|
1
|
Saadh MJ, Bishoyi AK, Ballal S, Singh A, Kareem RA, Devi A, Sharma GC, Naidu KS, Sead FF. MicroRNAs as behind-the-scenes molecules in breast cancer metastasis and their therapeutic role through novel microRNA-based delivery strategies. Gene 2025; 944:149272. [PMID: 39894085 DOI: 10.1016/j.gene.2025.149272] [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: 12/18/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
Breast cancer is the primary cause of cancer-related death and the most frequent malignancy among women in Western countries. Although there have been advancements in combination treatments and targeted therapies for the metastatic diseases management, metastatic breast cancer is still the second most common cause of cancer-related deaths among U.S. women. The routes of metastasis encompass invasion, intravasation, circulation, extravasation, infiltration into a remote location to establish a metastatic niche, and the formation of micro-metastases in a new environment. Each of these processes is regulated by changes in gene expression. MicroRNAs (miRNAs) are widely expressed by a variety of organisms and have a key role in cell activities including suppressing or promoting cancer through regulating various pathways. Target gene expression is post-transcriptionally regulated by miRNAs, which contribute to the development, spread, and metastasis of breast cancer. In this study, we comprehensively discussed the role of miRNAs as predictors of breast cancer metastasis, their correlation with the spread of the disease to certain organs, and their potential application as targets for breast cancer treatment. We also provided molecular mechanisms of miRNAs in the progression of breast cancer, as well as current challenges in miRNA-based therapeutic approaches. Furthermore, as one of the primary issues with the treatment of solid malignancies is the efficient delivery of miRNAs, we examined a number of cutting-edge carriers for miRNA-based therapies and CRISPR/Cas9 as a targeted therapy for breast cancer.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | - Ashok Kumar Bishoyi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, India
| | | | - Anita Devi
- Department of Chemistry Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali 140307, Punjab, India
| | - Girish Chandra Sharma
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Fadhil Faez Sead
- Department of Dentistry, College of Dentistry, The Islamic University, Najaf, Iraq; Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
| |
Collapse
|
|
2
|
Martínez CG, Therapontos S, Lorente JA, Lucena MA, Ortega FG, Serrano MJ. Evaluating MicroRNAs as diagnostic tools for lymph node metastasis in breast cancer: Findings from a systematic review and meta-analysis. Crit Rev Oncol Hematol 2025; 207:104598. [PMID: 39732303 DOI: 10.1016/j.critrevonc.2024.104598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 12/11/2024] [Accepted: 12/12/2024] [Indexed: 12/30/2024] Open
Abstract
Lymph node metastasis (LNM) significantly affects the prognosis and clinical management of breast cancer (BC) patients. This systematic review and meta-analysis aim to identify microRNAs (miRNAs) associated with LNM in BC and evaluate their potential diagnostic and prognostic value. Following PRISMA guidelines, a comprehensive literature search was conducted in PubMed, Web of Science, and SCOPUS databases, to assess the role of miRNAs in LNM BC. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to evaluate the quality of included studies. A total of 84 miRNAs were identified as differentially expressed in BC patients with LNM. Of these, a meta-analysis was performed in two microRNAs that were present in at least 3 different articles with a coherent expression direction: miR-155 and miR-34a. The meta-analysis returned a pooled a Log2 fold change of 1.50 for miR-155 (upregulated) and -0.53 for miR-34a (downregulated) with no evidence of publication bias, and a low risk of bias and applicability concerns. To conclude, this study names miR-155 and miR-34a as potential diagnostic biomarkers for LNM in BC, although further experimental validation is necessary to confirm these findings and develop non-invasive diagnostic tools for clinical use.
Collapse
Affiliation(s)
- Coral González Martínez
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and Cancer Interception Group, PTS Granada, Avenida de la Ilustración 114, Granada 18016, Spain; Biomedical Research Institute IBS-Granada, Avda. de Madrid, 15, Granada 18012, Spain; Laboratory of Genetic Identification, Legal Medicine and Toxicology Department, Faculty of Medicine, University of Granada, Avenida de la Investigación 11, Granada 18071, Spain; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain
| | - Stavros Therapontos
- Utrecht University, Heidelberglaan 8, Utrecht 3584 CS, Netherlands; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain
| | - Jose A Lorente
- Laboratory of Genetic Identification, Legal Medicine and Toxicology Department, Faculty of Medicine, University of Granada, Avenida de la Investigación 11, Granada 18071, Spain; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain
| | - Miriam Alcaide Lucena
- Unidad de Patología Mamaria, Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario San Cecilio, Granada, Spain; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain
| | - F Gabriel Ortega
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and Cancer Interception Group, PTS Granada, Avenida de la Ilustración 114, Granada 18016, Spain; Biomedical Research Institute IBS-Granada, Avda. de Madrid, 15, Granada 18012, Spain; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain.
| | - M Jose Serrano
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Liquid biopsy and Cancer Interception Group, PTS Granada, Avenida de la Ilustración 114, Granada 18016, Spain; Biomedical Research Institute IBS-Granada, Avda. de Madrid, 15, Granada 18012, Spain; Unidad de Patología Mamaria, Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario San Cecilio, Granada, Spain; Integral Oncology Division, Virgen de las Nieves University Hospital, Av. Dr. Olóriz 16, Granada 18012, Spain; Molecular Pathology Lab. Pathological Anatomy Unit, University Hospital Virgen de las Nieves, Granada 18016, Spain.
| |
Collapse
|
|
3
|
Garroni G, Cruciani S, Serra D, Pala R, Coradduzza D, Cossu ML, Ginesu GC, Ventura C, Maioli M. Effects of the MCF-7 Exhausted Medium on hADSC Behaviour. Int J Mol Sci 2024; 25:7026. [PMID: 39000134 PMCID: PMC11241546 DOI: 10.3390/ijms25137026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/19/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Stem cells possess the ability to differentiate into different lineages and the ability to self-renew, thus representing an excellent tool for regenerative medicine. They can be isolated from different tissues, including the adipose tissue. Adipose tissue and human adipose-derived stem cells (hADSCs) are privileged candidates for regenerative medicine procedures or other plastic reconstructive surgeries. The cellular environment is able to influence the fate of stem cells residing in the tissue. In a previous study, we exposed hADSCs to an exhausted medium of a breast cancer cell line (MCF-7) recovered at different days (4, 7, and 10 days). In the same paper, we inferred that the medium was able to influence the behaviour of stem cells. Considering these results, in the present study, we evaluated the expression of the major genes related to adipogenic and osteogenic differentiation. To confirm the gene expression data, oil red and alizarin red colorimetric assays were performed. Lastly, we evaluated the expression of miRNAs influencing the differentiation process and the proliferation rate, maintaining a proliferative state. The data obtained confirmed that cells exposed to the medium maintained a stem and proliferative state that could lead to a risky proliferative phenotype.
Collapse
Affiliation(s)
- Giuseppe Garroni
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
| | - Diletta Serra
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
| | - Renzo Pala
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
| | - Donatella Coradduzza
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
| | - Maria Laura Cossu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy; (M.L.C.); (G.C.G.)
| | - Giorgio Carlo Ginesu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy; (M.L.C.); (G.C.G.)
| | - Carlo Ventura
- National Laboratory of Molecular Biology and Stem Cell Bioengineering of the National Institute of Biostructures and Biosystems (NIBB) c/o Eldor Lab, Via Corticella 183, 40129 Bologna, Italy;
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (S.C.); (D.S.); (R.P.); (D.C.)
- Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
| |
Collapse
|
|
4
|
Alkan AH, Ensoy M, Cansaran-Duman D. Strategic and Innovative Roles of lncRNAs Regulated by Naturally-derived Small Molecules in Cancer Therapy. Curr Med Chem 2024; 31:6672-6691. [PMID: 37921177 DOI: 10.2174/0109298673264372230919102758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/22/2023] [Accepted: 08/17/2023] [Indexed: 11/04/2023]
Abstract
In the field of precision and personalized medicine, the next generation sequencing method has begun to take an active place as genome-wide screening applications in the diagnosis and treatment of diseases. Studies based on the determination of the therapeutic efficacy of personalized drug use in cancer treatment in the size of the transcriptome and its extension, lncRNA, have been increasing rapidly in recent years. Targeting and/or regulating noncoding RNAs (ncRNAs) consisting of long noncoding RNAs (lncRNAs) are promising strategies for cancer treatment. Within the scope of rapidly increasing studies in recent years, it has been shown that many natural agents obtained from biological organisms can potentially alter the expression of many lncRNAs associated with oncogenic functions. Natural agents include effective small molecules that provide anti-cancer effects and have been used as chemotherapy drugs or in combination with standard anti-cancer drugs used in routine treatment. In this review, it was aimed to provide detailed information about the potential of natural agents to regulate and/or target non-coding RNAs and their mechanisms of action to provide an approach for cancer therapy. The discovery of novel anti-cancer targets and subsequent development of effective drugs or combination strategies that are still needed for most cancers will be promising for cancer treatment.
Collapse
Affiliation(s)
- Ayşe Hale Alkan
- Biotechnology Institute, Ankara University, Keçiören, Ankara, Turkey
- Department of Molecular Biology and Genetics, Faculty of Science, Bartın University, Bartın, Turkey
| | - Mine Ensoy
- Biotechnology Institute, Ankara University, Keçiören, Ankara, Turkey
| | | |
Collapse
|
|
5
|
Liu Y, Shen Z, Wei X, Gu L, Zheng M, Zhang Y, Cheng X, Fu Y, Lu W. CircSLC39A8 attenuates paclitaxel resistance in ovarian cancer by regulating the miR‑185‑5p/BMF axis. Transl Oncol 2023; 36:101746. [PMID: 37499410 PMCID: PMC10413200 DOI: 10.1016/j.tranon.2023.101746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/11/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023] Open
Abstract
Chemoresistance to paclitaxel (PTX) is one of the main reasons for treatment failure and poor prognosis in patients with advanced ovarian cancer. Therefore, it is imperative to explore the mechanisms related to chemotherapy resistance in ovarian cancer to find potential therapeutic targets. Circular RNAs (circRNAs) play important roles in cancer development and progression. However, their biological functions and clinical significance in ovarian cancer have not been fully elucidated. Therefore, in this study, we aimed to investigate the function and underlying mechanism of hsa_circ_0002782 (circSLC39A8), identified by circRNA sequencing, in regulating PTX resistance. The effects of circSLC39A8 on PTX resistance was assessed by cell viability, colony formation, flow cytometry assays and an in vivo subcutaneous xenografted tumor mouse model. RNA immunoprecipitation and dual-luciferase reporter assays were performed to verify the interaction between circSLC39A8 and the miR-185-5p/BMF signal axis. We found that circSLC39A8 was downregulated in PTX-resistant ovarian cancer cells and tissues, and its low expression was associated with poor prognosis. Biologically, circSLC39A8 knockdown promoted PTX resistance in vitro and in vivo, while circSLC39A8 overexpression showed the opposite effect. Mechanistically, circSLC39A8, acting as an endogenous sponge for miR-185-5p, could relieve the inhibition of miR-185-5p on the expression of its downstream target, BMF; thus enhancing the sensitivity of ovarian cancer to PTX. Our findings demonstrate that circSLC39A8 can promote PTX sensitivity by regulating the miR-185-5p/BMF axis. This may be a valuable prognostic biomarker and a promising therapeutic target for patients with ovarian cancer.
