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1
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Wang J, Huang W, Chai S, Gan J, Zeng Y, Long P, Pang L. A comprehensive analysis of CEBPA on prognosis and function in uterine corpus endometrial carcinoma. Sci Rep 2024; 14:23773. [PMID: 39390018 PMCID: PMC11467350 DOI: 10.1038/s41598-024-74242-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024] Open
Abstract
Uterine corpus endometrial carcinoma (UCEC) is one of the most common tumours of the female reproductive system. CCAAT enhancer-binding protein alpha (CEBPA) is a member of the transcription factor family involved in regulating processes such as cell proliferation, differentiation, metabolism, and the immune response. However, the role of CEBPA in UCEC has not been clarified. Here, we performed a comprehensive analysis to explore the expression level, prognostic value, immune infiltration and biological function of CEBPA in UCEC. In this study, we found that CEBPA expression was upregulated and associated with poor prognosis in UCEC patients. KEGG and GO analyses revealed that the genes positively correlated with CEBPA were enriched primarily in immune regulation and oxidative phosphorylation. Immune infiltration analysis revealed that CEBPA is strongly correlated with immune cell infiltration in UCEC. RT-qPCR indicated that CEBPA may regulate the OXPHOS level in Ishikawa cells. CCK-8, cell cycle, Transwell and scratch wound healing assays revealed that CEBPA promoted Ishikawa cell proliferation, invasion and migration. In addition, PPI and survival analyses suggested that CEBPG may be a potential target of CEBPA in UCEC. These results demonstrated that CEBPA may be a potential therapeutic target in UCEC.
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Affiliation(s)
- Jiaxing Wang
- Department of Prenatal Diagnosis, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Thalassemia Research, Nanning, Guangxi, China
- National Health Commission Key Laboratory of Thalassemia Medicine (Guangxi Medical University), Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
| | - Weiyu Huang
- Department of Reproductive Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shiwei Chai
- Department of Gynecology, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan, China
| | - Jiayi Gan
- Department of Prenatal Diagnosis, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
| | - Yulu Zeng
- Department of Prenatal Diagnosis, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
| | - Ping Long
- Department of Laboratory Medicine, Guizhou Qiannan People's Hospital, Duyun, Guizhou, China.
| | - Lihong Pang
- Department of Prenatal Diagnosis, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
- Guangxi Key Laboratory of Thalassemia Research, Nanning, Guangxi, China.
- National Health Commission Key Laboratory of Thalassemia Medicine (Guangxi Medical University), Nanning, Guangxi, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China.
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2
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Zhao J, Ma Y, Zheng X, Sun Z, Lin H, Du C, Cao J. Bladder cancer: non-coding RNAs and exosomal non-coding RNAs. Funct Integr Genomics 2024; 24:147. [PMID: 39217254 DOI: 10.1007/s10142-024-01433-9] [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: 07/28/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Bladder cancer (BCa) is a highly prevalent type of cancer worldwide, and it is responsible for numerous deaths and cases of disease. Due to the diverse nature of this disease, it is necessary to conduct significant research that delves deeper into the molecular aspects, to potentially discover novel diagnostic and therapeutic approaches. Lately, there has been a significant increase in the focus on non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), due to their growing recognition for their involvement in the progression and manifestation of BCa. The interest in exosomes has greatly grown due to their potential for transporting a diverse array of active substances, including proteins, nucleic acids, carbohydrates, and lipids. The combination of these components differs based on the specific cell and its condition. Research indicates that using exosomes could have considerable advantages in identifying and forecasting BCa, offering a less invasive alternative. The distinctive arrangement of the lipid bilayer membrane found in exosomes is what makes them particularly effective for administering treatments aimed at managing cancer. In this review, we have tried to summarize different ncRNAs that are involved in BCa pathogenesis. Moreover, we highlighted the role of exosomal ncRNAs in BCa.
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Affiliation(s)
- Jingang Zhao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Yangyang Ma
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China
| | - Xiaodong Zheng
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Zhen Sun
- Department of the First Surgery, Zhejiang Provincial Corps Hospital of Chinese People's Armed Police Force, Hangzhou, 310051, Zhe'jiang, China
| | - Hongxiang Lin
- Department of Urology, Ganzhou Donghe Hospital, Ganzhou, 341000, Jiang'xi, China
| | - Chuanjun Du
- Department of Urology, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, 310009, Zhe'jiang, China
| | - Jing Cao
- Department of Urology, Hangzhou Mingzhou Hospital, Hangzhou, 311215, Zhe'jiang, China.
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3
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Gan L, Zheng L, Zou J, Luo P, Chen T, Zou J, Li W, Chen Q, Cheng L, Zhang F, Qian B. Critical roles of lncRNA-mediated autophagy in urologic malignancies. Front Pharmacol 2024; 15:1405199. [PMID: 38939836 PMCID: PMC11208713 DOI: 10.3389/fphar.2024.1405199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
Urologic oncology is a significant public health concern on a global scale. Recent research indicates that long chain non-coding RNAs (lncRNAs) and autophagy play crucial roles in various cancers, including urologic malignancies. This article provides a summary of the latest research findings, suggesting that lncRNA-mediated autophagy could either suppress or promote tumors in prostate, kidney, and bladder cancers. The intricate network involving different lncRNAs, target genes, and mediated signaling pathways plays a crucial role in urological malignancies by modulating the autophagic process. Dysregulated expression of lncRNAs can disrupt autophagy, leading to tumorigenesis, progression, and enhanced resistance to therapy. Consequently, targeting particular lncRNAs that control autophagy could serve as a dependable diagnostic tool and a promising prognostic biomarker in urologic oncology, while also holding potential as an effective therapeutic approach.
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Affiliation(s)
- Lifeng Gan
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Liying Zheng
- Department of Graduate, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junrong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Peiyue Luo
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Tao Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Jun Zou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Wei Li
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Qi Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Le Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Fangtao Zhang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
| | - Biao Qian
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Urology and Andrology of Ganzhou, Ganzhou, Jiangxi, China
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4
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Mehmandar-Oskuie A, Jahankhani K, Rostamlou A, Arabi S, Sadat Razavi Z, Mardi A. Molecular landscape of LncRNAs in bladder cancer: From drug resistance to novel LncRNA-based therapeutic strategies. Biomed Pharmacother 2023; 165:115242. [PMID: 37531786 DOI: 10.1016/j.biopha.2023.115242] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/04/2023] Open
Abstract
Bladder cancer (BC) is a common and serious type of cancer that ranks among the top ten most prevalent malignancies worldwide. Due to the high occurrence rate of BC, the aggressive nature of cancer cells, and their resistance to medication, managing this disease has become a growing challenge in clinical care. Long noncoding RNAs (lncRNAs) are a group of RNA transcripts that do not code for proteins and are more than 200 nucleotides in length. They play a significant role in controlling cellular pathways and molecular interactions during the onset, development and progression of different types of cancers. Recent advancements in high-throughput gene sequencing technology have led to the identification of various differentially expressed lncRNAs in BC, which indicate abnormal expression. In this review, we summarize that these lncRNAs have been found to impact several functions related to the development of BC, including proliferation, cell growth, migration, metastasis, apoptosis, epithelial-mesenchymal transition, and chemo- and radio-resistance. Additionally, lncRNAs may improve prognosis prediction for BC patients, indicating a future use for them as prognostic and diagnostic biomarkers for BC patients. This review highlights that genetic tools and anti-tumor agents, such as CRISPR/Cas systems, siRNA, shRNA, antisense oligonucleotides, and vectors, have been created for use in preclinical cancer models. This has led to a growing interest in using lncRNAs based on positive research findings.
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Affiliation(s)
- Amirreza Mehmandar-Oskuie
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kasra Jahankhani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arman Rostamlou
- Department of Medical Biology, Faculty of Medicine, University of EGE, IZMIR, Turkey
| | - Sepideh Arabi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zahra Sadat Razavi
- Department of Immunology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Amirhossein Mardi
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
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5
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Yu M, Xue S, Chen X, Wu K, Ju L, Tang J, Xiong A, Chen X, Ying X. Long Non-coding RNA UCA1a Promotes Proliferation via PKM2 in Cervical Cancer. Reprod Sci 2023; 30:601-614. [PMID: 35927414 DOI: 10.1007/s43032-022-01042-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 07/12/2022] [Indexed: 01/17/2023]
Abstract
Cervical cancer is a common malignancy that affects women worldwide. The long non-coding RNA (lncRNA) urothelial cancer-associated 1a (UCA1a) is reported to be significantly upregulated in cervical cancer. However, the exact role of UCA1a in cervical cancer remains unknown. This study aimed to identify two core promoter regions in UCA1a, which are essential for CEBPA-dependent transcription and FOXL1-, FOXL4-, and FOXL6-dependent activation, respectively. RNA sequencing results showed that overexpression of UCA1a resulted in extensive changes in the gene expression profile of HeLa cells, especially in the signaling pathway that regulates tumorgenesis. Mass spectrometry assay was conducted to show that pyruvate kinase M2 (PKM2) was a UCA1a-interacting protein. The 400 ~ 800 nt long region of UCA1a at the 5' end and the A1B domain of PKM2 were critical for the UCA1a-PKM2 interaction. Functional assays were performed to show that PKM2 was sufficient and necessary for UCA1a-induced proliferation of HeLa cells, which was partly due to the regulating of nuclear translocation and stabilization of PKM2. These findings provide a novel mechanism for UCA1a to regulate Hela cells by ubiquitination degradation of PKM2 and suggest that UCA1a may play a key role in the progression of cervical cancer.
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Affiliation(s)
- Minmin Yu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China. .,Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China.
| | - Songlin Xue
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Xin Chen
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Kaihua Wu
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Lili Ju
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Juan Tang
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Aiwei Xiong
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China
| | - Xiaoxiang Chen
- Department of Gynecologic Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research &, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
| | - Xiaoyan Ying
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, China.
