Sendai, 981-8555, Japan.
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Wang J, Li H, Wang Y, Wang L, Yan X, Zhang D, Ma X, Du Y, Liu X, Yang Y. MicroRNA-552 enhances metastatic capacity of colorectal cancer cells by targeting a disintegrin and metalloprotease 28. Oncotarget 2016; 7:70194-70210. [PMID: 27661126 PMCID: PMC5342546 DOI: 10.18632/oncotarget.12169] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 08/08/2016] [Indexed: 01/11/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common prevalent cancer types worldwide. MicroRNAs (miRNAs or miRs) have been demonstrated to play crucial roles in the development, metastasis and drug resistance of CRC. In the present study, a strikingly elevated expression of miR-552 was determined in CRC tumor tissues and cells by a miRNA profiling analysis. Importantly, the gene of A Disintegrin And Metalloprotease (ADAM) family member 28 (ADAM28) was identified as a target of miR-552, which was further validated in terms of genetic dual luciferase report assay. Furthermore, an inhibition of miR-552 in LOVE and LS174T CRC cells by transducing miR-552 inhibitor (antagomiR-552) with a lentiviral vector exhibited an ability to reduce cell proliferation, migration and clonogenicity. Moreover, both LOVO and LS174T cells stably expressing miR-552 inhibitor displayed a decreased ability to develop tumors in a murine xenograft model in vivo. In contrast, a knockdown of ADAM28 by short hairpin RNA could reverse the antagomiR-552-induced inhibition of metastatic features of CRC cells in vitro. These results suggested that miR-552 is an oncomir able to promote CRC metastasis in part through a mechanism of targeting ADAM28, which may be a novel target for CRC treatment and warrants for further investigation.
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Affiliation(s)
- Jian Wang
- The general hospital, Ningxia Medical University, Yinchuan 750004, China
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
| | - Hai Li
- Department of Colorectal Surgery, the General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Yong Wang
- The general hospital, Ningxia Medical University, Yinchuan 750004, China
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
| | - Libin Wang
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
| | - Xiurui Yan
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
| | - Dong Zhang
- Department of Colorectal Surgery, the General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoqiang Ma
- Department of Colorectal Surgery, the General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Yong Du
- The general hospital, Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoming Liu
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
| | - Yinxue Yang
- The general hospital, Ningxia Medical University, Yinchuan 750004, China
- Human Stem Cell Institute of the General Hospital at Ningxia Medical University, Yinchuan 750004, China
- Department of Colorectal Surgery, the General Hospital of Ningxia Medical University, Yinchuan 750004, China
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Sun S, Su C, Zhu Y, Li H, Liu N, Xu T, Sun C, Lv Y. MicroRNA-544a Regulates Migration and Invasion in Colorectal Cancer Cells via Regulation of Homeobox A10. Dig Dis Sci 2016; 61:2535-44. [PMID: 27165435 DOI: 10.1007/s10620-016-4186-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 04/26/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS MicroRNAs (miRNAs) are a group of small RNA molecules that post-transcriptionally regulate gene expression. Aberrant expression of miRNAs has been associated with tumorigenesis in various cancers. miR-544a is an understudied miRNA that has recently been implicated in regulating invasion in lung cancer. However, its role in regulating invasion and the underlying mechanism have not been investigated in colorectal cancer (CRC) cells. METHODS Microarray analysis was performed in metastatic colorectal tumor samples and their matched normal tissues to identify differentially expressed miRNAs. Quantitative real-time PCR was used to detect miR-544a levels in tumor samples and CRC cell lines with varying metastatic properties. miR-544a mimic or inhibitor was transfected into SW480 and HCT116 cells, respectively, followed by wound healing and invasion assays. Western Blot and luciferase assay were performed to investigate the direct target of miR-544a. Xenograft mouse models was used to examine in vivo function of miR-544a. RESULTS Our data showed that expression of miR-544a was significantly up-regulated in metastatic tumor samples and CRC cell lines. Inhibition of miR-544a reduced migration and invasion in HCT116 cells. Homeobox A10 (HOXA10) was the direct target of miR-544a which was required for the function of miR-544a in regulating invasiveness. miR-544a inhibitor and/or HOXA10 overexpression reduced lung metastases in HCT116 xenografts. CONCLUSIONS Our study demonstrates that miR-544a regulates invasive and metastatic properties of CRC cells by modulating HOXA10 expression level both in vitro and in vivo. miR-544a may represent a new therapeutic target for the intervention of metastatic colorectal cancer.