Collapse
Affiliation(s)
- Yuwan Liu
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Zhangjin Shen
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Xinyi Wei
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Lingkai Gu
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Mengxia Zheng
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Yanan Zhang
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Xiaodong Cheng
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yunfeng Fu
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
| | - Weiguo Lu
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China; Zhejiang Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
| |
Collapse
|
|
6
|
Yu S, Zhou Y, Niu L, Qiao Y, Yan Y. Mesenchymal stem cell-derived exosome mir-342-3p inhibits metastasis and chemo-resistance of breast cancer through regulating ID4. Genes Genomics 2022; 44:539-550. [PMID: 35023068 DOI: 10.1007/s13258-021-01200-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/27/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The mesenchymal stem cell-derived exosome (MSCs-exo) carrying microRNAs have been proved to regulate tumor biological activities. Clarifying molecular mechanism and identifying predictive microRNAs will be of great value in anti-tumor therapy improvement. OBJECTIVE We aimed to investigate the regulatory role of microRNA-342-3p (miR-342-3p) in MSCs-exo on breast cancer. METHODS Breast cancer tissues and cell lines were used to evaluate miR-342-3p expression in patients with or without lymph node/distal organ metastasis. The impact of MSCs-exo expression on tumor cell chemo-resistance and invasion/migration was measured. Dual-luciferase reporter gene assay was applied to identify binding site. Inhibitor of differentiation 4 (ID4) siRNA and miR-342-3p inhibitor transfection was conducted to further explore the miR-342-3p/ID4 axis on chemo-resistance and metastasis of breast cancer cells. RESULTS Breast cancer cells revealed significantly lower level of miR-342-3p in patients with metastatic diseases. miR-342-3p suppressed invasive and chemo-resistant behavior of breast cancer tumor cells. Binding site between miR-342-3p and ID4 was proved. ID4 could reverse the influence of miR-342-3p on chemo-resistance. The tumor inhibition effect of IDA siRNA in vivo was also identified. CONCLUSIONS This study demonstrated that miR-342-3p acted as potential tumor suppressor by inhibiting metastasis and chemo-resistance of breast cancer cells through targeting ID4. This study might provide potential therapy targets for the treatment of breast cancer.
Collapse
Affiliation(s)
- Shuyao Yu
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yuhui Zhou
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Ligang Niu
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yan Qiao
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China
| | - Yu Yan
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, Yanta West Road, Shaanxi Province, 710061, Xi'an, China.
| |
Collapse
|
|
7
|
Dong W, Wang S, Qian W, Li S, Wang P. Cedrol alleviates the apoptosis and inflammatory response of IL-1β-treated chondrocytes by promoting miR-542-5p expression. In Vitro Cell Dev Biol Anim 2021; 57:962-972. [PMID: 34893958 DOI: 10.1007/s11626-021-00620-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/21/2021] [Indexed: 12/16/2022]
Abstract
Cedrol has been shown to exert anti-tumor, anti-inflammatory, and anti-oxidative effects, but its role in osteoarthritis (OA) is unclear. This study aimed to explore the effect of cedrol in OA. Chondrocytes were isolated from newborn rats and cultured in Dulbecco's modified Eagle's medium (DMEM). Then, Alcian blue staining was used to identify the chondrocytes. IL-1β and cedrol were used to treat chondrocytes. Cell viability and apoptosis were measured by MTT and flow cytometry assays, respectively. The expressions of miR-542-5p, miR-26b-5p, miR-572, miR-138-5p, miR-328-3p, miR-1254, Bcl-2, Bax, iNOS, COX-2, and MMP-13 were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot. NO and PGE2 levels were detected by ELISA. All the cells extracted from the newborn rats were dyed blue, indicating that the cells were chondrocytes. IL-1β could reduce the viability and promote apoptosis and inflammatory response of chondrocytes, while cedrol could reverse the effect of IL-1β. In addition, cedrol could significantly increase the expression of miR-542-5p in IL-1β-treated chondrocytes. Moreover, miR-542-5p inhibitor could partly reverse the effect of cedrol in the apoptosis and inflammation response of chondrocytes. Cedrol alleviated IL-1β-induced apoptosis and inflammatory response of chondrocytes by promoting miR-542-5p expression.
Collapse
Affiliation(s)
- Wangchao Dong
- Department of Orthopedics, Nanjing Hospital of Chinese Medicine, Nanjing, China
| | - Shanshan Wang
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Weiqing Qian
- Department of Orthopedics, Nanjing Hospital of Chinese Medicine, Nanjing, China
| | - Suming Li
- Department of Orthopedics, Nanjing Hospital of Chinese Medicine, Nanjing, China
| | - Peimin Wang
- Department of Orthopedics, Jiangsu Province Hospital of Chinese Medicine, Qinhuai District, 155 Hanzhong Road, Nanjing, 210000, Jiangsu Province, China.
| |
Collapse
|
|
8
|
Escuin D, López-Vilaró L, Mora J, Bell O, Moral A, Pérez I, Arqueros C, García-Valdecasas B, Ramón Y Cajal T, Lerma E, Barnadas A. Circulating microRNAs in Early Breast Cancer Patients and Its Association With Lymph Node Metastases. Front Oncol 2021; 11:627811. [PMID: 34513655 PMCID: PMC8428362 DOI: 10.3389/fonc.2021.627811] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 08/04/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs have emerged as important regulators of the metastatic process. In addition, circulating miRNAs appear to be surprisingly stable in peripheral blood making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to investigate the expression profile of circulating miRNAs and their association with the metastatic lymph node status in early breast cancer patients. Sentinel lymph node status was detected by one-step nucleic acid (OSNA) analysis. We performed RNA-sequencing in 16 plasma samples and validated the results by qPCR. Gene Ontology term enrichment and KEGG pathway analyses were carried out using DAVID tools. We found16 differentially expressed miRNAs (q < 0.01) in patients with positive SLNs. Fourteen miRNAs were down-regulated (miR-339-5p, miR-133a-3p, miR-326, miR-331-3p, miR-369-3p, miR-328-3p, miR-26a-3p, miR-139-3p, miR-493-3p, miR-664a-5p, miR-146a-5p, miR-323b-3p, miR-1307-3p and miR-423-3p) and 2 were up-regulated (miR-101-3pand miR-144-3p). Hierarchical clustering using differentially expressed miRNAs clearly distinguished patients according to their lymph node status. Gene ontology analysis showed a significant enrichment of biological processes associated with the regulation of the epithelial mesenchymal transition, cell proliferation and transcriptional regulation. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further validation in a larger cohort of patients will be necessary to confirm our results.
Collapse
Affiliation(s)
- Daniel Escuin
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Laura López-Vilaró
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Josefina Mora
- Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Olga Bell
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Antonio Moral
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain
| | - Ignacio Pérez
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Cristina Arqueros
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Teresa Ramón Y Cajal
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Enrique Lerma
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain
| | - Agustí Barnadas
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain.,Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| |
Collapse
|
|
9
|
Qiao EQ, Yang HJ, Zhang XP. Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis. J Zhejiang Univ Sci B 2021; 21:495-508. [PMID: 32478495 DOI: 10.1631/jzus.b1900584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2 (Her-2)-positive breast cancer (BC). We analyzed correlations between microRNAs (miRNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas (TCGA) database. The expression levels of miR-455, miR-143, and miR-99a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed miR-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of miR-455 was significantly and positively correlated to the prognosis and overall survival (OS) of the BC (P=0.028), according to TCGA information. The expression level of miR-455 was positively correlated with OS and relapse-free survival (RFS) of patients with Her-2-positive BC, and was negatively correlated with the number of metastatic lymph nodes (P<0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive (P<0.01) after being transfected with miR-455 mimics. During the qRT-PCR, the expression level of MALAT1 declined significantly after transfection (P<0.01). Overexpressed miR-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that miR-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. miR-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.
Collapse
Affiliation(s)
- En-Qi Qiao
- Department of Breast Surgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China
| | - Hong-Jian Yang
- Department of Breast Surgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China
| | - Xi-Ping Zhang
- Department of Breast Surgery, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China
| |
Collapse
|
|
10
|
Zhang K, Wang YY, Xu Y, Zhang L, Zhu J, Si PC, Wang YW, Ma R. A two-miRNA signature of upregulated miR-185-5p and miR-362-5p as a blood biomarker for breast cancer. Pathol Res Pract 2021; 222:153458. [PMID: 33962174 DOI: 10.1016/j.prp.2021.153458] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/24/2021] [Accepted: 04/24/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Differentially expressed microRNAs (miRNAs) in the blood of breast cancer patients may serve as diagnostic biomarkers. METHODS In this study, miRNA microarray of the blood of breast cancer patients and healthy controls was performed. Candidate differentially expressed miRNAs were further verified by real-time polymerase chain reaction in 68 breast cancer patients and 13 healthy controls. RESULTS Six upregulated blood miRNAs (miR-26b-5p, miR-106b-5p, miR-142-3p, miR-142-5p, miR-185-5p, and miR-362-5p) were identified in breast cancer patients. These six miRNAs could discriminate breast cancer patients from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.8891, 0.8158, 0.8529, 0.8507, 0.9050, and 0.9333, respectively. Bioinformatic analysis showed that the six miRNAs were potentially involved in numerous cancer-related pathways, including the mitogen-activated protein kinase signaling pathway, nuclear factor-kappa B signaling pathway, and the transforming growth factor-beta signaling pathway. Importantly, two miRNAs (miR-185-5p and miR-362-5p) were used to construct a two-miRNA panel by logistic regression. The two-miRNA panel displayed a better diagnostic performance than each of the miRNAs alone, with a higher AUC (0.957), sensitivity (92.65 %), and specificity (92.31 %). Additionally, the high expression of the six miRNAs or the two-miRNA panel was associated with poor prognosis of breast cancer. CONCLUSIONS We identified six upregulated miRNAs and a two-miRNA panel in the blood as potential biomarkers for the diagnosis and prognosis of breast cancer.
Collapse
Affiliation(s)
- Kai Zhang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China
| | - Yan-Yan Wang
- Health Management Center, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China
| | - Yao Xu
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China
| | - Li Zhang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China
| | - Jiang Zhu
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China
| | - Peng-Chao Si
- Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials (Ministry of Education), Research Center for Carbon Nanomaterials, School of Materials Science and Engineering, Shandong University, Jinan, 250061, Shandong, People's Republic of China
| | - Ya-Wen Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China.
| | - Rong Ma
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China.
| |
Collapse
|
|
11
|
Expression of Estrogen Receptor- and Progesterone Receptor-Regulating MicroRNAs in Breast Cancer. Genes (Basel) 2021; 12:genes12040582. [PMID: 33923732 PMCID: PMC8073827 DOI: 10.3390/genes12040582] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/17/2022] Open
Abstract
In ~70% of breast cancer (BC) cases, estrogen and progesterone receptors (ER and PR) are overexpressed, which can change during tumor progression. Expression changes of these receptors during cancer initiation and progression can be caused by alterations in microRNA (miR, miRNA) expression. To assess the association of BC progression with aberrant expression of miRNAs that target ER and PR mRNAs, we quantified miR-19b, -222, -22, -378a, and -181a in BC samples (n = 174) by real-time PCR. Underexpression of miR-222 and miR-378a in stage T2–T4 BC was characteristic for HER2-overexpressing tumors. In addition, the expression of miR-181a and miR-378a was higher in these tumors than in tumors with a HER2 IHC score of 0 or 1+. In tumors with a Ki-67 index ≥ 14%, all tested miRNAs were underexpressed in BC with a high Allred PR score (6–8). In ER-and-PR–negative tumors, miR-22, miR-222, miR-181a, and miR-378a underexpression was associated with Ki-67 index > 35% (median value). MiR-19b and miR-22 underexpression could be a marker of lymph node metastasis in ER- and/or PR-positive tumors with HER2 IHC score 0. Thus, the association of miR-19b, miR-22, miR-222, miR-378a, and miR-181a levels with BC characteristics is influenced by the status of tumor ER, PR, HER2, and Ki-67.