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6
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Tang L, Wang S, Wang Y, Li K, Li Q. LncRNA-UCA1 regulates lung adenocarcinoma progression through competitive binding to miR-383. Cell Cycle 2023; 22:213-228. [PMID: 35980157 PMCID: PMC9817116 DOI: 10.1080/15384101.2022.2111929] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 01/09/2023] Open
Abstract
The present study aimed to assess the role of the long non-coding RNA-urothelial cancer associated 1 (lncRNA-UCA1)/microRNA (miR)-383/vascular endothelial growth factor A (VEGFA) axis in regulating lung adenocarcinoma physiology through in vivo and in vitro experiments. The expression profile of lncRNA-UCA1 was analyzed by genome-wide analysis from GSE146459. The cell counting Kit-8, colony formation, wound healing and transwell assays were performed to evaluate the effects of lncRNA-UCA1 in vitro. In addition, luciferase reporter assays were performed to confirm the binding site. The expression levels of miR-383 and VEGFA in tumor cells were measured using reverse transcription-quantitative PCR. HCC-78 was also transfected with miR-383 mimics, inhibitors and siRNA-VEGFA before their viability was also assessed. Xenograft models were established in nude mice to investigate the tumor characteristics in vivo. The expression of lncRNA-UCA1 was significantly increased in tumor tissues and cells compared with adjacent tissues or HBE cells. Silencing lncRNA-UCA1 expression in cells resulted in a reduction in lung cancer cell viability. In addition, lncRNA-UCA1 silencing increased the expression of miR-383. Inhibiting miR-383 expression increased HCC-78 proliferation, migration and invasion, whilst reducing their apoptosis. miR-383 was shown to specifically target VEGFA to inhibit its expression at both the protein and mRNA levels. VEGFA knockdown resulted in a reduction in all aforementioned aspects of HCC-78 cell activity. In addition, inhibiting miR-383 expression led to larger tumor sizes in vivo. To conclude, the results of the study suggest that lncRNA-UCA1 can regulate the expression of miR-383 and, in turn, VEGFA.
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Affiliation(s)
- Li Tang
- School of Nursing Internal Medicine Department, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Sheng Wang
- Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yapeng Wang
- School of Nursing Internal Medicine Department, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Kang Li
- School of Nursing Laboratory Center, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Qiang Li
- Department of dermatology, Air Force Characteristic Medical Center, Beijing, China
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Revealing the role of miRNA-489 as a new onco-suppressor factor in different cancers based on pre-clinical and clinical evidence. Int J Biol Macromol 2021; 191:727-737. [PMID: 34562537 DOI: 10.1016/j.ijbiomac.2021.09.089] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 01/17/2023]
Abstract
Recently, microRNAs (miRNAs) have shown to be potential therapeutic, diagnostic and prognostic targets in disease therapy. These endogenous non-coding RNAs contribute to regulation of different cellular events that are necessary for maintaining physiological condition. Dysregulation of miRNAs is correlated with development of various pathological events such as neurological disorders, cardiovascular diseases, and cancer. miRNA-489 is a new emerging miRNA and studies are extensively investigating its role in pathological conditions. Herein, potential function of miRNA-489 as tumor-suppressor in various cancers is described. miRNA-489 is able to sensitize cancer cells into chemotherapy by disrupting molecular pathways involved in cancer growth such as PI3K/Akt, and induction of apoptosis. The PROX1 and SUZ12 as oncogenic pathways, are affected by miRNA-489 in suppressing metastasis of cancer cells. Wnt/β-catenin as an oncogenic factor ensuring growth and malignancy of tumors is inhibited via miRNA-489 function. For enhancing drug sensitivity of tumors, restoring miRNA-489 expression is a promising strategy. The lncRNAs can modulate miRNA-489 expression in tumors and studies about circRNA role in miRNA-489 modulation should be performed. The expression level of miRNA-489 is a diagnostic tool for tumor detection. Besides, down-regulation of miRNA-489 in tumors provides unfavorable prognosis.
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HES5 Activates Long Noncoding RNA UCA1 to Induce Colorectal Cancer Progression by Modulating miR-185/NOTCH3 Signaling. Gastroenterol Res Pract 2021; 2021:7249818. [PMID: 34733326 PMCID: PMC8560272 DOI: 10.1155/2021/7249818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common diagnosed cancers around the world. The poor prognosis and high fatality caused by metastasis are still the challenges for clinical treatment. Therefore, it is promising to clarify the detailed molecular mechanism of CRC metastasis. Accumulating evidences indicate that long noncoding RNAs (lncRNAs) play important roles in cancer progression including CRC. In this study, the function of lncRNA UCA1 was investigated. UCA1 was confirmed to be highly expressed in colorectal cancer. Moreover, the UCA1 expression level was positively related to tumor stages. Silencing UCA1 showed inhibitory effect on cell proliferation and metastasis. Both UCA1 and NOTCH3 were validated as direct targets of miR-185. Silencing UCA1 repressed NOTCH3 expression through the miR-185 sponge. NOTCH3 was found to be highly expressed in CRC patients and positively related to UCA1 expression. Furthermore, HES5 was verified as a transcription factor of UCA1, which induced UCA1 expression. In conclusion, UCA1 is a direct target of HES5. UCA1 promotes CRC metastasis through regulating the miR-185/NOTCH3 axis.
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Biological functions and clinical significance of long noncoding RNAs in bladder cancer. Cell Death Discov 2021; 7:278. [PMID: 34611133 PMCID: PMC8492632 DOI: 10.1038/s41420-021-00665-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/02/2021] [Accepted: 09/17/2021] [Indexed: 12/24/2022] Open
Abstract
Bladder cancer (BCa) is one of the 10 most common cancers with high morbidity and mortality worldwide. Long noncoding RNAs (lncRNAs), a large class of noncoding RNA transcripts, consist of more than 200 nucleotides and play a significant role in the regulation of molecular interactions and cellular pathways during the occurrence and development of various cancers. In recent years, with the rapid advancement of high-throughput gene sequencing technology, several differentially expressed lncRNAs have been discovered in BCa, and their functions have been proven to have an impact on BCa development, such as cell growth and proliferation, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and drug-resistance. Furthermore, evidence suggests that lncRNAs are significantly associated with BCa patients' clinicopathological characteristics, especially tumor grade, TNM stage, and clinical progression stage. In addition, lncRNAs have the potential to more accurately predict BCa patient prognosis, suggesting their potential as diagnostic and prognostic biomarkers for BCa patients in the future. In this review, we briefly summarize and discuss recent research progress on BCa-associated lncRNAs, while focusing on their biological functions and mechanisms, clinical significance, and targeted therapy in BCa oncogenesis and malignant progression.
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Mirzaei S, Paskeh MDA, Hashemi F, Zabolian A, Hashemi M, Entezari M, Tabari T, Ashrafizadeh M, Raee P, Aghamiri S, Aref AR, Leong HC, Kumar AP, Samarghandian S, Zarrabi A, Hushmandi K. Long non-coding RNAs as new players in bladder cancer: Lessons from pre-clinical and clinical studies. Life Sci 2021; 288:119948. [PMID: 34520771 DOI: 10.1016/j.lfs.2021.119948] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/02/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022]
Abstract
The clinical management of bladder cancer (BC) has become an increasing challenge due to high incidence rate of BC, malignant behavior of cancer cells and drug resistance. The non-coding RNAs are considered as key factors involved in BC progression. The long non-coding RNAs (lncRNAs) are RNA molecules and do not encode proteins. They have more than 200 nucleotides in length and affect gene expression at epigenetic, transcriptional and post-transcriptional phases. The lncRNAs demonstrate abnormal expression in BC cells and tissues. The present aims to identifying lncRNAs with tumor-suppressor and tumor-promoting roles, and evaluating their roles as regulatory of growth and migration. Apoptosis, glycolysis and EMT are tightly regulated by lncRNAs in BC. Response of BC cells to cisplatin, doxorubicin and gemcitabine chemotherapy is modulated by lncRNAs. LncRNAs regulate immune cell infiltration in tumor microenvironment and affect response of BC cells to immunotherapy. Besides, lncRNAs are able to regulate microRNAs, STAT3, Wnt, PTEN and PI3K/Akt pathways in affecting both proliferation and migration of BC cells. Noteworthy, anti-tumor compounds and genetic tools such as siRNA, shRNA and CRISPR/Cas systems can regulate lncRNA expression in BC. Finally, lncRNAs and exosomal lncRNAs can be considered as potential diagnostic and prognostic tools in BC.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey.
| | - Pourya Raee
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahin Aghamiri
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Xsphera Biosciences Inc., 6 Tide Street, Boston, MA 02210, USA
| | - Hin Chong Leong
- Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
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Li HJ, Gong X, Li ZK, Qin W, He CX, Xing L, Zhou X, Zhao D, Cao HL. Role of Long Non-coding RNAs on Bladder Cancer. Front Cell Dev Biol 2021; 9:672679. [PMID: 34422802 PMCID: PMC8371405 DOI: 10.3389/fcell.2021.672679] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/17/2021] [Indexed: 12/30/2022] Open
Abstract
Bladder cancer (BC) is the most common malignant tumor in the urinary system, and its early diagnosis is conducive to improving clinical prognosis and prolonging overall survival time. However, few biomarkers with high sensitivity and specificity are used as diagnostic markers for BC. Multiple long non-coding RNAs (lncRNAs) are abnormally expressed in BC, and play key roles in tumorigenesis, progression and prognosis of BC. In this review, we summarize the expression, function, molecular mechanisms and the clinical significance of lncRNAs on bladder cancer. There are more than 100 dysregulated lncRNAs in BC, which are involved in the regulation of proliferation, cell cycle, apoptosis, migration, invasion, metabolism and drug resistance of BC. Meanwhile, the molecular mechanisms of lncRNAs in BC was explored, including lncRNAs interacting with DNA, RNA and proteins. Additionally, the abnormal expression of thirty-six lncRNAs is closely associated with multiple clinical characteristics of BC, including tumor size, metastasis, invasion, and drug sensitivity or resistance of BC. Furthermore, we summarize some potential diagnostic and prognostic biomarkers of lncRNA for BC. This review provides promising novel biomarkers in early diagnosis, prognosis and monitoring of BC based on lncRNAs.