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Affiliation(s)
- Shangfeng Sun
- Department of Colorectal Anal Surgery, The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang, 277800, Shandong, China.
| | - Changying Su
- Department of Colorectal Anal Surgery, The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang, 277800, Shandong, China
| | - Yunxiao Zhu
- Department of Colorectal Anal Surgery, The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang, 277800, Shandong, China
| | - Haiyan Li
- Department of Colorectal Anal Surgery, The Central Hospital of Zaozhuang Mining Group of Shandong, Qilianshan Road, High-tech Zone, Zaozhuang, 277800, Shandong, China.
| | - Ning Liu
- Department of Information Technology, Jining Medical University, Hehua Road, Jining, 272067, Shandong, China
| | - Tong Xu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Guhuai Road, Jining, 272029, Shandong, China
| | - Chao Sun
- Central Laboratory, Second Hospital of Shandong University, Jinan, 250014, China
| | - Yanfeng Lv
- Department of General Surgery, Second Hospital of Shandong University, Jinan, 250014, China
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Abstract
MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved small non-coding RNAs, which play a vital role in tumour formation, development, metastasis and recurrence by inducing DNA methylation, changing tumor microenvironment and regulating signal pathways such as Wnt/β-catenin, phosphoinositide3-kinase (PI3K), K-RAS, epithelial mesenchymal transitions (EMT) and so on. Recent studies have found that the expression of many miRNAs is dyregulated in colorectal cancer, and they participate in and control the formation and development of colorectal cancer. Thus, understanding the roles and mechanisms of action of miRNAs in colorectal cancer can provide a new avenue for its early diagnosis, clinical staging, treatment and prognosis evaluation.
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Yang G, Zhang L, Li R, Wang L. The role of microRNAs in gallbladder cancer. Mol Clin Oncol 2016; 5:7-13. [PMID: 27330755 DOI: 10.3892/mco.2016.905] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 03/21/2016] [Indexed: 01/17/2023] Open
Abstract
MicroRNAs (also referred to as miRNAs or miRs) play a crucial role in post-transcriptional gene regulation and serve as negative gene regulators by controlling a variety of target genes and regulating diverse biological processes, such as cell proliferation, invasion, migration and apoptosis. Aberrant expression of miRNAs is associated with the development and progression of cancer. Recent studies have reported that miRNAs may repress or promote the expression of cancer-related genes via several different signaling pathways in gallbladder cancer (GBC) patients and may function as tumor suppressors or oncogenes, thus providing a promising tool for the diagnosis and therapeutics of GBCs. In this review, we summarize the role of dysregulawted miRNA expression in the signaling pathways implicated in GBC and discuss the significant role of circulating miRNAs in GBC. Therefore, miRNAs may serve as novel therapeutic targets as well as diagnostic or prognostic markers in GBC.
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Affiliation(s)
- Ganghua Yang
- Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lei Zhang
- Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ruixiang Li
- Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lin Wang
- Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Cowley D, Pandya K, Khan I, Kerwin J, Owen K, Griner E. Registered report: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. eLife 2015; 4. [PMID: 26335297 PMCID: PMC4558562 DOI: 10.7554/elife.08245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/08/2015] [Indexed: 01/04/2023] Open
Abstract
The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from ‘A coding-independent function of gene and pseudogene mRNAs regulates tumour biology’ by Poliseno et al. (2010), published in Nature in 2010. The key experiments to be replicated are reported in Figures 1D, 2F-H, and 4A. In these experiments, Poliseno and colleagues report microRNAs miR-19b and miR-20a transcriptionally suppress both PTEN and PTENP1 in prostate cancer cells (Figure 1D; Poliseno et al., 2010). Decreased expression of PTEN and/or PTENP1 resulted in downregulated PTEN protein levels (Figure 2H), downregulation of both mRNAs (Figure 2G), and increased tumor cell proliferation (Figure 2F; Poliseno et al., 2010). Furthermore, overexpression of the PTEN 3′ UTR enhanced PTENP1 mRNA abundance limiting tumor cell proliferation, providing additional evidence for the co-regulation of PTEN and PTENP1 (Figure 4A; Poliseno et al., 2010). The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published in eLife. DOI:http://dx.doi.org/10.7554/eLife.08245.001
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Affiliation(s)
- Dale Cowley
- TransViragen Inc, Chapel Hill, North Carolina
| | | | - Israr Khan
- Alamo Laboratories Inc, San Antonio, Texas
| | - John Kerwin
- Biotechnology Research and Education Program, University of Maryland, College Park, Maryland
| | - Kate Owen
- University of Virginia, Charlottesville, Virginia
| | - Erin Griner
- University of Virginia, Charlottesville, Virginia
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