Collapse
|
|
12
|
Zhao Y, Zhang H, Ju Q, Li X, Zheng Y. Comprehensive Analysis of Survival-Related lncRNAs, miRNAs, and mRNAs Forming a Competing Endogenous RNA Network in Gastric Cancer. Front Genet 2021; 12:610501. [PMID: 33737947 PMCID: PMC7960915 DOI: 10.3389/fgene.2021.610501] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
To analyze and construct a survival-related endogenous RNA (ceRNA) network in gastric cancer (GC) with lymph node metastasis, we obtained expression profiles of long non-coding RNAs (lncRNAs), mRNAs, and microRNAs (miRNAs) in GC from The Cancer Genome Atlas database. The edgeR package was used to screen differentially expressed lncRNAs, mRNAs, and miRNAs between GC patients with lymphatic metastasis and those without lymphatic metastasis. Then, we used univariate Cox regression analysis to identify survival-related differentially expressed RNAs. In addition, we used multivariate Cox regression analysis to screen lncRNAs, miRNAs, and mRNAs for use in the prognostic prediction models. The results showed that 2,247 lncRNAs, 155 miRNAs, and 1,253 mRNAs were differentially expressed between the two patient groups. Using univariate Cox regression analysis, we found that 395 lncRNAs, eight miRNAs, and 180 mRNAs were significantly related to the survival time of GC patients. We next created a survival-related network consisting of 59 lncRNAs, seven miRNAs, and 36 mRNAs. In addition, we identified eight RNAs associated with prognosis by multivariate Cox regression analysis, comprising three lncRNAs (AC094104.2, AC010457.1, and AC091832.1), two miRNAs (miR-653-5p and miR-3923), and three mRNAs (C5orf46, EPHA8, and HPR); these were used to construct the prognostic prediction models, and their risk scores could be used to assess GC patients' prognosis. In conclusion, this study provides new insights into ceRNA networks in GC and the screening of prognostic biomarkers for GC.
Collapse
Affiliation(s)
- Yanjie Zhao
- School of Public Health, Qingdao University, Qingdao, China
| | - Heng Zhang
- School of Public Health, Qingdao University, Qingdao, China
| | - Qiang Ju
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xinmei Li
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao, China
| |
Collapse
|
|
13
|
Chen G, Wan J, Wang Z, Li L, Jia H, Xing S, Chen S, Fan X, Li R. miR-3196 acts as a Tumor Suppressor and Predicts Survival Outcomes in Patients With Gastric Cancer. Technol Cancer Res Treat 2021; 19:1533033820923427. [PMID: 32419651 PMCID: PMC7235653 DOI: 10.1177/1533033820923427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastric cancer is one of the most common malignancies worldwide with high mortality. Therefore, identifying cancer-related biomarkers for predicting prognosis and progression of gastric cancer is essential. This study aimed to investigate the clinical value and functional role of microRNA-3196 in gastric cancer. METHODS The relative expression levels of microRNA-3196 in gastric cancer tissues and adjacent normal tissues were detected by quantitative reverse transcription-polymerase chain reaction. In this study, quantitative reverse transcription-polymerase chain reaction, cell proliferation assay, and Transwell migration and invasion assays were performed to explore microRNA-3196 expression level and its effects on cell proliferation, migration, and invasion in gastric cancer cells. The Kaplan-Meier method and multivariate Cox regression analyses were used to explore the prognostic significance of microRNA-3196 in gastric cancer. Dual-luciferase report assay was performed to validate the potential target gene regulated by microRNA-3196 in gastric cancer. RESULTS The expression of microRNA-3196 was downregulated in gastric cancer tissues and cell lines. Downregulation of microRNA-3196 was associated with lymph node metastasis and Tumor Node Metastasis (TNM) stage. The Kaplan-Meier curve analysis indicated that patients with low expression of microRNA-3196 had a poor prognosis, and the Cox regression analysis results showed microRNA-3196 expression was an independent prognostic factor of gastric cancer. Moreover, overexpression of microRNA-3196 inhibited cell proliferation, migration, and invasion, while knockdown of microRNA-3196 promoted these cellular behaviors in AGS and MKN45 cells. OTX1 may be a potential target gene regulated by microRNA-3196 in gastric cancer. CONCLUSIONS These results suggested that microRNA-3196 might not only a tumor suppressor in gastric cancer cells by modulating OTX1 but also might be an independent prognostic biomarker and therapeutic target of gastric cancer.
Collapse
Affiliation(s)
- Guo Chen
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Jinliang Wan
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Zhenbo Wang
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Lei Li
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Hongying Jia
- Operating Room, People's Hospital of Yangxin County, Binzhou, Shandong, China
| | - Shaozhi Xing
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Shaoshui Chen
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xiaocheng Fan
- Department of Oncology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Rui Li
- Department of Ultrasound, Binzhou Medical University Hospital, Binzhou, Shandong, China
| |
Collapse
|
|
14
|
FCGCNMDA: predicting miRNA-disease associations by applying fully connected graph convolutional networks. Mol Genet Genomics 2020; 295:1197-1209. [DOI: 10.1007/s00438-020-01693-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/27/2020] [Indexed: 01/02/2023]
|
|
15
|
Alexandrova E, Lamberti J, Saggese P, Pecoraro G, Memoli D, Mirici Cappa V, Ravo M, Iorio R, Tarallo R, Rizzo F, Collina F, Cantile M, Di Bonito M, Botti G, Nassa G, Weisz A, Giurato G. Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer. Cells 2020; 9:cells9040874. [PMID: 32260128 PMCID: PMC7226848 DOI: 10.3390/cells9040874] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/30/2020] [Accepted: 04/01/2020] [Indexed: 12/17/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.
Collapse
Affiliation(s)
- Elena Alexandrova
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
- Genomix4Life Srl, 84081 Baronissi, Italy
| | - Jessica Lamberti
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Pasquale Saggese
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Domenico Memoli
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Valeria Mirici Cappa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Maria Ravo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
- Genomix4Life Srl, 84081 Baronissi, Italy
| | | | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Francesca Collina
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Monica Cantile
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Maurizio Di Bonito
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Gerardo Botti
- Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
- Correspondence: (A.W.); (G.G.); Tel.: + 39-089-965043 (A.W.)
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy
- Correspondence: (A.W.); (G.G.); Tel.: + 39-089-965043 (A.W.)
| |
Collapse
|
|
16
|
Kiliç N, Islakoğlu YÖ, Büyük İ, Gür-Dedeoğlu B, Cansaran-Duman D. Determination of Usnic Acid Responsive miRNAs in Breast Cancer Cell Lines. Anticancer Agents Med Chem 2020; 19:1463-1472. [PMID: 30417797 DOI: 10.2174/1871520618666181112120142] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/17/2018] [Accepted: 10/28/2018] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Breast Cancer (BC) is the most common type of cancer diagnosed in women. A common treatment strategy for BC is still not available because of its molecular heterogeneity and resistance is developed in most of the patients through the course of treatment. Therefore, alternative medicine resources as being novel treatment options are needed to be used for the treatment of BC. Usnic Acid (UA) that is one of the secondary metabolites of lichens used for different purposes in the field of medicine and its anti-proliferative effect has been shown in certain cancer types, suggesting its potential use for the treatment. METHODS Anti-proliferative effect of UA in BC cells (MDA-MB-231, MCF-7, BT-474) was identified through MTT analysis. Microarray analysis was performed in cells treated with the effective concentration of UA and UA-responsive miRNAs were detected. Their targets and the pathways that they involve were determined using a miRNA target prediction tool. RESULTS Microarray experiments showed that 67 miRNAs were specifically responsive to UA in MDA-MB-231 cells while 15 and 8 were specific to BT-474 and MCF-7 cells, respectively. The miRNA targets were mostly found to play role in Hedgehog signaling pathway. TGF-Beta, MAPK and apoptosis pathways were also the prominent ones according to the miRNA enrichment analysis. CONCLUSION The current study is important as being the first study in the literature which aimed to explore the UA related miRNAs, their targets and molecular pathways that may have roles in the BC. The results of pathway enrichment analysis and anti-proliferative effects of UA support the idea that UA might be used as a potential alternative therapeutic agent for BC treatment.
Collapse
Affiliation(s)
- Nil Kiliç
- Ankara University, Biotechnology Institute, System Biotechnology Advance Research Unit, Tandogan, Ankara, Turkey
| | - Yasemin Ö Islakoğlu
- Ankara University, Biotechnology Institute, System Biotechnology Advance Research Unit, Tandogan, Ankara, Turkey
| | - İlker Büyük
- Ankara University, Science Faculty, Biology Department, Tandogan, Ankara, Turkey
| | - Bala Gür-Dedeoğlu
- Ankara University, Biotechnology Institute, System Biotechnology Advance Research Unit, Tandogan, Ankara, Turkey
| | - Demet Cansaran-Duman
- Ankara University, Biotechnology Institute, System Biotechnology Advance Research Unit, Tandogan, Ankara, Turkey
| |
Collapse
|
|
17
|
Yang X, Zhang Z, Zhang L, Zhou L. MicroRNA hsa-mir-3923 serves as a diagnostic and prognostic biomarker for gastric carcinoma. Sci Rep 2020; 10:4672. [PMID: 32170105 PMCID: PMC7070044 DOI: 10.1038/s41598-020-61633-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 03/01/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric carcinoma (GC) refers to a common digestive system disease that exhibits a very high incidence. MicroRNA hsa-mir-3923 belongs to a type of miRNA, of which the function has been merely investigated in breast, pancreatic cancers and pre-neoplasic stages of gastric cancer. It has not been studied or reported in gastric carcinoma, so the relationship between gastric hsa-mir-3923 expression and the clinics feature and pathology of GC cases was examined. This study employed data mining for analyzing gastric carcinoma data in The Cancer Genome Atlas database. A Chi squared test was performed for assessing the relations of hsa-mir-3923 expression with clinics-related and pathology-regulated variables. This study conducted the assessment of the role of hsa-mir-3923 in prognostic process using Kaplan-Meier curves, Receiver operating characteristic (ROC) analysis and proportional hazards model (Cox) study. With the use of Gene Expression Omnibus, this study carried out gene set enrichment analysis (GSEA). In the meantime, the common miRNA database was compared to predict potential target genes; as revealed by co-expression analysis, a regulatory network probably existed, containing hsa-mir-3923. For the analysis of the most tightly associated cytological behavior and pathway in GC, this study adopted the databases for Annotation, Visualization and Integrated Discovery (David) and KO-Based Annotation System (KOBAS). Cytoscape, R and STRING were employed for mapping probable regulatory networks displaying relations to hsa-mir-3923. Lastly, we obtained 69 genes most tightly associated with hsa-mir-3923 and described their relationship with Circos plot. As revealed from the results, hsa-mir-3923 displayed up-regulation in gastric carcinoma, and it displayed associations with vital status, N stage and histologic grade when being expressed. The predicted results of miRNA target genes suggested that there may be a close relationship between 66 genes and hsa-mir-3923 in gastric cancer. As indicated from co-expression data, a small regulating network of 4 genes probably existed. Our results elucidated that hsa-mir-3923 high-expression reveals poor prognosis of GC patients.
Collapse
Affiliation(s)
- Xiaohui Yang
- Department of Obstetrics & Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Ze Zhang
- Department of General Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Lichao Zhang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Li Zhou
- Department of Obstetrics & Gynecology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| |
Collapse
|
|
18
|
Rong HT, Liu DW. Identification of differentially expressed miRNAs associated with thermal injury in epidermal stem cells based on RNA-sequencing. Exp Ther Med 2020; 19:2218-2228. [PMID: 32104287 PMCID: PMC7027234 DOI: 10.3892/etm.2020.8448] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 11/06/2019] [Indexed: 12/27/2022] Open
Abstract
Current research indicates that epidermal stem cells (EpSCs) play an important role in promoting wound healing, but the mechanism of action of these cells during wound repair following thermal damage remains unclear. In the present study, the trypsin digestion method was used to isolate human EpSCs and the cells were incubated in a 51.5°C water tank for 35 sec to construct a thermal injury model. The differentially expressed miRNAs were identified using high-throughput sequencing technology, and bioinformatic methods were used to predict their target genes and signaling pathways that may be involved in wound repair. A total of 33 miRNAs including, hsa-miR-1973, hsa-miR-4485-3p, hsa-miR-548-5p, hsa-miR-212-3p and hsa-miR-4461 were upregulated, whereas 21 miRNAs including, hsa-miR-4520-5p, hsa-miR-4661-5p, hsa-miR-191-3p, hsa-miR-129-5p, hsa-miR-147b and hsa-miR-6868-3p were downregulated following thermal injury of the human EpSCs. The bioinformatic analysis indicated that the differentially expressed miRNAs are involved in biological processes such as cell proliferation and differentiation, cell growth apoptosis, cell adhesion and migration. The results showed that there is a differential expression pattern of miRNAs after thermal injury of human EpSCs and these differences are involved in the regulation of the wound healing process. These findings provide new clues for further study of the wound healing mechanism and targeted therapy.