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Affiliation(s)
- Hui-Jin Li
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Xue Gong
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Zheng-Kun Li
- College of Medical Technology, Xi'an Medical University, Xi'an, China
| | - Wei Qin
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Chun-Xia He
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Lu Xing
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Xin Zhou
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Dong Zhao
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Hui-Ling Cao
- Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, and Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
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12
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Liu Z, Wang Y, Yuan S, Wen F, Liu J, Zou L, Zhang J. Regulatory role of long non-coding RNA UCA1 in signaling pathways and its clinical applications. Oncol Lett 2021; 21:404. [PMID: 33777227 PMCID: PMC7988699 DOI: 10.3892/ol.2021.12665] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 02/11/2021] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNA metastasis-associated urothelial carcinoma associated 1 (UCA1) plays a pivotal role in various human diseases. Its gene expression is regulated by several factors, including transcription factors, chromatin remodeling and epigenetic modification. UCA1 is involved in the regulation of the PI3K/AKT, Wnt/β-catenin, MAPK, NF-κB and JAK/STAT signaling pathways, affecting a series of cellular biological functions, such as cell proliferation, apoptosis, migration, invasion and tumor drug resistance. Furthermore, UCA1 is used as a novel potential biomarker for disease diagnosis and prognosis, as well as a target for clinical gene therapy. The present review systematically summarizes and elucidates the mechanisms of upstream transcriptional regulation of UCA1, the regulatory role of UCA1 in multiple signaling pathways in the occurrence and development of several diseases, and its potential applications in clinical treatment.
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Affiliation(s)
- Zhaoping Liu
- Department of Rheumatology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yanyan Wang
- Department of Rheumatology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shunling Yuan
- Department of Rheumatology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Feng Wen
- Department of Hematology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jing Liu
- Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, P.R. China
| | - Liheng Zou
- Department of Rheumatology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ji Zhang
- Department of Rheumatology, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China.,Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518033, P.R. China
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13
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Brisotto G, Guerrieri R, Colizzi F, Steffan A, Montico B, Fratta E. Long Noncoding RNAs as Innovative Urinary Diagnostic Biomarkers. Methods Mol Biol 2021; 2292:73-94. [PMID: 33651353 DOI: 10.1007/978-1-0716-1354-2_7] [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: 02/06/2023]
Abstract
The characterization of circulating tumor cells (CTCs) is now widely studied as a promising source of cancer-derived biomarkers because of their role in tumor formation and progression. However, CTCs analysis presents some limitations and no standardized method for CTCs isolation from urine has been defined so far. In fact, besides blood, urine represents an ideal source of noninvasive biomarkers, especially for the early detection of genitourinary tumors. Besides CTCs, long noncoding RNAs (lncRNAs) have also been proposed as potential noninvasive biomarkers, and the evaluation of the diagnostic accuracy of urinary lncRNAs has dramatically increased over the last years, with many studies being published. Therefore, this review provides an update on the clinical utility of urinary lncRNAs as novel biomarkers for the diagnosis of bladder and prostate cancers.
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Affiliation(s)
- Giulia Brisotto
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Roberto Guerrieri
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Francesca Colizzi
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Barbara Montico
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Elisabetta Fratta
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
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14
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Zhou Z, Chen S, Tian Z, Deng S, Yi X, Yang S, Yang X, Jin L, Shi W. miR-20b-5p attenuates hypoxia-induced apoptosis in cardiomyocytes via the HIF-1α/NF-κB pathway. Acta Biochim Biophys Sin (Shanghai) 2020; 52:927-934. [PMID: 32510153 DOI: 10.1093/abbs/gmaa056] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 10/17/2019] [Accepted: 12/26/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hypoxia is a common inducer of end-stage cardiovascular disease. In cells under hypoxia, the hypoxia-inducible factor-1 (HIF-1) plays a vital role in regulating downstream target genes. However, the mechanism of hypoxia in cardiomyocytes is still unclear. In this study, we aimed to identify novel downstream epigenetic targets of HIF-1α in cardiomyocytes under hypoxia. H9c2 cells were exposed to hypoxia condition, and quantitative real-time PCR analysis was performed to evaluate the expression of miR-20b-5p. The results indicated that the expression of miR-20b-5p was down-regulated in H9c2 cells under low oxygen condition. Meanwhile, HIF-1α overexpression further down-regulated the miR-20b-5p expression in H9c2 cells transfected with HIF-1α plasmids. In addition, Annexin-V-FITC/PI flow cytometry analysis suggested that overexpression of miR-20b-5p attenuated cell apoptosis under hypoxia condition in H9c2 cells. Western blot analysis showed that the hypoxia apparently increased Bax and cleaved-caspase-3, but decreased Bcl-2 expression in H9c2 cells, indicating that hypoxia-induced NF-κB signaling pathway activation is mediated by miR-20b-5p. Hypoxia-induced H9c2 cell apoptosis was reduced after HIF-1α knockdown as shown by the flow cytometry analysis. In conclusion, we identified that miR-20b-5p plays an important role in mediating cardiomyocytes apoptosis under hypoxia, which is mediated by the HIF-1/NF-κB signaling pathway.
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Affiliation(s)
- Zhongquan Zhou
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Songwen Chen
- Department of Cardiology, Shanghai General Hospital, Shanghai 200000, China
| | - Zhiming Tian
- Department of Cardiology, First School of Clinical Medicine College, Yangtze University, Jingzhou 434000, China
| | - Shibing Deng
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Xuying Yi
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Shaning Yang
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Xuexin Yang
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Lijun Jin
- Department of Cardiology, The First Hospital of Jingzhou City (the First Affiliated Hospital of Yangtze University), Jingzhou 434000, China
| | - Wanqing Shi
- The First Hospital of Jingzhou City, The Interventional Center, Jingzhou 434000, China
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15
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Kubota S, Ishikawa T, Kawata K, Hattori T, Nishida T. Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes. Int J Mol Sci 2020; 21:ijms21051564. [PMID: 32106563 PMCID: PMC7084347 DOI: 10.3390/ijms21051564] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/14/2022] Open
Abstract
Retrotransposons are genetic elements that copy and paste themselves in the host genome through transcription, reverse-transcription, and integration processes. Along with their proliferation in the genome, retrotransposons inevitably modify host genes around the integration sites, and occasionally create novel genes. Even now, a number of retrotransposons are still actively editing our genomes. As such, their profound role in the evolution of mammalian genomes is obvious; thus, their contribution to mammalian skeletal evolution and development is also unquestionable. In mammals, most of the skeletal parts are formed and grown through a process entitled endochondral ossification, in which chondrocytes play central roles. In this review, current knowledge on the evolutional, physiological, and pathological roles of retrotransposons in mammalian chondrocyte differentiation and cartilage development is summarized. The possible biological impact of these mobile genetic elements in the future is also discussed.
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16
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Abstract
Long non-coding RNAs (lncRNAs) are regulators of cellular machinery that are commonly dysregulated in genitourinary malignancies. Accordingly, the investigation of lncRNAs is improving our understanding of genitourinary cancers, from development to progression and dissemination. lncRNAs are involved in major oncogenic events in genitourinary malignancies, including androgen receptor (AR) signalling in prostate cancer, hypoxia-inducible factor (HIF) pathway activation in renal cell carcinoma and invasiveness in bladder cancer, as well as multiple other proliferation and survival mechanisms. In line with their putative oncogenic roles, new lncRNA-based classifications are emerging as potent predictors of prognosis. In clinical practice, detection of oncogenic lncRNAs in serum or urine might enable early cancer detection, and lncRNAs might also be promising therapeutic targets for patients with genitourinary cancer. Furthermore, as predictors of sensitivity to anticancer treatments, lncRNAs could be integrated into future precision medicine strategies. Overall, lncRNAs are promising new candidates for molecular studies and for discovery of innovative biomarkers and are putative therapeutic targets in genitourinary oncology.
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17
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Shi FT, Chen LD, Zhang LF. Long Noncoding RNA UCA1 Overexpression Is Associated with Poor Prognosis in Digestive System Malignancies: A Meta-analysis. Curr Med Sci 2019; 39:694-701. [PMID: 31612385 DOI: 10.1007/s11596-019-2094-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 09/03/2019] [Indexed: 10/25/2022]
Abstract
Long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) has been reported to be highly expressed in many kinds of cancers. This meta-analysis summarized its potential prognostic value in digestive system malignancies. A meta-analysis was performed through a comprehensive search in PubMed, EMBASE, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI) for suitable articles on the prognostic impact of UCA1 in digestive system malignancies from inception to June 27, 2019. Pooled hazard ratios (HRs) with 95% confidence interval (95%CI) were calculated to summarize the effect. Sixteen studies were included in the study, with a total of 1504 patients. A significant association was observed between UCA1 abundance and poor overall survival (OS), and shorter disease-free survival (DFS) for patients with digestive system malignancies, with pooled HR of 2.07 (95%CI: 1.74-2.47), and of 2.50 (95%CI: 1.62-3.86). Subgroup analysis and sensitivity analysis suggested the reliability of our findings. It is suggested that UCA1 abundance may serve as a reliable predictive factor for poor prognosis in patients with digestive system malignancies.
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Affiliation(s)
- Fei-Tao Shi
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Li-Dong Chen
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lian-Feng Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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18
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Zhang L, Zheng C, Sun Z, Wang H, Wang F. Long non-coding RNA urothelial cancer associated 1 can regulate the migration and invasion of colorectal cancer cells (SW480) via myocardin-related transcription factor-A. Oncol Lett 2019; 18:4185-4193. [PMID: 31579420 PMCID: PMC6757313 DOI: 10.3892/ol.2019.10737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-associated mortalities. Long non-coding RNAs (lncRNAs) have been identified as key regulators in the occurrence and development of CRC. The lncRNA urothelial cancer associated 1 (UCA1) has been demonstrated to promote the development of numerous different types of cancer. In the present study, a novel molecular mechanism of UCA1, regulating the migratory and invasive capabilities of SW480 CRC cells was identified. UCA1 promoted the migration and invasion of SW480 cells by suppressing phosphorylation of myocardin-related transcription factor-A (MRTF-A). Our findings indicated that UCA1 competes with extracellular signal-regulated kinases1/2 to inhibit the phosphorylation of MRTF-A. These novel discoveries may reveal additional functions of UCA1, which may support future clinical development of novel drug targets.
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Affiliation(s)
- Long Zhang
- Cancer Diagnosis and Treatment Center, Nankai University People's Hospital, Tianjin 300071, P.R. China
| | - Chengcheng Zheng
- Cancer Diagnosis and Treatment Center, Nankai University People's Hospital, Tianjin 300071, P.R. China
| | - Zhen Sun
- Cancer Diagnosis and Treatment Center, Nankai University People's Hospital, Tianjin 300071, P.R. China
| | - Huaqing Wang
- Cancer Diagnosis and Treatment Center, Nankai University People's Hospital, Tianjin 300071, P.R. China
| | - Fengwei Wang
- Cancer Diagnosis and Treatment Center, Nankai University People's Hospital, Tianjin 300071, P.R. China
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19
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UCA1 long non-coding RNA: An update on its roles in malignant behavior of cancers. Biomed Pharmacother 2019; 120:109459. [PMID: 31585301 DOI: 10.1016/j.biopha.2019.109459] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/06/2019] [Accepted: 09/12/2019] [Indexed: 12/24/2022] Open
Abstract
The lncRNA urothelial carcinoma-associated 1 (UCA1) is a 1.4 kb long transcript which has been firstly recognized in human bladder cancer cell line. Subsequent studies revealed its over-expression in a wide array of human cancer cell lines and patients' samples. In addition to conferring malignant phenotype to cells, it enhances resistance to conventional anti-cancer drugs. Moreover, transcript levels of this lncRNA have been regarded as diagnostic markers in several cancer types including gastric, bladder and liver cancers. The underlying mechanism of its participation in carcinogenesis has been identified in some cancer types. Sponging tumor suppressor miRNAs, interacting with cancer-promoting signaling pathways and enhancing cell cycle progression are among these mechanisms. Although few studies have shown anti-carcinogenic properties for this lncRNA, the bulk of evidence supports its oncogenic roles. In the current study, we have reviewed the current literature on the role of UCA1 in the carcinogenic process based on the results of in vitro studies, investigations in animal models and assessment of UCA1 expression in clinical samples.
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20
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Bourguignon LYW. Matrix Hyaluronan-CD44 Interaction Activates MicroRNA and LncRNA Signaling Associated With Chemoresistance, Invasion, and Tumor Progression. Front Oncol 2019; 9:492. [PMID: 31293964 PMCID: PMC6598393 DOI: 10.3389/fonc.2019.00492] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022] Open
Abstract
Tumor malignancies involve cancer cell growth, issue invasion, metastasis and often drug resistance. A great deal of effort has been placed on searching for unique molecule(s) overexpressed in cancer cells that correlate(s) with tumor cell-specific behaviors. Hyaluronan (HA), one of the major ECM (extracellular matrix) components have been identified as a physiological ligand for surface CD44 isoforms which are frequently overexpressed in malignant tumor cells during cancer progression. The binding interaction between HA and CD44 isoforms often stimulates aberrant cellular signaling processes and appears to be responsible for the induction of multiple oncogenic events required for cancer-specific phenotypes and behaviors. In recent years, both microRNAs (miRNAs) (with ~20–25 nucleotides) and long non-coding RNAs (lncRNAs) (with ~200 nucleotides) have been found to be abnormally expressed in cancer cells and actively participate in numerous oncogenic signaling events needed for tumor cell-specific functions. In this review, I plan to place a special emphasis on HA/CD44-induced signaling pathways and the presence of several novel miRNAs (e.g., miR-10b/miR-302/miR-21) and lncRNAs (e.g., UCA1) together with their target functions (e.g., tumor cell migration, invasion, and chemoresistance) during cancer development and progression. I believe that important information can be obtained from these studies on HA/CD44-activated miRNAs and lncRNA that may be very valuable for the future development of innovative therapeutic drugs for the treatment of matrix HA/CD44-mediated cancers.
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Affiliation(s)
- Lilly Y W Bourguignon
- Endocrine Unit (111N2), Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA, United States
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21
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Wu J, Li W, Ning J, Yu W, Rao T, Cheng F. Long noncoding RNA UCA1 targets miR-582-5p and contributes to the progression and drug resistance of bladder cancer cells through ATG7-mediated autophagy inhibition. Onco Targets Ther 2019; 12:495-508. [PMID: 30666128 PMCID: PMC6331189 DOI: 10.2147/ott.s183940] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Rently, the incidence of bladder cancer has been on the rise. Accumulating researches have been conducted to clarify the molecular mechanisms and potential therapeutic targets of bladder cancer. The present study aims to explore the regulatory mechanism of the urothelial carcinoma-associated 1 (UCA1)-miR-582-5p-ATG7 axis in bladder cancer. METHODS Quantitative real-time polymerase chain reaction was used to detect mRNA level. Relative protein expression was detected by western blot. wound healing assay and transwell were used to determine migration and invasion of cells. in addtion, luciferase reporter assay and immunohistochemistry were performed. RESULTS UCA1 expression was upregulated in bladder cancer tissues and cells, while the depletion of UCA1 by shRNA resulted in the suppression of cell proliferation, invasion, migration, and drug resistance. Further studies demonstrated that UCA1 could directly interact with miR-582-5p, and that there was an inverse correlation between miR-582-5p and UCA1. In addition, we found that ATG7 is a target of miR-582-5p and can be downregulated by either miR-582-5p overexpression or UCA1 knockdown. In particular, the autophagy is reduced when UCA1 shRNA is introduced. Moreover, the in vivo experiment further demonstrated the contribution of UCA1 in bladder cancer including tumor growth, invasion, and migration, and UCA1 knockdown can inhibit the aforementioned activities. CONCLUSION These results provided evidence for a novel UCA1 interaction regulatory network in bladder cancer, that is, UCA1-miR-582-5p-ATG7-autophagy axis. Our study provides a new insight into the treatment of bladder cancer.
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Affiliation(s)
- Junfeng Wu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Wei Li
- Department of Anesthesiology, People's Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,
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22
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Neve B, Jonckheere N, Vincent A, Van Seuningen I. Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer. Cancers (Basel) 2018; 10:E440. [PMID: 30441811 PMCID: PMC6266399 DOI: 10.3390/cancers10110440] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.
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Affiliation(s)
- Bernadette Neve
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Nicolas Jonckheere
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Audrey Vincent
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Isabelle Van Seuningen
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
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23
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Sadek KM, Lebda MA, Nasr NE, Nasr SM, El-Sayed Y. Role of lncRNAs as prognostic markers of hepatic cancer and potential therapeutic targeting by S-adenosylmethionine via inhibiting PI3K/Akt signaling pathways. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:20057-20070. [PMID: 29748795 DOI: 10.1007/s11356-018-2179-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 04/30/2018] [Indexed: 06/08/2023]
Abstract
Hepatic cancer (HCC) is a well-identified dilemma throughout the world, and hence, the molecular mechanisms and strategy for preventive protection against this malignancy are critical. S-adenosylmethionine (SAM) is a unique methyl granter in vast reactions, including DNA methylation, and secures the genome against hypomethylation, which is a hallmark of tumors. Consequently, SAM may control the rate of gene expression. The objective of this investigation was to evaluate the expression of long noncoding RNAs (lncRNAs) transcript involved in hepatic tumorigenesis, including additional coding CEBPA (ecCEBPA) and urothelial carcinoma related 1 (UCA1), antioxidant enzymes transcripts, and relevant signaling pathway in diethylnitrosamine (DEN)-prompted HCC along with their conceivable targeting by SAM at different stages of HCC in rats. Our outcomes revealed that SAM particularly when given at the starting phase downregulates ecCEBPA and UCA1 gene transcripts and ameliorate histopathological alterations in DEN-initiated HCC. Interestingly, SAM attenuates DEN-induced upregulation of PI3K/Akt protein expression. However, SAM upregulates the antioxidant enzymes mRNA transcripts and effectively diminishing DNA oxidation. The results of a DNA fragmentation assay further support the capacity of SAM to ameliorate DEN-induced hepatic malignancy. These results revealed the role of ecCEBPA and UCA1 in HCC and suggest that these lncRNAs may be helpful as prognostic and analytical biomarkers of HCC. Curiously, SAM readily targets the studied genes via inhibiting PI3K/Akt signaling pathway, which should make SAM an appealing agent for both chemoprevention and treatment of HCC.