Collapse
Affiliation(s)
- Hao-Tian Rong
- Burns Institute, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- First Clinical Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - De-Wu Liu
- Burns Institute, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| |
Collapse
|
|
19
|
Ozawa PMM, Vieira E, Lemos DS, Souza ILM, Zanata SM, Pankievicz VC, Tuleski TR, Souza EM, Wowk PF, Urban CDA, Kuroda F, Lima RS, Almeida RC, Gradia DF, Cavalli IJ, Cavalli LR, Malheiros D, Ribeiro EMSF. Identification of miRNAs Enriched in Extracellular Vesicles Derived from Serum Samples of Breast Cancer Patients. Biomolecules 2020; 10:E150. [PMID: 31963351 PMCID: PMC7022833 DOI: 10.3390/biom10010150] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/10/2020] [Accepted: 01/15/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs derived from extracellular vesicles (EV-miRNAs) are circulating miRNAs considered as potential new diagnostic markers for cancer that can be easily detected in liquid biopsies. In this study, we performed RNA sequencing analysis as a screening strategy to identify EV-miRNAs derived from serum of clinically well-annotated breast cancer (BC) patients from the south of Brazil. EVs from three groups of samples (healthy controls (CT), luminal A (LA), and triple-negative (TNBC)) were isolated from serum using a precipitation method and analyzed by RNA-seq (screening phase). Subsequently, four EV-miRNAs (miR-142-5p, miR-150-5p, miR-320a, and miR-4433b-5p) were selected to be quantified by quantitative real-time PCR (RT-qPCR) in individual samples (test phase). A panel composed of miR-142-5p, miR-320a, and miR-4433b-5p distinguished BC patients from CT with an area under the curve (AUC) of 0.8387 (93.33% sensitivity, 68.75% specificity). The combination of miR-142-5p and miR-320a distinguished LA patients from CT with an AUC of 0.9410 (100% sensitivity, 93.80% specificity). Interestingly, decreased expression of miR-142-5p and miR-150-5p were significantly associated with more advanced tumor grades (grade III), while the decreased expression of miR-142-5p and miR-320a was associated with a larger tumor size. These results provide insights into the potential application of EVs-miRNAs from serum as novel specific markers for early diagnosis of BC.
Collapse
Affiliation(s)
- Patricia M. M. Ozawa
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Evelyn Vieira
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Débora S. Lemos
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Ingrid L. Melo Souza
- Department of Cell and Molecular Biology, Federal University of Paraná, Curitiba 81531-980, Brazil; (I.L.M.S.); (S.M.Z.)
| | - Silvio M. Zanata
- Department of Cell and Molecular Biology, Federal University of Paraná, Curitiba 81531-980, Brazil; (I.L.M.S.); (S.M.Z.)
| | - Vânia C. Pankievicz
- Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba 81531-980, Brazil; (V.C.P.); (T.R.T.); (E.M.S.)
| | - Thalita R. Tuleski
- Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba 81531-980, Brazil; (V.C.P.); (T.R.T.); (E.M.S.)
| | - Emanuel M. Souza
- Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba 81531-980, Brazil; (V.C.P.); (T.R.T.); (E.M.S.)
| | - Pryscilla F. Wowk
- Carlos Chagas Institute - Fiocruz-Paraná, Curitiba 81350-010, Brazil;
| | - Cícero de Andrade Urban
- Positivo University Medical School, Curitiba 81280-330, Brazil
- Nossa Senhora das Graças Hospital Breast Unit, Curitiba 80810-040, Brazil; (F.K.); (R.S.L.)
| | - Flavia Kuroda
- Nossa Senhora das Graças Hospital Breast Unit, Curitiba 80810-040, Brazil; (F.K.); (R.S.L.)
| | - Rubens S. Lima
- Nossa Senhora das Graças Hospital Breast Unit, Curitiba 80810-040, Brazil; (F.K.); (R.S.L.)
| | - Rodrigo C. Almeida
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
- Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, 2300 R Leiden, The Netherlands
| | - Daniela F. Gradia
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Iglenir J. Cavalli
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Luciane R. Cavalli
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA;
- Research Institute Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba 80230-020, Brazil
| | - Danielle Malheiros
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| | - Enilze M. S. F. Ribeiro
- Department of Genetics, Federal University of Paraná, Curitiba 81531-980, Brazil; (P.M.M.O.); (E.V.); (D.S.L.); (R.C.A.); (D.F.G.); (I.J.C.)
| |
Collapse
|
|
20
|
Bai H, Wu S. miR-451: A Novel Biomarker and Potential Therapeutic Target for Cancer. Onco Targets Ther 2019; 12:11069-11082. [PMID: 31908476 PMCID: PMC6924581 DOI: 10.2147/ott.s230963] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/28/2019] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded small RNAs involved in a variety of cellular processes, including ontogeny, cell proliferation, differentiation, and apoptosis. They can also function as oncogenes or tumor suppressor genes. Recent studies have revealed that miRNA-451 (miR-451) is involved in the regulation of various human physiological and pathological processes. Furthermore, it has been shown that miR-451 not only directly affects the biological functions of tumor cells but also indirectly affects tumor cell invasion and metastasis upon secretion into the tumor microenvironment via exosomes. Thus, miR-451 also influences the progression of tumorigenesis and drug resistance. This review summarizes the expression of miR-451 in various cancer types and the relationship between miR-451 and the diagnosis, treatment, and drug resistance of solid tumors. In addition, we address possible mechanisms of action of miR-451 and its potential application as a biomarker in the diagnosis and treatment of human cancers.
Collapse
Affiliation(s)
- Hua Bai
- Department of Gynecology and Obstetrics, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Suhui Wu
- Department of Gynecology and Obstetrics, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| |
Collapse
|
|
21
|
Zhang W, Xu J, Wang K, Tang X, He J. miR‑139‑3p suppresses the invasion and migration properties of breast cancer cells by targeting RAB1A. Oncol Rep 2019; 42:1699-1708. [PMID: 31485677 PMCID: PMC6775813 DOI: 10.3892/or.2019.7297] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Accumulated evidence indicates that aberrant microRNAs (miRNAs) expression plays an important role in the initiation and progression of various cancers, including breast cancer. Previous studies suggested that miR-139-3p might serve as a tumor suppressor and is downregulated in several cancer types. However, the expression patterns and exact role of miR-139-3p in breast cancer remain to be elucidated. In this study, we aimed to analyze the effect of miR-139-3p on the progression of breast cancer and the mechanism involved. Through bioinformatics analysis and in vitro experimental studies, we found that miR-139-3p was decreased in breast cancer tissues and cell lines, and decreased miR-139-3p is associated with a poor prognosis in breast cancer patients. Overexpression of miR-139-3p by transfection significantly inhibits cell proliferation, migration, and invasion of breast cancer cells. Bioinformatics analysis and luciferase reporter gene assay confirmed that RAB1A was a potential target of miR-139-3p. Furthermore, overexpression of RAB1A counteracted the suppressing effects of miR-139-3p on breast cancer cell migration, invasion and epithelial-to-mesenchymal transition (EMT). Taken together, these data suggest that miR-139-3p plays a tumor suppressive role in breast cancer by targeting RAB1A and may serve as a potential new biomarker for breast cancer prognosis.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jing Xu
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ke Wang
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaojiang Tang
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jianjun He
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
22
|
Klinge CM, Piell KM, Tooley CS, Rouchka EC. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Sci Rep 2019; 9:9430. [PMID: 31263129 PMCID: PMC6603045 DOI: 10.1038/s41598-019-45636-8] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2/B1) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers, readers, and erasers of m6A and report that HNRNPA2/B1 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental, tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA2/B1 affects miRNA expression, HNRNPA2/B1 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated, respectively, 48 h after transfection and 177 and 172 up- and down-regulated, respectively, 72 h after transfection. MetaCore Enrichment analysis identified progesterone receptor action and transforming growth factor β (TGFβ) signaling via miRNA in breast cancer as pathways downstream of the upregulated miRNAs and TGFβ signaling via SMADs and Notch signaling as pathways of the downregulated miRNAs. GO biological processes for mRNA targets of HNRNPA2/B1-regulated miRNAs included response to estradiol and cell-substrate adhesion. qPCR confirmed HNRNPA2B1 downregulation of miR-29a-3p, miR-29b-3p, and miR-222 and upregulation of miR-1266-5p, miR-1268a, miR-671-3p. Transient overexpression of HNRNPA2/B1 reduced MCF-7 sensitivity to 4-hydroxytamoxifen and fulvestrant, suggesting a role for HNRNPA2/B1 in endocrine-resistance.
Collapse
Affiliation(s)
- Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
| | - Kellianne M Piell
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Christine Schaner Tooley
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14203, USA
| | - Eric C Rouchka
- Bioinformatics and Biomedical Computing Laboratory, Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40292, USA
| |
Collapse
|
|
23
|
Alqurashi N, Hashimi SM, Alowaidi F, Ivanovski S, Farag A, Wei MQ. miR-496, miR-1185, miR-654, miR-3183 and miR-495 are downregulated in colorectal cancer cells and have putative roles in the mTOR pathway. Oncol Lett 2019; 18:1657-1668. [PMID: 31423233 PMCID: PMC6614670 DOI: 10.3892/ol.2019.10508] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/02/2019] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by suppressing the target mRNA and inhibiting translation in order to regulate multiple biological processes. miRNAs play important roles as oncogenes or tumor suppressors in the development of various types of human cancer. The regulation of mammalian target of rapamycin (mTOR) by miRNAs has been studied in several types of cancer, including colorectal cancer (CRC). However, to the best of our knowledge, only limited information regarding the function of miRNAs in human CRC is available. In the present study, the expression of 22 miRNAs in CRC cell lines were investigated in regard to key genes in the mTOR pathway. Initially, it was revealed that mTOR, regulatory-associated protein of mTOR complex I and rapamycin-intensive companion of mTOR were overexpressed in CRC cell lines when compared with a normal colorectal cell line. Subsequently, putative miRNA-mRNA associations were identified via multiple miRNA target prediction programs. The expression levels for the candidate miRNAs were validated using quantitative real-time polymerase chain reaction. Expression analysis revealed that, among 20 miRNAs, five miRNAs (miR-496, miR-1185, miR-654, miR-3183 and miR-495) exhibited significant downregulation in association with the mTOR signaling pathway. Taken together, the results from the present study suggest that several miRNAs that are associated with CRC, with possible roles in mTOR signaling, may have potential therapeutic or diagnostic benefits in CRC treatment.
Collapse
Affiliation(s)
- Naif Alqurashi
- Department of Basic Science, Deanship of Preparatory Year and Supporting Studies, and Department of Stem Cells, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Saeed M Hashimi
- Department of Basic Science, Deanship of Preparatory Year and Supporting Studies, and Department of Stem Cells, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Faisal Alowaidi
- Department of Pathology and Laboratory Medicine, College of Medicine and University Hospitals, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saso Ivanovski
- School of Dentistry, The University of Queensland, Brisbane, QLD 4006, Australia
| | - Amro Farag
- School of Dentistry, The University of Queensland, Brisbane, QLD 4006, Australia
| | - Ming Q Wei
- Division of Molecular and Gene Therapies, School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia
| |
Collapse
|
|
24
|
Upregulation of the long noncoding RNA ADPGK-AS1 promotes carcinogenesis and predicts poor prognosis in gastric cancer. Biochem Biophys Res Commun 2019; 513:127-134. [PMID: 30944080 DOI: 10.1016/j.bbrc.2019.03.140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 03/21/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Numerous previous studies have revealed that many long non-coding RNAs (lncRNAs) are upregulated in gastric cancer (GC) and are associated with tumor onset and progression in GC. ADPGK-AS1, a novel lncRNA, has been discovered as an oncogenic lncRNA in pancreatic cancer while its function in GC remains unclear. MATERIALS AND METHODS The expression of ADPGK-AS1 and miR-3196 was determined by RT-qPCR. The expression of KDM1B was assessed by RT-qPCR and WB. The association between ADPGK-AS1 and overall survival of GC patients was explored using Kaplan-Meier curves. The function of ADPGK-AS1 in GC was examined through CCK-8, EdU, transwell as well as flow cytometry analysis. The interaction of miR-3196 and ADPGK-AS1 or KDM1B was confirmed by RIP, RNA pull down and luciferase reporter assay.Materials and Methods RESULTS: ADPGK-AS1 was increased in GC tissues and cell lines. GC patients with an increased expression of ADPGK-AS1 had a poor prognosis compared to those with a reduced expression. ADPGK-AS1 knockdown led to inhibition of GC cell proliferation and migration. The suppressive effect of ADPGK-AS1 silence on GC progression was abolished by KDM1B upregulation.Results CONCLUSIONS: We unveiled that ADPGK-AS1 could promote GC progression via sponging miR-3196 and therefore upregulating KDM1B, providing a novel prognostic biomarker and therapeutic target for GC patients. CONCLUSIONS
Collapse
|
|
25
|
McAnena P, Lowery A, Kerin MJ. Role of micro-RNAs in breast cancer surgery. Br J Surg 2018; 105:e19-e30. [PMID: 29341144 DOI: 10.1002/bjs.10790] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND The management of breast cancer has changed dramatically in the molecular era. Micro-RNAs can contribute to multiple facets of cancer surgery. METHODS This narrative review, based on years of research on the role of micro-RNAs, focused on the potential of these small, robust RNAs to influence all aspects of breast cancer surgery. RESULTS Micro-RNAs have a potential role as biomarkers in the diagnosis, prognosis and evaluation of response to therapy in breast cancer. They may also contribute to future therapeutic strategies. CONCLUSION The molecular era has changed understanding of cancer. Micro-RNAs have the potential for use in personalized cancer strategies.
Collapse
Affiliation(s)
- P McAnena
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland, Galway, Ireland
| | - A Lowery
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland, Galway, Ireland
| | - M J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland, Galway, Ireland
| |
Collapse
|
|
26
|
Shiino S, Matsuzaki J, Shimomura A, Kawauchi J, Takizawa S, Sakamoto H, Aoki Y, Yoshida M, Tamura K, Kato K, Kinoshita T, Kitagawa Y, Ochiya T. Serum miRNA-based Prediction of Axillary Lymph Node Metastasis in Breast Cancer. Clin Cancer Res 2018; 25:1817-1827. [PMID: 30482779 DOI: 10.1158/1078-0432.ccr-18-1414] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 09/07/2018] [Accepted: 11/20/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. RESULTS An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84-0.92), a specificity of 0.69 (0.61-0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. CONCLUSIONS Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.
Collapse
Affiliation(s)
- Sho Shiino
- Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan.,Keio University School of Medicine, Tokyo, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Akihiko Shimomura
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | | | | | - Hiromi Sakamoto
- Department of Biobank and Tissue Resources, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Masayuki Yoshida
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Kenji Tamura
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takayuki Kinoshita
- Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
| |
Collapse
|
|
27
|
Li Y, Wang Y, Fan H, Zhang Z, Li N. miR-125b-5p inhibits breast cancer cell proliferation, migration and invasion by targeting KIAA1522. Biochem Biophys Res Commun 2018; 504:277-282. [PMID: 30177391 DOI: 10.1016/j.bbrc.2018.08.172] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Abnormal gene expression due to the dysregulation of microRNAs (miRNAs) often occurred in the initiation or progression of cancers. The aim of this present study was to investigate the function role of miR-125b-5p in breast cancer (BC). Expression levels of miR-125b-5p were determined by quantitative Real-time PCR. Biological functions of miR-125b-5p in the progression of BC were investigated with a series of in vitro experiments including cell counting kit-8 assay, colony formation assay, wound-healing assay and transwell invasion assay. The target of miR-125b-5p in BC was validated by luciferase activity reporter assay and western blot assay. We found miR-125b-5p expression was significantly reduced in BC cell lines compared to the normal breast epithelial cell line. Functional assays showed that cell proliferation, colony formation ability, cell migration, and cell invasion can be suppressed by miR-125b-5p overexpression. Besides, KIAA1522 was validated as a direct target of miR-125b-5p in BC. Collectively, our study showed that miR-125b-5p functions as a tumor suppressor and regulates BC progression through targeting KIAA1522.
Collapse
Affiliation(s)
- Yongzhen Li
- Department of Pathology, Xinxiang Medical University, No. 601 Jinsui Avenue, Hongqi District, Xinxiang, 453003, PR China
| | - Yongxia Wang
- Department of Pathology, Xinxiang Medical University, No. 601 Jinsui Avenue, Hongqi District, Xinxiang, 453003, PR China
| | - Hongzhe Fan
- Cardiothoracic Surgery, The Third Affiliated Hospital of Xinxiang Medical University, East Hualan Avenue, Hongqi District, Xinxiang, 453000, PR China
| | - Zheying Zhang
- Department of Pathology, Xinxiang Medical University, No. 601 Jinsui Avenue, Hongqi District, Xinxiang, 453003, PR China
| | - Na Li
- Department of Pathology, Xinxiang Medical University, No. 601 Jinsui Avenue, Hongqi District, Xinxiang, 453003, PR China.
| |
Collapse
|
|
28
|
Zhang L, Cao Y, Wei M, Jiang X, Jia D. Long noncoding RNA‐RNCR3 overexpression deleteriously affects the growth of glioblastoma cells through miR‐185‐5p/Krüppel‐like factor 16 axis. J Cell Biochem 2018; 119:9081-9089. [PMID: 29953649 DOI: 10.1002/jcb.27167] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/14/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Liang Zhang
- Department of Neurosurgery Tangdu Hospital, The Fourth Military Medical University Xi’an Shaanxi China
| | - Yidong Cao
- Department of Neurosurgery Tangdu Hospital, The Fourth Military Medical University Xi’an Shaanxi China
| | - Minghao Wei
- Department of Neurosurgery Tangdu Hospital, The Fourth Military Medical University Xi’an Shaanxi China
| | - Xue Jiang
- Operating Room Tangdu Hospital, The Fourth Military Medical University Xi’an Shaanxi China
| | - Dong Jia
- Department of Neurosurgery Tangdu Hospital, The Fourth Military Medical University Xi’an Shaanxi China
| |
Collapse
|
|
29
|
The microRNA expression signature of CD4+ T cells in the transition of brucellosis into chronicity. PLoS One 2018; 13:e0198659. [PMID: 29897958 PMCID: PMC5999269 DOI: 10.1371/journal.pone.0198659] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/23/2018] [Indexed: 12/19/2022] Open
Abstract
Brucellosis is a serious infectious disease that continues to be a significant cause of morbidity worldwide and across all ages. Despite early diagnosis and treatment, 10–30% of patients develop chronic brucellosis. Although there have been recent advances in our knowledge of Brucella virulence factors and hosts’ immune response to the infection, there is a lack of clear data regarding how the infection bypasses the immune system and becomes chronic. The present study investigated immunological factors and their roles in the transition of brucellosis from an acute to a chronic infection in CD4+ T cells. CD4+ T cells sorted from peripheral blood samples of patients with acute or chronic brucellosis and healthy controls using flow cytometry as well as more than 2000 miRNAs were screened using the GeneSpring GX (Agilent) 13.0 miRNA microarray software and were validated using reverse transcription polymerase chain reaction (RT-qPCR). Compared to acute cases, the expression levels of 28 miRNAs were significantly altered in chronic cases. Apart from one miRNA (miR-4649-3p), 27 miRNAs were not expressed in the acute cases (p <0.05, fold change> 2). According to KEGG pathway analysis, these miRNAs are involved in the regulation of target genes that were previously involved in the MAPK signalling pathway, regulation of the actin cytoskeleton, endocytosis, and protein processing in the endoplasmic reticulum. This indicates the potential role of these miRNAs in the development of chronic brucellosis. We suggest that these miRNAs can be used as markers to determine the transition of the disease into chronicity. This is the first study of miRNA expression that analyses human CD4+ T cells to clarify the mechanism of chronicity in brucellosis.
Collapse
|
|
30
|
MicroRNA‑142‑5p modulates breast cancer cell proliferation and apoptosis by targeting phosphatase and tensin homolog. Mol Med Rep 2018; 17:7529-7536. [PMID: 29620260 PMCID: PMC5983952 DOI: 10.3892/mmr.2018.8812] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 01/12/2018] [Indexed: 12/11/2022] Open
Abstract
A total of 60 breast cancer (BC) tissues and adjacent healthy tissues from patients who underwent surgery in Renmin Hospital of Wuhan University were collected for analysis in the present study. Results from reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) demonstrated that, compared with the adjacent healthy tissues, the expression levels of microRNA (miR)‑142‑5p were significantly elevated in BC tissues. Bioinformatics analysis was performed using TargetScan for the prediction of potential target sites that matched the seed region of miR‑142‑5p; phosphatase and tensin homolog (PTEN) exhibited the highest score and was selected for further analysis. Results of RT‑qPCR analysis demonstrated that, compared with the adjacent healthy tissues, the mRNA expression levels of PTEN were significantly decreased in breast cancer tissues. miR‑142‑5p and PTEN expression levels were positively and negatively associated, respectively, with patient tumor size and metastasis. MDA‑MB‑231 cells were divided into three groups including the Control group, the miR‑NC inhibitor group and the miR‑142‑5p inhibitor group. As for alterations in cell behavior, including cell viability and cell apoptosis, and protein expression levels, there were no significant differences between Control and miR‑NC inhibitor groups. MTT assay results revealed that, compared with Control and miR‑NC inhibitor groups, miR‑142‑5p inhibitor reduced MDA‑MB‑231 cell proliferation. Flow cytometric analysis demonstrated that, compared with Control and miR‑NC inhibitor groups, miR‑142‑5p inhibitor treatment induced MDA‑MB‑231 cell apoptosis. Western blotting results demonstrated that, compared with Control and miR‑NC inhibitor groups, miR‑142‑5p inhibitor treatment significantly increased the expression of PTEN, reduced the activation of phosphatidylinositol‑4,5‑bisphosphate 3‑kinase/RACα serine/threonine‑protein kinase signaling. Finally, PTEN was demonstrated to interact with miR‑142‑5p from the results of dual‑luciferase reporter assay in the present study. The findings of the present study suggested that miR‑142‑5p may be a potential therapeutic target for the future investigations and insights for breast cancer.
Collapse
|
|
31
|
Xu C, Zhang L, Duan L, Lu C. MicroRNA-3196 is inhibited by H2AX phosphorylation and attenuates lung cancer cell apoptosis by downregulating PUMA. Oncotarget 2018; 7:77764-77776. [PMID: 27780918 PMCID: PMC5363619 DOI: 10.18632/oncotarget.12794] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 10/14/2016] [Indexed: 12/30/2022] Open
Abstract
Histone H2AX is a tumor suppressor protein that plays an important role in apoptosis. However, the mechanism underlying the association of H2AX with apoptosis in cancer cells remains elusive. Here, we showed that H2AX knockdown in lung cancer A549 cells affected the expression of 16 microRNAs (miRNAs), resulting in the downregulation of 1 and the upregulation of 15 miRNAs. MicroRNA-3196 (miR-3196) was identified as a target of H2AX and shown to inhibit apoptosis in lung cancer cells by targeting p53 upregulated modulator of apoptosis (PUMA). Phosphorylated H2AX (γH2AX) was shown to bind to the promoter of miR-3196 and regulate its expression. In addition, H2AX phosphorylation increased H3K27 trimethylation in the promoter region of miR-3196 and inhibited the binding of RNA polymerase II to the promoter of miR-3196, leading to the inhibition of miR-3196 transcription. Taken together, these results indicated that H2AX phosphorylation regulates apoptosis in lung cancer cells via the miR-3196/PUMA pathway.