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Affiliation(s)
- Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
| | - Mohamed A Lebda
- Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt
| | - Nasr E Nasr
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Sherif M Nasr
- Department of Molecular Biology and Genetics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Yasser El-Sayed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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Li H, Ma SQ, Huang J, Chen XP, Zhou HH. Roles of long noncoding RNAs in colorectal cancer metastasis. Oncotarget 2018; 8:39859-39876. [PMID: 28418892 PMCID: PMC5503659 DOI: 10.18632/oncotarget.16339] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 02/20/2017] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is the 3rd most common malignancies worldwide. Metastasis is responsible for more than 90% CRC patients' death. Long noncoding RNAs (lncRNAs) are an important class of transcribed RNA molecules greater than 200 nucleotides in length. With the development of whole genome sequencing technologies, they have been gained more attention. Accumulating evidences suggest that abnormal expression of lncRNAs in diverse diseases are involved in various biological functions such as proliferation, apoptosis, metastasis and differentiation by acting as epigenetic, splicing, transcriptional or post-transcriptional regulators. Aberrant expression of lncRNAs has also been found in CRC. Besides, recent studies have indicated that lncRNAs play important roles in tumourigenesis and cancer metastasis. They participate in the process of metastasis by activing or inhibiting the metastatic pathways. However, their functions on the development of cancer metastasis are poorly understood. In this review, we highlight the findings of roles for lncRNAs in CRC metastasis and review the metastatic pathways of lncRNAs leading to cancer metastasis in CRC, including escape of apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis and invasion, migration and proliferation. Furthermore, we also discuss the potential clinical application of lncRNAs in CRC as diagnostic markers and therapeutic targets.
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Affiliation(s)
- He Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
| | - Si-Qing Ma
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
| | - Jin Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, P. R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, P. R. China
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25
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Gou L, Liu M, Xia J, Wan Q, Jiang Y, Sun S, Tang M, Zhou L, He T, Zhang Y. BMP9 Promotes the Proliferation and Migration of Bladder Cancer Cells through Up-Regulating lncRNA UCA1. Int J Mol Sci 2018; 19:ijms19041116. [PMID: 29642505 PMCID: PMC5979556 DOI: 10.3390/ijms19041116] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 02/06/2023] Open
Abstract
As the most common malignant tumor of the urinary system worldwide, the bladder tumor has a high mortality rate, which is mainly due to its onset of concealment. Therefore, research into novel diagnostic markers and treatment of bladder cancer is urgently needed. BMP9 (Bone morphogenetic protein 9) is a member of BMP, which belongs to the TGF-β (transforming growth factor-β) superfamily. It has been associated with multiple tumors. We found that BMP9 is highly expressed in bladder cancer cells and it could significantly promote the proliferation and migration of bladder cancer cells. In the study of the mechanism of this effect, we found that BMP9 can increase the expression of lncRNA UCA1 (Urothelial cancer associated 1) through phosphorylated AKT. The promoting effect of BMP9 on bladder cancer cells was rescued after interfering with UCA1 in BMP9 overexpressed bladder cancer cells both in vitro and in vivo. Our research confirms that BMP9 promotes the proliferation and migration of bladder cancer cells through up-regulated lncRNA UCA1. It also shows that BMP9 is a novel diagnostic marker and a potential therapeutic target in bladder cancer.
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Affiliation(s)
- Liyao Gou
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Mengyao Liu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Jing Xia
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Qun Wan
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Yayun Jiang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Shilei Sun
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Min Tang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Lan Zhou
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
| | - Tongchuan He
- Molecular Oncology Laboratory, Department of Surgery, University of Chicago Medical Center, Chicago, IL 60637, USA.
| | - Yan Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
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26
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Hu G, Niu F, Humburg BA, Liao K, Bendi S, Callen S, Fox HS, Buch S. Molecular mechanisms of long noncoding RNAs and their role in disease pathogenesis. Oncotarget 2018; 9:18648-18663. [PMID: 29719633 PMCID: PMC5915100 DOI: 10.18632/oncotarget.24307] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/13/2018] [Indexed: 12/13/2022] Open
Abstract
LncRNAs are long non-coding regulatory RNAs that are longer than 200 nucleotides. One of the major functions of lncRNAs is the regulation of specific gene expression at multiple steps including, recruitment and expression of basal transcription machinery, post-transcriptional modifications and epigenetics [1]. Emerging evidence suggests that lncRNAs also play a critical role in maintaining tissue homeostasis during physiological and pathological conditions, lipid homeostasis, as well as epithelial and smooth muscle cell homeostasis, a topic that has been elegantly reviewed [2-5]. While aberrant expression of lncRNAs has been implicated in several disease conditions, there is paucity of information about their contribution to the etiology of diseases [6]. Several studies have compared the expression of lncRNAs under normal and cancerous conditions and found differential expression of several lncRNAs, suggesting thereby an involvement of lncRNAs in disease processes [7, 8]. Furthermore, the ability of lncRNAs to influence epigenetic changes also underlies their role in disease pathogenesis since epigenetic regulation is known to play a critical role in many human diseases [1]. LncRNAs thus are not only involved in homeostatic functioning but also play a vital role in the progression of many diseases, thereby underscoring their potential as novel therapeutic targets for the alleviation of a variety of human disease conditions.
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Affiliation(s)
- Guoku Hu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Fang Niu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bree A. Humburg
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ke Liao
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sunil Bendi
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shannon Callen
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Howard S. Fox
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shilpa Buch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
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27
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Wang X, Peng F, Cheng L, Yang G, Zhang D, Liu J, Chen X, Zhao S. Prognostic and clinicopathological role of long non-coding RNA UCA1 in various carcinomas. Oncotarget 2018; 8:28373-28384. [PMID: 28423704 PMCID: PMC5438656 DOI: 10.18632/oncotarget.16059] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 02/27/2017] [Indexed: 12/26/2022] Open
Abstract
Urothelial cancer associated 1 (UCA1) as an oncogenic long non-coding RNA (LncRNA) was aberrantly upregulated in various solid tumors. Numerous studies have demonstrated overexpression of UCA1 is an unfavorable prognostic indicator in cancer patients. This study aimed to further explore the prognosis role and clinical significance of UCA1 in cancer. Eligible studies were recruited by a systematic search in PubMed, Embase, Cochrane Library and Web of Science databases. A total of 19/16 studies with 1587/1291 cancer patients were included to evaluate the association between UCA1 expression and overall survival (OS) and clinicopathological factors of malignancies by computing hazard ratio (HR), odds ratios (OR) and confidence interval (CI). The meta-analysis indicated overexpression of UCA1 was significantly correlated with unexpected OS in patients with cancer (pooled HR = 1.85, 95% CI 1.62-2.10, p < 0.001). There was also a significantly negative association between high level of UCA1 and poor grade cancer (pooled OR = 2.74, 95% CI 2.04-3.70, p < 0.001) and positive lymphatic metastasis (pooled OR = 2.43, 95% CI 1.72-3.41, p < 0.001). In conclusion, our study suggested that UCA1 was correlated with more advanced clinicopathological features and poor prognosis as a novel predictive biomarker of patients with various tumors.
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Affiliation(s)
- Xiaoxiong Wang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Fei Peng
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Liang Cheng
- College of Bioinformatics Science and Technology, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Guang Yang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Daming Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Jiaqi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Xin Chen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
| | - Shiguang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China.,Institute of Brain Science, Harbin Medical University, Nangang District, Harbin, Heilongjiang Province, 150001, People's Republic of China
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28
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Nasrollahzadeh-Khakiani M, Emadi-Baygi M, Schulz WA, Nikpour P. Long noncoding RNAs in gastric cancer carcinogenesis and metastasis. Brief Funct Genomics 2018; 16:129-145. [PMID: 27122631 DOI: 10.1093/bfgp/elw011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Recent studies of the human transcriptome, most prominently by the ENCyclopedia Of DNA Elements project, have revealed an unexpected number of noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) are typically referred to a heterogeneous group of polyadenylated long ncRNAs, with a length of > 200 nt. LncRNAs constitute an integral part of tumor biology, with many lncRNAs discovered to be aberrantly expressed in various cancer types. They are involved in many aspects of cancer pathogenesis from its initiation to progression, metastasis and treatment response. Gastric cancer (GC) is the third leading cause of cancer death worldwide. Despite the current improvements of life expectancy and survival rate, most of the patients are diagnosed when their cancer has been progressed to advanced stages. Therefore, unraveling the molecular mechanisms of GC to find early-stage biomarkers is urgent. As the list of lncRNAs with deregulated expression in GC is steadily expanding, these molecules offer a source for developing GC-specific biomarkers. In this review, we will present and discuss those lncRNAs whose expression has been shown to be deregulated in GC.
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29
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Alteration of Epigenetic Regulation by Long Noncoding RNAs in Cancer. Int J Mol Sci 2018; 19:ijms19020570. [PMID: 29443889 PMCID: PMC5855792 DOI: 10.3390/ijms19020570] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are important regulators of the epigenetic status of the human genome. Besides their participation to normal physiology, lncRNA expression and function have been already associated to many diseases, including cancer. By interacting with epigenetic regulators and by controlling chromatin topology, their misregulation may result in an aberrant regulation of gene expression that may contribute to tumorigenesis. Here, we review the functional role and mechanisms of action of lncRNAs implicated in the aberrant epigenetic regulation that has characterized cancer development and progression.
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30
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Li E, Zhao Z, Ma B, Zhang J. Long noncoding RNA HOTAIR promotes the proliferation and metastasis of osteosarcoma cells through the AKT/mTOR signaling pathway. Exp Ther Med 2017; 14:5321-5328. [PMID: 29285059 PMCID: PMC5740751 DOI: 10.3892/etm.2017.5248] [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: 10/06/2016] [Accepted: 07/27/2017] [Indexed: 11/05/2022] Open
Abstract
It has been proven that long non-coding (lnc)RNAs serve an important role in the tumorigenesis and development of several types of human malignancy. Previous studies have demonstrated that the lncRNA Hox transcript antisense intergenic RNA (HOTAIR) is involved in the development various types of cancer, including osteosarcoma (OS). However, the underlying mechanisms by which it has an affect are still largely unknown. In the present study, it was observed that the expression of HOTAIR was significantly upregulated in OS tissues compared to matched adjacent normal tissues, using reverse transcription-quantitative polymerase chain reaction analysis. HOTAIR was silenced using specific small interfering RNA (siRNA/siR), siR-HOTAIR, in order to investigate its role in regulating OS cell proliferation, apoptosis, migration and invasion. siR-HOTAIR inhibited the proliferation of MG-63 cells due to the induction of G1 phase arrest. In addition, the results of in vitro assays demonstrated that the suppression of HOTAIR in MG-63 OS cells significantly reduced migration and invasion. The silencing of HOTAIR also significantly decreased the expression of matrix metalloproteinase (MMP) 2 and MMP9, but increased E-cadherin expression through regulating the RAC α serine/threonine protein kinase-mammalian target of rapamycin signaling pathway. The results indicated that siR-HOTAIR may be a potential OS therapy.
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Affiliation(s)
- Enqi Li
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Zhe Zhao
- Department of Surgery of Traditional Chinese Medicine, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Baotong Ma
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Jinli Zhang
- Department of Orthopaedic Trauma, Tianjin Hospital, Tianjin 300211, P.R. China
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31
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LncRNA ZEB2-AS1 promotes bladder cancer cell proliferation and inhibits apoptosis by regulating miR-27b. Biomed Pharmacother 2017; 96:299-304. [PMID: 28992472 DOI: 10.1016/j.biopha.2017.08.060] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 07/21/2017] [Accepted: 08/11/2017] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The aim of this study was to explore the role of lncRNA zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1), as a new tumor-associated lncRNA, in bladder cancer (BC) pathogenesis. METHODS BC tissues and tumor-adjacent normal bladder tissues were collected for detection of the expression profile of ZEB2-AS1 and miR-27b in BC. The endogenous expression of ZEB2-AS1 and miR-27b was modulated by the recombinant expression vector in vitro. The interaction between ZEB2-AS1 and miR-27b was identified by luciferase report gene assays and RNA immunoprecipitation (RIP) assays. The proliferation and apoptosis of BC cells was determined using CCK-8 assays and flow cytometric analysis. RESULTS The expression of ZEB2-AS1 was significantly increased in both BC tissues and BC cells (J82, 5637, T24); while miR-27b was down-regulated in BC tissues. More importantly, ZEB2-AS1 was significantly negative correlated with miR-27b expression in BC tissues (R2=0.1688, P<0.05). ZEB2-AS1 silencing inhibited BC cell proliferation and promoted apoptosis. Further studies confirmed that miR-27b was negatively regulated by ZEB2-AS1 in BC cells 5637 and T24, and the effects of ZEB2-AS1 on BC cells was mediated by miR-27b. CONCLUSION Our data provided strong evidence that ZEB2-AS1 promoted tumorigenesis and development of BC through down-regulating tumor-suppressive miR-27b.
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32
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Molecular Crosstalking among Noncoding RNAs: A New Network Layer of Genome Regulation in Cancer. Int J Genomics 2017; 2017:4723193. [PMID: 29147648 PMCID: PMC5632862 DOI: 10.1155/2017/4723193] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/24/2017] [Accepted: 08/24/2017] [Indexed: 02/06/2023] Open
Abstract
Over the past few years, noncoding RNAs (ncRNAs) have been extensively studied because of the significant biological roles that they play in regulation of cellular mechanisms. ncRNAs are associated to higher eukaryotes complexity; accordingly, their dysfunction results in pathological phenotypes, including cancer. To date, most research efforts have been mainly focused on how ncRNAs could modulate the expression of protein-coding genes in pathological phenotypes. However, recent evidence has shown the existence of an unexpected interplay among ncRNAs that strongly influences cancer development and progression. ncRNAs can interact with and regulate each other through various molecular mechanisms generating a complex network including different species of RNAs (e.g., mRNAs, miRNAs, lncRNAs, and circRNAs). Such a hidden network of RNA-RNA competitive interactions pervades and modulates the physiological functioning of canonical protein-coding pathways involved in proliferation, differentiation, and metastasis in cancer. Moreover, the pivotal role of ncRNAs as keystones of network structural integrity makes them very attractive and promising targets for innovative RNA-based therapeutics. In this review we will discuss: (1) the current knowledge on complex crosstalk among ncRNAs, with a special focus on cancer; and (2) the main issues and criticisms concerning ncRNAs targeting in therapeutics.
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Abstract
The pivotal role of the long non-coding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) in anti-cancer drug resistance has been confirmed in many cancers. Overexpression of lncRNA UCA1 correlates with resistance to chemotherapeutics such as cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib and EGFR-TKIs, whereas lncRNA UCA1 knockdown restores drug sensitivity. These studies highlight the potential of lncRNA UCA1 as a diagnostic and prognostic biomarker, and a therapeutic target in malignant tumors. In this review, we address the role of lncRNA UCA1 in anti-cancer drug resistance and discuss its potential in future clinical applications.
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34
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Wang ZQ, Cai Q, Hu L, He CY, Li JF, Quan ZW, Liu BY, Li C, Zhu ZG. Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer. Cell Death Dis 2017; 8:e2839. [PMID: 28569779 PMCID: PMC5520878 DOI: 10.1038/cddis.2017.143] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 01/22/2017] [Accepted: 03/01/2017] [Indexed: 01/13/2023]
Abstract
Long noncoding RNA UCA1 has emerged as a novel regulator in cancer initiation and progression of various cancers. However, function and underlying mechanism of UCA1 in the progression of gastric cancer (GC) remain unclear. In the present study, we report that UCA1 expressed highly in GC tissues and GC cells, which was partly induced by SP1. UCA1 promoted GC cell proliferation and G1/S transition in vitro and in vivo. Moreover, UCA1 exerted its function through interacting with EZH2, promoting direct interaction with cyclin D1 promoter to activate the translation of cyclin D1. Furthermore, AKT/GSK-3B/cyclin D1 axis was activated to upregulate cyclin D1 due to overexpression of UCA1. In addition, EZH2 and phosphorylated AKT induced by UCA1 could impact each other to form a positive feedback to promote cyclin D1 expression. This study demonstrated that UCA1 as a critical regulator involved in GC proliferation and cell cycle progression by promoting cyclin D1 expression, which indicates that it may be clinically a potential therapeutic target in GC.
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Affiliation(s)
- Zhen-Qiang Wang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Cai
- Department of General Surgery, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Hu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang-Yu He
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Fang Li
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Wei Quan
- Department of General Surgery, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing-Ya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Li
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Gang Zhu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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35
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Lee JJ, Kim M, Kim HP. Epigenetic regulation of long noncoding RNA UCA1 by SATB1 in breast cancer. BMB Rep 2017; 49:578-583. [PMID: 27697109 PMCID: PMC5227301 DOI: 10.5483/bmbrep.2016.49.10.156] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Indexed: 01/31/2023] Open
Abstract
Special AT-rich sequence binding protein 1 (SATB1) is a nuclear matrix-associated DNA-binding protein that functions as a chromatin organizer. SATB1 is highly expressed in aggressive breast cancer cells and promotes growth and metastasis by reprograming gene expression. Through genomewide cross-examination of gene expression and histone methylation, we identified SATB1 target genes for which expression is associated with altered epigenetic marks. Among the identified genes, long noncoding RNA urothelial carcinoma-associated 1 (UCA1) was upregulated by SATB1 depletion. Upregulation of UCA1 coincided with increased H3K4 trimethylation (H3K4me3) levels and decreased H3K27 trimethylation (H3K27me3) levels. Our study showed that SATB1 binds to the upstream region of UCA1 in vivo, and that its promoter activity increases with SATB1 depletion. Furthermore, simultaneous depletion of SATB1 and UCA1 potentiated suppression of tumor growth and cell survival. Thus, SATB1 repressed the expression of oncogenic UCA1, suppressing growth and survival of breast cancer cells. [BMB Reports 2016; 49(10): 578-583].
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Affiliation(s)
- Jong-Joo Lee
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Mikyoung Kim
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hyoung-Pyo Kim
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
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36
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Yang Y, Wang Y, Lai J, Shen S, Wang F, Kong J, Zhang W, Yang H. Long non-coding RNA UCA1 contributes to the progression of oral squamous cell carcinoma by regulating the WNT/β-catenin signaling pathway. Cancer Sci 2016; 107:1581-1589. [PMID: 27560546 PMCID: PMC5132283 DOI: 10.1111/cas.13058] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 08/07/2016] [Accepted: 08/13/2016] [Indexed: 01/25/2023] Open
Abstract
With the development of functional genomics studies, a mass of long non-coding RNAs (LncRNA) were discovered from the human genome. Long non-coding RNAs serve as pivotal regulators of genes that are able to generate LncRNA-binding protein complexes to modulate a great number of genes. Recently, the LncRNA urothelial carcinoma-associated 1 (UCA1) has been revealed to be dysregulated, which plays a critical role in the development of a few cancers. However, the role of the biology and clinical significance of UCA1 in the tumorigenesis of oral squamous cell carcinoma (OSCC) remain unknown. We found that UCA1 expression levels were upregulated aberrantly in tongue squamous cell carcinoma tissues and associated with lymph node metastasis and TNM stage. We explored the expression, function, and molecular mechanism of LncRNA UCA1 in OSCC. In the present work, we revealed that UCA1 silencing suppressed proliferation and metastasis and induced apoptosis of OSCC cell lines in vitro and in vivo, which might be related to the activation level of the WNT/β-catenin signaling pathway. Our research results emphasize the pivotal role of UCA1 in the oncogenesis of OSCC and reveal a novel LncRNA UCA1-β-catenin-WNT signaling pathway regulatory network that could contribute to our understanding in the pathogenesis of OSCC and assist in the discovery of a viable LncRNA-directed diagnostic and therapeutic strategy for this fatal disease.