Collapse
Affiliation(s)
- Chengshan Xu
- Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China.,Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Ling Zhang
- Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China
| | - Lianning Duan
- Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China
| | - Chengrong Lu
- Aviation Medicine Research Laboratory, Air Force General Hospital, PLA, Beijing 100142, China
| |
Collapse
|
|
32
|
The SNPs in pre-miRNA are related to the response of capecitabine-based therapy in advanced colon cancer patients. Oncotarget 2018; 9:6793-6799. [PMID: 29467929 PMCID: PMC5805515 DOI: 10.18632/oncotarget.23190] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/01/2017] [Indexed: 12/21/2022] Open
Abstract
The single nucleotide polymorphisms (SNPs) in the microRNA precursor (pre-miRNA) may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to chemotherapy. Here we investigated the correlation between 23 SNPs in the pre-miRNA and the efficacy of capecitabine-based chemotherapy in 274 advanced colon cancer patients. Statistical analysis indicated that much more patients with rs744591 A/C(48.03%), C/C (53.45%) or C allele (49.73%) responded to the chemotherapy than those with the A/A genotype (33.71%). The response rates of rs745666 G/C heterozygous patients (35.25%) and C allele carriers (39.69%) were apparently less than that of the G/G homozygous patients (56.25%). Moreover, three SNPs rs2114358, rs35770269, and rs73239138 were significantly associated with the occurrence of side effects of chemotherapy. The patients with rs2114358 C allele (OR = 2.016) or rs35770269 T allele (OR = 2.299) were much more prone to endure adverse events. However, the incidence of side effect was lower in the patients carrying rs73239138 A allele than those with G/G genotype (OR = 0.500). Our findings demonstrate that genetic variations in pre-miRNA may influence the efficacy of capecitabine-based chemotherapy in advanced colon cancer patients.
Collapse
|
|
33
|
Zhu QN, Renaud H, Guo Y. Bioinformatics-based identification of miR-542-5p as a predictive biomarker in breast cancer therapy. Hereditas 2018; 155:17. [PMID: 29371858 PMCID: PMC5769523 DOI: 10.1186/s41065-018-0055-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 01/04/2018] [Indexed: 01/04/2023] Open
Abstract
Background Tamoxifen is the first-line hormone therapy for estrogen receptor alpha positive (ERα+) breast cancer. However, about 40% of patients with ERα + breast cancer who receive tamoxifen therapy eventually develop resistance resulting in a poor prognosis. The aim of this study was to mine available data sets in the Gene Expression Omnibus (GEO) database, including in vitro (cell lines) and in vivo (tissue samples), and to identify all miRNAs associated with tamoxifen resistance (TamR) in breast cancer. Secondly, this study aimed to predict the key gene regulatory networks of newly found TamR-related miRNAs and evaluate the potential role of the miRNAs and targets as potential prognosis biomarkers for breast cancer patients. Result Microarray data sets from two different studies were used from the GEO database: 1. GSE66607: miRNA of MCF-7 TamR cells; 2. GSE37405: TamR tissues. Differentially expressed microRNAs (miRNAs) were identified in both data sets and 5 differentially expressed miRNAs were found to overlap between the two data sets. Profiles of GSE37405 and data from the Kaplan-Meier Plotter Database (KMPD) along with Gene Expression Profiling Interactive Analysis (GEPIA) were used to reveal the relationship between these 5 miRNAs and overall survival. The results showed that has-miR-542-5p was the only miRNA associated with overall survival of ERα + breast cancer patients who received adjuvant tamoxifen. Targets of has-miR-542-5p were predicted by miRanda and TargetScan, and the mRNA expression of the three 3 target gene, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Beta (YWHAB), Lymphocyte Antigen 9 (LY9), and Secreted Frizzled Related Protein 1 (SFRP1) were associated with overall survival in 2 different databases. Copy-number alterations (CNAs) of SFRP1 confer survival disadvantage to breast cancer patients and alter the mRNA expression of SFRP1 in cBioPortal database. Conclusion This study indicates that miRNA has-miR-542-5p is associated with TamR and can predict prognosis of breast cancer patients. Furthermore, has-miR-542-5p may be acting through a mechanism involving the target genes YWHAB, LY9, and SFRP1. Overall, has-miR-542-5p is a predictive biomarker and potential target for therapy of breast cancer patients. Electronic supplementary material The online version of this article (10.1186/s41065-018-0055-7) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Qiong-Ni Zhu
- 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008 People's Republic of China.,2Institute of Clinical Pharmacology, Central South University, Changsha, 410078 People's Republic of China.,3Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078 People's Republic of China
| | - Helen Renaud
- 4University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Ying Guo
- 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008 People's Republic of China.,2Institute of Clinical Pharmacology, Central South University, Changsha, 410078 People's Republic of China.,3Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078 People's Republic of China
| |
Collapse
|
|
34
|
Zeng L, Zhong J, He G, Li F, Li J, Zhou W, Liu W, Zhang Y, Huang S, Liu Z, Deng X. Identification of Nucleobindin-2 as a Potential Biomarker for Breast Cancer Metastasis Using iTRAQ-based Quantitative Proteomic Analysis. J Cancer 2017; 8:3062-3069. [PMID: 28928897 PMCID: PMC5604457 DOI: 10.7150/jca.19619] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 03/17/2017] [Indexed: 12/19/2022] Open
Abstract
Metastasis is a lethal step in the progression of breast cancer. None of the metastasis-associated biomarkers identified up to now has a definite prognostic value in breast cancer patients. This study was designed to identify biomarkers for breast cancer metastasis and predictors of the prognosis of breast cancer patients. The differentially expressed proteins between 23 paired primary breast tumor and metastatic lymph nodes were identified by quantitative iTRAQ proteomic analysis. Immunohistochemistry was applied to locate and assess the expression of NUCB2 in paired primary breast tumor and metastatic lymph node tissues (n = 106). The relationship between NUCB2 expression and the clinicopathological characteristics of breast cancer patients (n = 189) were analyzed by χ2 test. Kaplan-Meier analysis and Cox hazard regression analysis were utilized to investigate the relationship between its expression and prognosis of breast cancer patients. The iTRAQ proteomic results showed that 4,837 confidential proteins were identified, 643 of which were differentially expressed in the primary breast cancer tissues and the paired metastatic lymph nodes. NUCB2 protein was found decreased in paired metastatic lymph nodes (P = 0.000), with the positive expression rate being 82% in primary breast cancer tissues and 47% in paired metastatic lymph nodes, respectively. According to Kaplan-Meier analysis, the overall survival time of patients with positive expression of NUCB2 protein were shorter than those with negative NUCB2 expression (P = 0.004). Cox regression model suggested that NUCB2 was a risk factor of breast cancer patients (P = 0.045, RR = 1.854). We conclude that NUCB2 can be used as a potential biomarker for breast cancer metastasis and a prognostic predictor of breast cancer patients.
Collapse
Affiliation(s)
- Liang Zeng
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China.,Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Jingmin Zhong
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Guangchun He
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan 410013, China
| | - Fangjun Li
- Department of Social Medicine, Hunan Provincial People's Hospital & The Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410007, China
| | - Jing Li
- Department of Breast Internal Medicine, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wen Zhou
- Key Laboratory of Cancer of the Ministry of Health, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan 4100078, China
| | - Wenbin Liu
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Yun Zhang
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Sanqian Huang
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Zhihong Liu
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Xiyun Deng
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan 410013, China
| |
Collapse
|
|
35
|
Cui YX, Bradbury R, Flamini V, Wu B, Jordan N, Jiang WG. MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells. Br J Cancer 2017; 117:89-101. [PMID: 28571043 PMCID: PMC5563947 DOI: 10.1038/bjc.2017.156] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/02/2017] [Accepted: 05/11/2017] [Indexed: 01/24/2023] Open
Abstract
Background: MicroRNA-7 (miR-7) has been observed as a potent tumour suppressor in multiple cancer types including breast cancer. The aim of this study was to investigate the response sensitivities of metastatic breast cancer cells to miR-7 and the roles of miR-7 in the interaction of endothelial cells and metastatic cancer cells. Methods: Expression profile of miRNAs in a breast cancer specimen cohort and breast cancer cells were determined using real-time quantitative miRNA assays. Effect of the altering expression of miR-7 on migration, invasion, proliferation, interaction and underlying molecular mechanism of breast cancer cells and endothelial cells was investigated after treatment with the synthesised mimic of miR-7. Luciferase activity analysis was performed to validate Wave-3 as a novel target of miR-7. Results: miR-7 expression was negatively correlated with the stage, grade and survival of the breast cancer patients. There was also differential expression of miRNAs including miR-7 in the breast cancer cells. The synthesised mimic of miR-7 inhibits the motility and wound healing potential of breast cancer cells. The highly metastatic MDA-MB-231 cells are more sensitive to the miR-7 treatment than the poorly invasive MCF-7 cells. Treatment with miR-7 downregulated the expression of EGFR, IGF1R and Wave3 in MDA-MB-231 cells but not in MCF-7 cells. In addition, we further demonstrated that miR-7 inhibited the proliferation, migration and invasion of endothelial cells. And more importantly, miR-7 suppressed the homing and migration of endothelial cells to more aggressive tumour cell conditions. Conclusions: Given the dual inhibitory effect of miR-7 on metastatic breast cancer cells alone and the interaction of endothelial cells with the tumour-conditioned microenvironment, we suggest miR-7 may be a new therapeutic candidate for its capacity not only to prevent breast cancer cell spreading but also to inhibit tumour-associated angiogenesis in the metastatic breast cancer.
Collapse
Affiliation(s)
- Yu-Xin Cui
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Robyn Bradbury
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Valentina Flamini
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Bo Wu
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.,Department of Histology and Embryology, Key Laboratory of Cancer Metastasis (Beijing), Capital Medical University, Beijing 100069, China
| | - Nicola Jordan
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| |
Collapse
|
|
36
|
Nikitina AS, Sharova EI, Danilenko SA, Butusova TB, Vasiliev AO, Govorov AV, Prilepskaya EA, Pushkar DY, Kostryukova ES. Novel RNA biomarkers of prostate cancer revealed by RNA-seq analysis of formalin-fixed samples obtained from Russian patients. Oncotarget 2017; 8:32990-33001. [PMID: 28380430 PMCID: PMC5464844 DOI: 10.18632/oncotarget.16518] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/15/2017] [Indexed: 01/23/2023] Open
Abstract
Due to heterogeneous multifocal nature of prostate cancer (PCa), there is currently a lack of biomarkers that stably distinguish it from benign prostatic hyperplasia (BPH), predict clinical outcome and guide the choice of optimal treatment. In this study RNA-seq analysis was applied to formalin-fixed paraffin-embedded (FFPE) tumor and matched normal tissue samples collected from Russian patients with PCa and BPH. We identified 3384 genes differentially expressed (DE) (FDR < 0.05) between tumor tissue of PCa patients and adjacent normal tissue as well as both tissue types from BPH patients. Overexpression of four of the discovered genes (ANKRD34B, NEK5, KCNG3, and PTPRT) was validated by RT-qPCR. Furthermore, the enrichment analysis of overrepresented microRNA and transcription factor (TF) recognition sites within DE genes revealed common regulatory elements of which 13 microRNAs and 53 TFs were thus linked to PCa for the first time. Moreover, 8 of these TFs (FOXJ2, GATA6, NFE2L1, NFIL3, PRRX2, TEF, EBF2 and ZBTB18) were found to be differentially expressed in this study making them not only candidate biomarkers of prostate cancer but also potential therapeutic targets.
Collapse
Affiliation(s)
- Anastasia S. Nikitina
- Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
- Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia
| | - Elena I. Sharova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
| | | | - Tatiana B. Butusova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
| | - Alexandr O. Vasiliev
- Department of Urology, Moscow State Medical Stomatological University, Moscow, Russia
| | - Alexandr V. Govorov
- Department of Urology, Moscow State Medical Stomatological University, Moscow, Russia
| | - Elena A. Prilepskaya
- Department of Urology, Moscow State Medical Stomatological University, Moscow, Russia
| | - Dmitry Y. Pushkar
- Department of Urology, Moscow State Medical Stomatological University, Moscow, Russia
| | - Elena S. Kostryukova
- Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
- Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia
| |
Collapse
|
|
37
|
Guo Y, Qi Y, Guo A, Du C, Zhang R, Chu X. miR-564 is downregulated in gastric carcinoma and targets E2F3. Oncol Lett 2017; 13:4155-4160. [PMID: 28588702 DOI: 10.3892/ol.2017.5964] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/27/2017] [Indexed: 12/17/2022] Open
Abstract
Numerous aberrantly expressed microRNAs (miRNAs/miRs) have been identified in gastric cancer (GC); however, only a fraction of these have been functionally investigated and novel deregulated miRNAs in GC remain to be explored. Through examining two public miRNA expression profile datasets, the present study identified aberrantly expressed miRNAs in GC. One of these miRNA, miR-564, was identified to be downregulated in GC, which was validated in tissue samples from patients with GC by reverse transcription-quantitative polymerase chain reaction analysis. Targets of miR-564 were then predicted bioinformatically, including transcription factor E2F3 (E2F3), which was identified to be functionally enriched in several cancer signaling pathways. Furthermore, overexpression of miR-564 decreased the activity of a luciferase reporter carrying the 3'-untranslated region of E2F3, in addition to the mRNA and protein level of E2F3, indicating that miR-564 directly targets E2F3. These data suggest that by targeting E2F3, miR-564 may act as a tumor suppressor gene in gastric carcinogenesis.
Collapse
Affiliation(s)
- Yong Guo
- Department of Pathology, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Yong Qi
- Outpatient Department, The People's Liberation Army Naval University of Engineering, Wuhan, Hubei 430033, P.R. China
| | - Aitao Guo
- Department of Pathology, The General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
| | - Chengxiong Du
- Department of General Surgery, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Rong Zhang
- Clinical Laboratory, Liuhuaqiao Hospital, Guangzhou, Guangdong 510010, P.R. China
| | - Xiaoyong Chu
- Medical Clinic of Military Economy Academy of the People's Liberation Army, Wuhan, Hubei 430035, P.R. China
| |
Collapse
|
|
38
|
Kang H, Rho JG, Kim C, Tak H, Lee H, Ji E, Ahn S, Shin AR, Cho HI, Huh YH, Song WK, Kim W, Lee EK. The miR-24-3p/p130Cas: a novel axis regulating the migration and invasion of cancer cells. Sci Rep 2017; 7:44847. [PMID: 28337997 PMCID: PMC5364481 DOI: 10.1038/srep44847] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 02/14/2017] [Indexed: 01/08/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by suppressing translation or facilitating mRNA decay. Differential expression of miRNAs is involved in the pathogenesis of several diseases including cancer. Here, we investigated the role of-miR-24-3p as a downregulated miRNA in metastatic cancer. miR-24-3p was decreased in metastatic cancer and lower expression of miR-24-3p was related to poor survival of cancer patients. Consistently, ectopic expression of miR-24-3p suppressed the cell migration, invasion, and proliferation of MCF7, Hep3B, B16F10, SK-Hep1, and PC-3 cells by directly targeting p130Cas. Stable expression of p130Cas restored miR-24-3p-mediated inhibition of cell migration and invasion. These results suggest that miR-24-3p functions as a tumor suppressor and the miR-24-3p/p130Cas axis is a novel factor of cancer progression by regulating cell migration and invasion.
Collapse
Affiliation(s)
- Hoin Kang
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jun Gi Rho
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Chongtae Kim
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyosun Tak
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Heejin Lee
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Eunbyul Ji
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sojin Ahn
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - A-Ri Shin
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, South Korea
| | - Hyun-Il Cho
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, South Korea
| | - Yun Hyun Huh
- Department of Life Science, Bio Imaging and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju, South Korea
| | - Woo Keun Song
- Department of Life Science, Bio Imaging and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju, South Korea
| | - Wook Kim
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Eun Kyung Lee
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Cancer Evolution Research Center, The Catholic University of Korea, Seoul, South Korea
| |
Collapse
|
|
39
|
Wu S, Gu Y, Huang Y, Wong TC, Ding H, Liu T, Zhang Y, Zhang X. Novel Biomarkers for Non-functioning Invasive Pituitary Adenomas were Identified by Using Analysis of microRNAs Expression Profile. Biochem Genet 2017; 55:253-267. [DOI: 10.1007/s10528-017-9794-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/10/2017] [Indexed: 01/08/2023]
|
|
40
|
A comparison of serum miRNAs influencing metastatic growth of EMT6 vs 4THM tumor cells in wild-type and CD200R1KO mice. Breast Cancer Res Treat 2017; 162:255-266. [DOI: 10.1007/s10549-017-4128-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 01/20/2017] [Indexed: 01/11/2023]
|
|
41
|
Zhang L, Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zhao XM. A microRNA-based prediction model for lymph node metastasis in hepatocellular carcinoma. Oncotarget 2016; 7:3587-98. [PMID: 26657296 PMCID: PMC4823129 DOI: 10.18632/oncotarget.6534] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 11/22/2015] [Indexed: 12/17/2022] Open
Abstract
We developed an efficient microRNA (miRNA) model that could predict the risk of lymph node metastasis (LNM) in hepatocellular carcinoma (HCC). We first evaluated a training cohort of 192 HCC patients after hepatectomy and found five LNM associated predictive factors: vascular invasion, Barcelona Clinic Liver Cancer stage, miR-145, miR-31, and miR-92a. The five statistically independent factors were used to develop a predictive model. The predictive value of the miRNA-based model was confirmed in a validation cohort of 209 consecutive HCC patients. The prediction model was scored for LNM risk from 0 to 8. The cutoff value 4 was used to distinguish high-risk and low-risk groups. The model sensitivity and specificity was 69.6 and 80.2 %, respectively, during 5 years in the validation cohort. And the area under the curve (AUC) for the miRNA-based prognostic model was 0.860. The 5-year positive and negative predictive values of the model in the validation cohort were 30.3 and 95.5 %, respectively. Cox regression analysis revealed that the LNM hazard ratio of the high-risk versus low-risk groups was 11.751 (95 % CI, 5.110–27.021; P < 0.001) in the validation cohort. In conclusion, the miRNA-based model is reliable and accurate for the early prediction of LNM in patients with HCC.
Collapse
Affiliation(s)
- Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zuo-Lin Xiang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhao-You Tang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiao-Mei Zhao
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
42
|
Pan Y, Jiao G, Wang C, Yang J, Yang W. MicroRNA-421 inhibits breast cancer metastasis by targeting metastasis associated 1. Biomed Pharmacother 2016; 83:1398-1406. [PMID: 27583980 DOI: 10.1016/j.biopha.2016.08.058] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/16/2016] [Accepted: 08/24/2016] [Indexed: 12/21/2022] Open
Abstract
Dysregulation of microRNAs is involved in the initiation and progression of several human cancers, including breast cancer, as strong evidence of miRNAs acting as oncogenes or tumour suppressor genes has been found. This study was performed to investigate the biological functions of microRNA-421 (miR-421) in breast cancer and the underlying mechanisms. The expression level of miR-421 was detected in 50 pairs of surgical specimens and human breast cancer cell lines. The results showed that miR-421 is downregulated in breast cancer tissues and metastatic cell lines. In addition, the decrease in miR-421 levels was significantly associated with lymph node metastasis, recurrence/metastasis, or pTNM stage. Functions of miR-421 in cell migration and invasion were assessed through its silencing and overexpression. The results showed that miR-421 knockdown promotes invasion and metastasis in MCF-7 cells and its overexpression suppresses invasion and metastasis in MDA-MB-231 cells. The specific target genes of miR-421 were predicted by TargetScan algorithm and determined by dual luciferase reporter assay, quantitative reverse transcriptase PCR, and western blot analysis. miR-421 could suppress luciferase activity of the reporter containing 3'-untranslated region of metastasis associated 1 (MTA1), a potent oncogene. miR-421 overexpression or knockdown had no effect on the mRNA expression of MTA1, but it could modulate MTA1 protein level. Furthermore, MTA1 knockdown receded the effect of miR-421 inhibitor on invasion and metastasis of MCF-7 cells, and its overexpression receded the effect of miR-421 on invasion and metastasis of MDA-MB-231 cells. Our findings clearly demonstrate that miR-421 suppresses breast cancer metastasis by directly inhibiting MTA1 expression. The present study provides a new insight into the tumour suppressor roles of miR-421 and suggests that miR-421/MTA1 pathway is a putative therapeutic target in breast cancer.
Collapse
Affiliation(s)
- Yongqin Pan
- Department of General Surgery, First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China
| | - Genlong Jiao
- Department of Orthopedics, First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China
| | - Cunchuan Wang
- Department of General Surgery, First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China.
| | - Jingge Yang
- Department of General Surgery, First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China.
| | - Wah Yang
- Department of General Surgery, First Affiliated Hospital of Jinan University, Guangzhou, 510632, PR China
| |
Collapse
|
|
43
|
Qian F, Feng Y, Zheng Y, Ogundiran TO, Ojengbede O, Zheng W, Blot W, Ambrosone CB, John EM, Bernstein L, Hu JJ, Ziegler RG, Nyante S, Bandera EV, Ingles SA, Press MF, Nathanson KL, Hennis A, Nemesure B, Ambs S, Kolonel LN, Olopade OI, Haiman CA, Huo D. Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry. Hum Genet 2016; 135:1145-59. [PMID: 27380242 DOI: 10.1007/s00439-016-1707-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/25/2016] [Indexed: 10/21/2022]
Abstract
MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.
Collapse
Affiliation(s)
- Frank Qian
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Ye Feng
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Yonglan Zheng
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Temidayo O Ogundiran
- Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Oladosu Ojengbede
- Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
| | - William Blot
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
| | | | - Esther M John
- Cancer Prevention Institute of California, Fremont, CA, USA.,Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine Stanford, Stanford, CA, USA
| | - Leslie Bernstein
- Division of Cancer Etiology, Department of Population Science, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Jennifer J Hu
- Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Regina G Ziegler
- Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, DC, USA
| | - Sarah Nyante
- Department of Epidemiology, Gillings School of Global Public Health and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Elisa V Bandera
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Sue A Ingles
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Michael F Press
- Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | | | - Anselm Hennis
- Chronic Disease Research Centre and Tropical Medicine Research Institute, University of the West Indies, Bridgetown, Barbados
| | - Barbara Nemesure
- Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA
| | - Laurence N Kolonel
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Dezheng Huo
- Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave., MC 2007, Chicago, IL, 60637, USA.
| |
Collapse
|
|
44
|
Transcriptome sequencing uncovers a three-long noncoding RNA signature in predicting breast cancer survival. Sci Rep 2016; 6:27931. [PMID: 27338266 PMCID: PMC4919625 DOI: 10.1038/srep27931] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 05/26/2016] [Indexed: 12/11/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) play a crucial role in tumorigenesis. The aim of this study is to identify lncRNA signature that can predict breast cancer patient survival. RNA expression data from 1064 patients were downloaded from The Cancer Genome Atlas project. Cox regression, Kaplan–Meier, and receiver operating characteristic (ROC) analyses were performed to construct a model for predicting the overall survival (OS) of patients and evaluate it. A model consisting of three lncRNA genes (CAT104, LINC01234, and STXBP5-AS1) was identified. The Kaplan–Meier analysis and ROC curves proved that the model could predict the prognostic survival with good sensitivity and specificity in both the validation set (AUC = 0.752, 95% confidence intervals (CI): 0.651–0.854) and the microarray dataset (AUC = 0.714, 95%CI: 0.615–0.814). Further study showed the three-lncRNA signature was not only pervasive in different breast cancer stages, subtypes and age groups, but also provides more accurate prognostic information than some widely known biomarkers. The results suggested that RNA-seq transcriptome profiling provides that the three-lncRNA signature is an independent prognostic biomarker, and have clinical significance. In addition, lncRNA, miRNA, and mRNA interaction network indicated lncRNAs may intervene in breast cancer pathogenesis by binding to miR-190b, acting as competing endogenous RNAs.