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Affiliation(s)
- Yong‐Tao Yang
- Graduate schoolGuangzhou Medical UniversityGuangzhouChina
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
| | - Yu‐Fan Wang
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
| | - Ju‐Yi Lai
- Shenzhen TCM HospitalGuangzhou University of Traditional Chinese MedicineShenzhenChina
| | - Shi‐Yue Shen
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
| | - Feng Wang
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
| | - Jie Kong
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
| | - Wei Zhang
- Biomedical Research InstituteShenzhen Peking University–The Hong Kong University of Science and Technology Medical CenterShenzhenChina
| | - Hong‐Yu Yang
- Department of Oral and Maxillofacial surgeryPeking University Shenzhen HospitalShenzhenChina
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Fu XL, Liu DJ, Yan TT, Yang JY, Yang MW, Li J, Huo YM, Liu W, Zhang JF, Hong J, Hua R, Chen HY, Sun YW. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma. Sci Rep 2016; 6:33535. [PMID: 27628540 PMCID: PMC5024322 DOI: 10.1038/srep33535] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 08/25/2016] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.
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Affiliation(s)
- Xue-Liang Fu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - De-Jun Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Ting-Ting Yan
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai cancer Institute, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, P.R. China
| | - Jian-Yu Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Min-Wei Yang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Jiao Li
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Wei Liu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Jun-Feng Zhang
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai cancer Institute, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, P.R. China
| | - Rong Hua
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
| | - Hao-Yan Chen
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai cancer Institute, Shanghai Institute of Digestive Diseases, 145 Middle Shandong Road, Shanghai 200001, P.R. China
| | - Yong-Wei Sun
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, P.R. China
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Li X, Wu Y, Liu A, Tang X. Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR-18a-HIF1α feedback regulatory loop. Tumour Biol 2016; 37:14733-14743. [DOI: 10.1007/s13277-016-5348-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 09/06/2016] [Indexed: 01/12/2023] Open
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Chen J, Miao Z, Xue B, Shan Y, Weng G, Shen B. Long Non-coding RNAs in Urologic Malignancies: Functional Roles and Clinical Translation. J Cancer 2016; 7:1842-1855. [PMID: 27698924 PMCID: PMC5039368 DOI: 10.7150/jca.15876] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 06/29/2016] [Indexed: 12/31/2022] Open
Abstract
Early diagnosis and surveillance for metastasis and recurrences are critical issues of urologic cancer. Deregulation of long non-coding RNAs (lncRNAs) has been implicated in urologic malignancies and represents potential markers or therapeutic targets. However, the utility of lncRNA as biomarkers appears to be overstated due to heterogeneous or irreproducible results from different studies. Thus, a critical and cautious review on the biomarker potential of lncRNAs is needed. This review provides an update on new findings of lncRNA-based markers for urologic cancer. The diverse mechanisms and associated examples of lncRNAs involved during the carcinogenesis of prostate cancer, bladder cancer and renal cancer were discussed in a more balanced and critical manner, as were the suitability of lncRNAs as diagnostic or prognostics markers.
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Affiliation(s)
- Jiajia Chen
- Center for Systems Biology, Soochow University, Suzhou 215006, China; School of Chemistry, Biological Engineering, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Zhijun Miao
- Center for Systems Biology, Soochow University, Suzhou 215006, China; Suzhou Dushuhu Hospital, Clinic Center, Soochow University, Suzhou 215123, China
| | - Boxin Xue
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Yuxi Shan
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Guobin Weng
- Ningbo Urologic and Nephrotic Hospital, Ningbo 315000, China
| | - Bairong Shen
- Center for Systems Biology, Soochow University, Suzhou 215006, China
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40
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Abstract
Despite great progress in research and treatment options, lung cancer remains the leading cause of cancer-related deaths worldwide. Oncogenic driver mutations in protein-encoding genes were defined and allow for personalized therapies based on genetic diagnoses. Nonetheless, diagnosis of lung cancer mostly occurs at late stages, and chronic treatment is followed by a fast onset of chemoresistance. Hence, there is an urgent need for reliable biomarkers and alternative treatment options. With the era of whole genome and transcriptome sequencing technologies, long noncoding RNAs emerged as a novel class of versatile, functional RNA molecules. Although for most of them the mechanism of action remains to be defined, accumulating evidence confirms their involvement in various aspects of lung tumorigenesis. They are functional on the epigenetic, transcriptional, and posttranscriptional level and are regulators of pathophysiological key pathways including cell growth, apoptosis, and metastasis. Long noncoding RNAs are gaining increasing attention as potential biomarkers and a novel class of druggable molecules. It has become clear that we are only beginning to understand the complexity of tumorigenic processes. The clinical integration of long noncoding RNAs in terms of prognostic and predictive biomarker signatures and additional cancer targets could provide a chance to increase the therapeutic benefit. Here, we review the current knowledge about the expression, regulation, biological function, and clinical relevance of long noncoding RNAs in lung cancer.
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Affiliation(s)
- Anna Roth
- Division of RNA Biology and Cancer, German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 280 (B150), 69120, Heidelberg, Germany
| | - Sven Diederichs
- Division of RNA Biology and Cancer, German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 280 (B150), 69120, Heidelberg, Germany.
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Xue M, Chen W, Li X. Urothelial cancer associated 1: a long noncoding RNA with a crucial role in cancer. J Cancer Res Clin Oncol 2016; 142:1407-19. [PMID: 26341664 DOI: 10.1007/s00432-015-2042-y] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 08/27/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Urothelial cancer associated 1 (UCA1) is a long noncoding RNA (lncRNA) which has gained more attention in recent years due to its aberrant expression in embryogenesis and a broad range of cancer tissues and cells. Importantly, multiple studies have shown that UCA1 plays oncogenic roles in tumor growth and metastasis, and it may act as a potential biomarker and therapeutic target for human cancers. However, the molecular mechanism of UCA1 in cancer initiation, progression and metastasis remains incompletely understood. Thus, gaining a better understanding of the functional mechanism of UCA1 in cancer onset and progression is of the utmost significance for evaluating the potential application of UCA1. RESULTS AND DISCUSSION In this review, we discuss UCA1 expression profiling, isoform, expression regulation, biological role and mechanism for UCA1 tumor-promoting effect. We further discuss the potential clinical application of UCA1 as a promising diagnostic biomarker or therapeutic target for human cancers. CONCLUSION UCA1 functions as an oncogenic lncRNA in several malignancies, and it might become a potential biomarker or therapeutic target for human cancers.
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Affiliation(s)
- Mei Xue
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China
| | - Wei Chen
- Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Xu Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.
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MiR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3. Biochem Biophys Res Commun 2016; 477:768-773. [PMID: 27363334 DOI: 10.1016/j.bbrc.2016.06.133] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 06/26/2016] [Indexed: 12/12/2022]
Abstract
MiR-27b downregulation is significantly associated with tamoxifen resistance in breast cancer cells. However, how it is downregulated in tamoxifen resistant (TamR) breast cancer cells and its downstream regulation were not clear. By performing MSP assay and QRT-PCR analysis with the use of 5-AZA-dC, a DNA methyltransferase inhibitor, we observed that TamR MCF-7 cells had significantly higher levels of methylation in the miR-27b promoter region than tamoxifen sensitive MCF-7 (TamS) cells and demethylation restored miR-27b expression. Re-expression of miR-27b sensitized TamR MCF-7 cells to tamoxifen, inhibited invasion and reversed epithelial-mesenchymal transition (EMT)-like properties. By using bioinformatics analysis and following dual luciferase and western blot analysis, this study confirmed a direct regulation of miR-27b on HMGB3 expression by binding to the 3'UTR. In addition, this study also found that silencing of HMGB3 indeed partially phenocopied the effects of miR-27b in reducing tamoxifen resistance and cell invasion and in reversing EMT-like properties. Therefore, we infer that HMGB3 is a functional target of miR-27b in modulation of tamoxifen resistance and EMT.
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43
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Hughes JM, Legnini I, Salvatori B, Masciarelli S, Marchioni M, Fazi F, Morlando M, Bozzoni I, Fatica A. C/EBPα-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia. Oncotarget 2016; 6:18534-44. [PMID: 26053097 PMCID: PMC4621908 DOI: 10.18632/oncotarget.4069] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 05/13/2015] [Indexed: 12/30/2022] Open
Abstract
Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-α (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPα occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPα-p30. We show that wild-type C/EBPα and C/EBPα-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPα represses, C/EBPα-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPα in AML.
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Affiliation(s)
- James M Hughes
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy
| | - Ivano Legnini
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy
| | - Beatrice Salvatori
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.,Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Silvia Masciarelli
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Marcella Marchioni
- Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Sapienza University of Rome, Rome, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Mariangela Morlando
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy
| | - Irene Bozzoni
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.,Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Sapienza University of Rome, Rome, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.,Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Alessandro Fatica
- Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy
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Li Y, Wang T, Li Y, Chen D, Yu Z, Jin L, Ni L, Yang S, Mao X, Gui Y, Lai Y. Identification of long-non coding RNA UCA1 as an oncogene in renal cell carcinoma. Mol Med Rep 2016; 13:3326-34. [PMID: 26935146 DOI: 10.3892/mmr.2016.4894] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 01/04/2016] [Indexed: 11/06/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, which is associated with poor prognosis and high recurrence. Long non‑coding RNAs (lncRNAs) have been reported to be dysregulated in cancer and to be important in the regulation of carcinogenesis, thus suggesting that this class of molecules may be used as biomarkers in cancer. The lncRNA urothelial carcinoma associated 1 (UCA1) has been observed to be upregulated and to function as an oncogene in certain types of cancer; however, the role of UCA1 in RCC remains to be elucidated. The present study aimed to determine the expression and function of UCA1 in RCC. Quantitative polymerase chain reaction (qPCR) was used to determine the expression levels of UCA1 in 46 paired RCC and adjacent normal tissue samples. Furthermore, qPCR was used to determine the expression levels of UCA1 in four RCC cell lines compared with the human embryonic kidney 293T cell line. The impact of UCA1 on cell migration, proliferation and apoptosis was investigated by wound scratch assay, MTT and flow cytometry, respectively. The results of the present study demonstrated that UCA1 expression levels were significantly increased in RCC tissues and cells, as compared with the controls. Ectopic expression and gene silencing of UCA1 in RCC cell lines exerted opposite effects on cellular proliferation, migration and apoptosis, and the results suggested that UCA1 may function as an oncogene in RCC. These results indicated that UCA1 may be considered as a promising biomarker for diagnosis, and a therapeutic target in RCC. Further research is required to elucidate the role and target genes of UCA1 in RCC.