Collapse
|
|
45
|
Rhodes LV, Martin EC, Segar HC, Miller DFB, Buechlein A, Rusch DB, Nephew KP, Burow ME, Collins-Burow BM. Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer. Oncotarget 2016; 6:16638-52. [PMID: 26062653 PMCID: PMC4599295 DOI: 10.18632/oncotarget.3184] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/23/2015] [Indexed: 12/31/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR-200b-3p over-expression represses EMT, which is evident through decreased migration and increased CDH1 expression. Despite the loss of migratory capacity following re-expression of miR-200b-3p, no subsequent loss of the conventional miR-200 family targets and EMT markers ZEB1/2 was observed. Next generation RNA-sequencing analysis showed that enhanced expression of pri-miR-200b lead to ectopic expression of both miR-200b-3p and miR-200b-5p with multiple isomiRs expressed for each of these miRNAs. Furthermore, miR-200b-5p was expressed in the receptor positive, epithelial breast cancer cell lines but not in the TNBC (mesenchymal) cell lines. In addition, a compensatory mechanism for miR-200b-3p/200b-5p targeting, where both miRNAs target the RHOGDI pathway leading to non-canonical repression of EMT, was demonstrated. Collectively, these data are the first to demonstrate dual targeting by miR-200b-3p and miR-200b-5p and a previously undescribed role for microRNA processing and strand expression in EMT and TNBC, the most aggressive breast cancer subtype.
Collapse
Affiliation(s)
- Lyndsay V Rhodes
- Department of Biological Sciences, Florida Gulf Coast University, Fort Myers, FL, USA
| | - Elizabeth C Martin
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA
| | - H Chris Segar
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA
| | - David F B Miller
- Medical Sciences and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA
| | - Aaron Buechlein
- Indiana University Center for Genomics and Bioinformatics, Bloomington, IN, USA
| | - Douglas B Rusch
- Indiana University Center for Genomics and Bioinformatics, Bloomington, IN, USA
| | - Kenneth P Nephew
- Medical Sciences and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA
| | - Matthew E Burow
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA.,Department of Pharmacology, Tulane University, New Orleans, LA, USA
| | - Bridgette M Collins-Burow
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA
| |
Collapse
|
|
46
|
Al-Khanbashi M, Caramuta S, Alajmi AM, Al-Haddabi I, Al-Riyami M, Lui WO, Al-Moundhri MS. Tissue and Serum miRNA Profile in Locally Advanced Breast Cancer (LABC) in Response to Neo-Adjuvant Chemotherapy (NAC) Treatment. PLoS One 2016; 11:e0152032. [PMID: 27064979 PMCID: PMC4827834 DOI: 10.1371/journal.pone.0152032] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 03/08/2016] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) are small non-coding RNA that plays a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. METHODS Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, and Spearman, Wilcoxon signed-ranks tests. P≤0.05 was considered statistically significant. RESULTS We analyzed 72 tissue samples and 108 serum samples from 9 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. This is one of the early reports on miR-3200 in response to treatment in breast cancer, as serum levels of miR-3200 found to decline during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates at time of diagnosis. CONCLUSION Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes.
Collapse
Affiliation(s)
- Manal Al-Khanbashi
- Medical Oncology Unit, Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Stefano Caramuta
- Department of Oncology-Pathology, Karolinska institute, Cancer Center Karolinska, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Adil M. Alajmi
- Department of Surgery, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Ibrahim Al-Haddabi
- Department of Pathology, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Marwa Al-Riyami
- Department of Pathology, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Weng-Onn Lui
- Department of Oncology-Pathology, Karolinska institute, Cancer Center Karolinska, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Mansour S. Al-Moundhri
- Medical Oncology Unit, Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| |
Collapse
|
|
47
|
Gao S, Zhou F, Zhao C, Ma Z, Jia R, Liang S, Zhang M, Zhu X, Zhang P, Wang L, Su F, Zhao J, Liu G, Peng B, Feng X. Gastric cardia adenocarcinoma microRNA profiling in Chinese patients. Tumour Biol 2016; 37:9411-22. [PMID: 26781873 DOI: 10.1007/s13277-016-4824-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 01/08/2016] [Indexed: 12/13/2022] Open
Abstract
Gastric cardia adenocarcinoma (GCA), which occurs at the gastroesophageal boundary, is one of the most malignant types of cancer. Over the past 30 years, the incidence of GCA has increased by approximately sevenfold, which has a more substantial increase than that of many other malignancies. However, as previous studies mainly focus on non-cardia gastric cancer, until now, the mechanisms behind GCA remain largely unknown. MicroRNAs (miRNAs) have been shown to play pivotal roles in carcinogenesis. To gain insight into the molecular mechanisms regulated by miRNAs in GCA development, we investigated miRNA expression profiles using 81 pairs of primary GCAs and corresponding non-tumorigenic tissues. First, 21 pairs of samples were used for microarray analysis, and then another 60 pairs of samples were used for further analysis. Our results showed that 464 miRNAs (237 upregulated, 227 downregulated, false discovery rate FDR <0.05) were differently expressed between GCA and non-tumor tissues. Pearson test and pathway analysis revealed that these dysregulated miRNA correlated coding RNAs may have effects on several cancer-related pathways. Four miRNAs (miR-1244, miR-135b-5p, miR-3196, and miR-628-3p) were found to be associated with GCA differentiation. One miRNA, miR-196a-5p, was found to be associated with age of GCA onset. Further, survival analysis showed that the expression level of miR-135b-5p was associated with GCA survival. Taken together, our study first provided the genome-wide expression profiles of miRNA in GCA and will be good help for further functional studies.
Collapse
Affiliation(s)
- Shegan Gao
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Fuyou Zhou
- Department of Oncology, Anyang People's Hospital, Anyang, 471500, China
| | - Chen Zhao
- Fudan-Zhangjiang Center for Clinical Genomics, Zuchongzhi Road 899, Shanghai, 201203, China
| | - Zhikun Ma
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Ruinuo Jia
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Shuo Liang
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Mengxi Zhang
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Xiaojuan Zhu
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Pengfei Zhang
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Lu Wang
- Zhangjiang Center for Translational Medicine, Zuchongzhi Road 899, Shanghai, 201203, China
| | - Feng Su
- Zhangjiang Center for Translational Medicine, Zuchongzhi Road 899, Shanghai, 201203, China
| | - Jiangman Zhao
- Zhangjiang Center for Translational Medicine, Zuchongzhi Road 899, Shanghai, 201203, China
| | - Gang Liu
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China
| | - Bo Peng
- Zhangjiang Center for Translational Medicine, Zuchongzhi Road 899, Shanghai, 201203, China.
| | - Xiaoshan Feng
- Henan Key Laboratory of Cancer Epigenetic; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China, 471003, Luoyang, 471003, China. .,Henan University of Science and Technology, Jing hua Road 24, Luoyang, 471500, China.
| |
Collapse
|
|
48
|
Xu W, Luo F, Sun B, Ye H, Li J, Shi L, Liu Y, Lu X, Wang B, Wang Q, Liu Q, Zhang A. HIF-2α, acting via miR-191, is involved in angiogenesis and metastasis of arsenite-transformed HBE cells. Toxicol Res (Camb) 2016; 5:66-78. [PMID: 30090327 PMCID: PMC6060623 DOI: 10.1039/c5tx00225g] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 11/02/2015] [Indexed: 12/11/2022] Open
Abstract
Arsenic is a well established human carcinogen that causes diseases of the lung. Some studies have suggested that hypoxia-inducible factors (HIFs) and microRNAs (miRNAs) are involved in human lung cancer; however, their molecular mechanisms that causally contribute to arsenite-caused malignant transformation of cells remain unclear. To elucidate the mechanisms of angiogenesis and metastasis of lung cancer caused by arsenite, we investigated the role of HIF-2α regulation of miRNA-191 (miR-191) in the angiogenic and metastatic properties of human bronchial epithelial (HBE) cells transformed by arsenite. In HBE cells, HIF-2α binds to the hypoxia response element (HRE) in the promoter region of miR-191 and initiates transcription of miR-191. Blocking of HIF-2α with siRNA inhibited the up-regulation of miR-191, Wilms' tumor 1 (WT1) protein, matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor (VEGF), and the down-regulation of brain acid-soluble protein 1 (BASP1). In arsenite-transformed HBE (T-HBE) cells, down-regulation of HIF-2α by siRNA blocked the process of angiogenesis and decreased their neoplastic properties and metastatic capacity, which were reversed by over-expression of miR-191 or by up-regulating WT1. Thus, HIF-2α up-regulates WT1 via miR-191, both of which are involved in the angiogenesis and metastasis of T-HBE cells. The results present a better understanding of the processes involved in lung cancer caused by arsenite exposure.
Collapse
Affiliation(s)
- Wenchao Xu
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Fei Luo
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Baofei Sun
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control , Ministry of Education , School of Public Health , Guiyang Medical University , Guiyang 550025 , Guizhou , People's Republic of China . ; ; Tel: +86-851-8841-6171
| | - Hua Ye
- School of Medicine , Yangzhou University , Yangzhou 225009 , Jiangsu , People's Republic of China
| | - Jun Li
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control , Ministry of Education , School of Public Health , Guiyang Medical University , Guiyang 550025 , Guizhou , People's Republic of China . ; ; Tel: +86-851-8841-6171
| | - Le Shi
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Yi Liu
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Xiaolin Lu
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Bairu Wang
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Qingling Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control , Ministry of Education , School of Public Health , Guiyang Medical University , Guiyang 550025 , Guizhou , People's Republic of China . ; ; Tel: +86-851-8841-6171
| | - Qizhan Liu
- Institute of Toxicology , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China
- The Key Laboratory of Modern Toxicology , Ministry of Education , School of Public Health , Nanjing Medical University , Nanjing 211166 , Jiangsu , People's Republic of China . ; ; Tel: +86-25-8686-8424
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control , Ministry of Education , School of Public Health , Guiyang Medical University , Guiyang 550025 , Guizhou , People's Republic of China . ; ; Tel: +86-851-8841-6171
| |
Collapse
|
|
49
|
Liu Q, Liao F, Wu H, Cai T, Yang L, Fang J. Different expression of miR-29b and VEGFA in glioma. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2015; 44:1927-1932. [DOI: 10.3109/21691401.2015.1111237] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
50
|
Jing R, Chen W, Wang H, Ju S, Cong H, Sun B, Jin Q, Chu S, Xu L, Cui M. Plasma miR-185 is decreased in patients with esophageal squamous cell carcinoma and might suppress tumor migration and invasion by targeting RAGE. Am J Physiol Gastrointest Liver Physiol 2015; 309:G719-29. [PMID: 26316588 DOI: 10.1152/ajpgi.00078.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/13/2015] [Indexed: 01/31/2023]
Abstract
The receptor for advanced-glycation end products (RAGE) is upregulated in various cancers and has been associated with tumor progression, but little is known about its expression and regulation by microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). Here, we describe miR-185, which represses RAGE expression, and investigate the biological role of miR-185 in ESCC. In this study, we found that the high level of RAGE expression in 29 pairs of paraffin-embedded ESCC tissues was correlated positively with the depth of invasion by immunohistochemistry, suggesting that RAGE was involved in ESCC. We used bioinformatics searches and luciferase reporter assays to investigate the prediction that RAGE was regulated directly by miR-185. Besides, overexpression of miR-185 in ESCC cells was accompanied by 27% (TE-11) and 49% (Eca-109) reduced RAGE expression. The effect was further confirmed in RAGE protein by immunofluorescence in both cell lines. The effects were reversed following cotransfection with miR-185 and high-level expression of the RAGE vector. Furthermore, the biological role of miR-185 in ESCC cell lines was investigated using assays of cell viability, Ki-67 staining, and cell migration and invasion, as well as in a xenograft model. We found that overexpression of miR-185 inhibited migration and invasion by ESCC cells in vitro and reduced their capacity to develop distal pulmonary metastases in vivo partly through the RAGE/heat shock protein 27 pathway. Interestingly, in clinical specimens, the level of plasma miR-185 expression was decreased significantly (P = 0.002) in patients with ESCC [0.500; 95% confidence interval (CI) 0.248-1.676] compared with healthy controls (2.410; 95% CI 0.612-5.671). The value of the area under the receiver-operating characteristic curve was 0.73 (95% CI 0.604-0.855). In conclusion, our findings shed novel light on the role of miR-185/RAGE in ESCC metastasis, and plasma miR-185 has potential as a novel diagnostic biomarker in ESCC.
Collapse
Affiliation(s)
- Rongrong Jing
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wen Chen
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Huimin Wang
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Hui Cong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Baolan Sun
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaopeng Chu
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Lili Xu
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Cui
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China;
| |
Collapse
|