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Affiliation(s)
- Yifan Li
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Tiantian Wang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yuchi Li
- Department of Urology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Duqun Chen
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Zuhu Yu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Lu Jin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Liangchao Ni
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xiangming Mao
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yaoting Gui
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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Zhang L, Cao X, Zhang L, Zhang X, Sheng H, Tao K. UCA1 overexpression predicts clinical outcome of patients with ovarian cancer receiving adjuvant chemotherapy. Cancer Chemother Pharmacol 2016; 77:629-34. [DOI: 10.1007/s00280-016-2963-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 01/05/2016] [Indexed: 01/21/2023]
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46
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LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett 2015; 371:99-106. [PMID: 26655272 DOI: 10.1016/j.canlet.2015.11.024] [Citation(s) in RCA: 293] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 11/13/2015] [Accepted: 11/14/2015] [Indexed: 12/11/2022]
Abstract
Recently, the long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified as an oncogenic gene in multiple human tumor entitles, and dysregulation of UCA1 was tightly linked to carcinogenesis and cancer progression. However, whether the aberrant expression of UCA1 in non-small cell lung cancer (NSCLC) is associated with malignancy, metastasis or prognosis has not been characterized. In this study, we found that UCA1 was upregulated in NSCLC tissues. Higher expression of UCA1 led to a significantly poorer survival time, and multivariate analysis revealed that UCA1 was an independent risk factor of prognosis. UCA1 overexpression enhanced, whereas UCA1 silencing impaired the proliferation and colony formation of NSCLC cells. Moreover, mechanistic investigations showed that UCA1 upregulated the expression of miR-193a-3p target gene ERBB4 through competitively 'spongeing' miR-193a-3p. Overall, we concluded that UCA1 functions as an oncogene in NSCLC, acting mechanistically by upregulating ERBB4 in part through 'spongeing' miR-193a-3p.
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47
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Tao K, Yang J, Hu Y, Sun Y, Tan Z, Duan J, Zhang F, Yan H, Deng A. Clinical significance of urothelial carcinoma associated 1 in colon cancer. Int J Clin Exp Med 2015; 8:21854-21860. [PMID: 26885155 PMCID: PMC4724001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/27/2015] [Indexed: 06/05/2023]
Abstract
This study aimed to investigate the expression levels of urothelial carcinoma associated 1 (UCA1) in cancer tissues and plasma of colon cancer patients, and evaluate its clinical significance. Quantitative real-time PCR was used to determine the expression levels of UCA1 in 80 pairs of colon cancer and adjacent normal tissues, plasma samples from 20 healthy controls, 20 colon cancer patients before and after tumor removal. The relationships between UCA1 expression and clinical features and overall survival were analyzed. Compared with adjacent normal tissues, UCA1 was significantly upregulated in colon cancer tissues, especially in cases with LNM and advanced TNM stages (P < 0.05). High UCA1 expression was associated with LMN, higher pT category, and advanced TNM stages (P < 0.05). Patients with high UCA1 expression had worse survival time than those with low UCA1 expression (adjusted HR = 2.002, 95% CI 1.007-3.981, P = 0.048). Furthermore, plasma levels of UCA1 in colon cancer patients were significantly higher than those of controls (P = 0.016). There was significant difference in plasma level of UCA1 between samples taken before and after surgery (P = 0.048). In conclusion, tissue expression of UCA1 is related to prognosis in colon cancer. Plasma UCA1 may serve as a potential biomarker for early diagnosis and disease monitoring of colon cancer patients.
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Affiliation(s)
- Kun Tao
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical UniversityShanghai 200433, China
| | - Jing Yang
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Yuemei Hu
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Yaohua Sun
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Zhenyu Tan
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Jinglin Duan
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Feng Zhang
- Department of Pathology, Tongren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 200336, China
| | - Hongli Yan
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical UniversityShanghai 200433, China
| | - Anmei Deng
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical UniversityShanghai 200433, China
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miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells. Biosci Rep 2015; 35:BSR20150167. [PMID: 26450928 PMCID: PMC4643328 DOI: 10.1042/bsr20150167] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 10/05/2015] [Indexed: 12/22/2022] Open
Abstract
miR-381 suppressed CX43 expression by directly targeting the 3′-UTR of C/EBPα, a novel transcription factor of Cx43 in human breast cancer cells. The miR-381–Cx43 axis might be a useful diagnostic and therapeutic target of metastatic breast cancer. Cx43 (connexin43) is an enhancer of the metastasis of breast cancer cells. Our previous study identified miR-381 as an indirect suppressor of Cx43 gene expression, with the precise mechanism being not understood. In the present study, using a reporter gene assay, we found that miR-381 suppressed Cx43 gene expression via the promoter region −500/−250. With site-directed gene mutation, we demonstrated that miR-381 could directly bind with the sequences CACUUGUAU in the 3′-UTR so as to inhibit C/EBPα (CCAAT/enhancer-binding protein α) expression. C/EBPα was further identified as a novel transcription factor by binding to a canonic element (AATTGTC) locating at −459/−453 in the promoter region of the Cx43 gene. Functionally, we demonstrated that miR-381 suppressed C/EBPα- and Cx43-dependent migration and invasion of breast cancer cells. Finally, we revealed that decreased levels of miR-381 as well as increased expression of C/EBPα and Cx43 in the metastatic breast cancer cells and tissues. Therefore we are the first to identify that miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells. The miR-381–C/EBPα–Cx43 axis might be a useful diagnostic and therapeutic target of metastatic breast cancer.
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49
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Ni B, Yu X, Guo X, Fan X, Yang Z, Wu P, Yuan Z, Deng Y, Wang J, Chen D, Wang L. Increased urothelial cancer associated 1 is associated with tumor proliferation and metastasis and predicts poor prognosis in colorectal cancer. Int J Oncol 2015; 47:1329-1338. [PMID: 26238511 DOI: 10.3892/ijo.2015.3109] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 06/26/2015] [Indexed: 01/16/2023] Open
Abstract
Long non-coding RNA, urothelial cancer associated 1 (UCA1), is reported to play a critical role in progression of carcinogenesis. In the present study, we identified differential expression of UCA1 in colorectal cancer (CRC) and paired peritumoral tissues using gene expression microarray analyses. qPCR analysis confirmed that UCA1 was upregulated in CRC (p<0.001) and the expression of UCA1 was statistically correlated with lymph node metastasis (P=0.040), distant metastasis (P=0.043) and tumor stage (P=0.010). Kaplan-Meier analysis indicated that patients with high UCA1 expression had a poor prognosis. Moreover, multivariate analysis identified UCA1 overexpression as an independent predictor for CRC. We also found that knockdown of UCA1 significantly suppressed cell proliferation and metastasis in CRC cells. Flow cytometry assays showed UCA1 silencing induced G0/G1 growth arrest and apoptosis of CRC cells. To further investigate the regulatory mechanisms of UCA1, we identified that Ets-2 bound to the UCA1 core promoter using luciferase assays. Collectively, our findings suggested that UCA1 might be an important prognostic indicator in CRC and may be a potential target for diagnosis and gene therapy.
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Affiliation(s)
- Beibei Ni
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xihu Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xiaoyan Guo
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xinjuan Fan
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Zihuan Yang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Peihuang Wu
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Zixu Yuan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Dianke Chen
- Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Lei Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510655, P.R. China
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Long Noncoding RNA CUDR Regulates HULC and β-Catenin to Govern Human Liver Stem Cell Malignant Differentiation. Mol Ther 2015; 23:1843-53. [PMID: 26347501 DOI: 10.1038/mt.2015.166] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 09/01/2015] [Indexed: 12/14/2022] Open
Abstract
Long noncoding RNA cancer upregulated drug resistant (CUDR) is overexpressed in many tumors and promotes tumorigenesis. Herein, we demonstrate CUDR could enhance the human embryonic stem cells (ESC) differentiation into hepatocyte-like cells by reducing trimethylation on histone H3 twenty-seventh lysine (H3K27me3). On the other hand, excessive CUDR triggers hepatocyte-like cells malignant transformation. Mechanistically, we identify CUDR causes highly upregulated in liver cancer (HULC) and β-catenin abnormal expression by inhibiting HULC promoter methylation and promoting β-catenin promoter-enhancer chromatin looping formation mediated by CUDR-ccctc-binding factor (CTCF) complex, which recruits more RNA polII and P300. Strikingly, HULC and β-catenin activity are crucial for CUDR oncogenic function. These findings provide the first demonstration that CUDR plays a positive potential role in liver cancer stem cell through the cascade of CUDR-HULC/CUDR-β-catenin signaling, and offer insights into a novel link between long noncoding RNA (lncRNA) and the epigenetic modification in cancer stem cells.
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