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Zhang S, Liu N, Cao P, Qin Q, Li J, Yang L, Xin Y, Jiang M, Zhang S, Yang J, Lu J. LncRNA BC200 promotes the development of EBV-associated nasopharyngeal carcinoma by competitively binding to miR-6834-5p to upregulate TYMS expression. Int J Biol Macromol 2024; 278:134837. [PMID: 39179085 DOI: 10.1016/j.ijbiomac.2024.134837] [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: 07/18/2024] [Revised: 08/15/2024] [Accepted: 08/15/2024] [Indexed: 08/26/2024]
Abstract
Nasopharyngeal carcinoma (NPC) is closely related to Epstein-Barr virus (EBV) infection. Long noncoding RNAs (lncRNAs) play important roles in cancers. However, the molecular mechanism underlying the roles of lncRNAs in EBV-associated NPC remains largely unclear. In this study, we confirmed that the expression of the lncRNA brain cytoplasmic 200 (BC200) was significantly increased in EBV-infected NPC cells and tissues. BC200 facilitated the growth and migration of NPC cells, suggesting that it participated in NPC progression by functioning as an oncogene. Mechanistically, BC200 was found to act as a ceRNA by sponging and inhibiting miR-6834-5p. Thymidylate synthetase (TYMS), whose high expression was reported to be an independent indicator of poor prognosis in NPC via an unknown mechanism, was identified as a target gene of miR-6834-5p in the present study. BC200 upregulated TYMS expression in a manner that depends on miR-6834-5p. TYMS was abnormally upregulated in EBV-positive NPC cells and tissues, and its ectopic expression contributed to the proliferation and migration of NPC cells. This study highlights the role of lncRNA BC200, which is upregulated by EBV, in promoting the development of NPC, suggesting that BC200-mediated ceRNA network may be valuable biomarkers for the diagnosis and treatment of EBV-associated NPC.
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Affiliation(s)
- Senmiao Zhang
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Na Liu
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Pengfei Cao
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Qingshuang Qin
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Jing Li
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Li Yang
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Yujie Xin
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Mingjuan Jiang
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Siwei Zhang
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Jing Yang
- Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China
| | - Jianhong Lu
- Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; Department of Medical Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha, Hunan 410078, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, Hunan 410078, China.
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Arima J, Yoshino H, Fukumoto W, Kawahara I, Saito S, Li G, Fukuda I, Iizasa S, Mitsuke A, Sakaguchi T, Inoguchi S, Matsushita R, Nakagawa M, Tatarano S, Yamada Y, Enokida H. LncRNA BCYRN1 as a Potential Therapeutic Target and Diagnostic Marker in Serum Exosomes in Bladder Cancer. Int J Mol Sci 2024; 25:5955. [PMID: 38892143 PMCID: PMC11172611 DOI: 10.3390/ijms25115955] [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: 03/29/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Bladder cancer (BC) is a common genitourinary malignancy that exhibits silent morbidity and high mortality rates because of a lack of diagnostic markers and limited effective treatments. Here, we evaluated the role of the lncRNA brain cytoplasmic RNA 1 (BCYRN1) in BC. We performed loss-of-function assays to examine the effects of BCYRN1 downregulation in T24 and BOY BC cells. We found that BCYRN1 downregulation significantly inhibited the proliferation, migration, invasion, and three-dimensional spheroid formation ability and induced apoptosis in BC cells. Additionally, gene set enrichment analysis (GSEA) using RNA sequences from tumor fractions showed that BCYRN1 downregulation decreased the expression of mRNAs associated with the cell cycle. These findings were supported by observations of G2/M arrest in flow cytometry assays. Finally, we examined the expression of serum exosomal BCYRN1 as a biomarker. Clinically, BCYRN1 expression in serum exosomes from patients with BC (n = 31) was significantly higher than that in healthy donors (n = 19; mean difference: 4.1-fold higher, p < 0.01). Moreover, in patients who had undergone complete resection of BC, serum exosomal BCYRN1 levels were significantly decreased (n = 8). Thus, serum exosomal BCYRN1 may be a promising diagnostic marker and therapeutic target in patients with BC.
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Affiliation(s)
| | - Hirofumi Yoshino
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
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Zhou S, Van Bortle K. The Pol III transcriptome: Basic features, recurrent patterns, and emerging roles in cancer. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1782. [PMID: 36754845 PMCID: PMC10498592 DOI: 10.1002/wrna.1782] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
The RNA polymerase III (Pol III) transcriptome is universally comprised of short, highly structured noncoding RNA (ncRNA). Through RNA-protein interactions, the Pol III transcriptome actuates functional activities ranging from nuclear gene regulation (7SK), splicing (U6, U6atac), and RNA maturation and stability (RMRP, RPPH1, Y RNA), to cytoplasmic protein targeting (7SL) and translation (tRNA, 5S rRNA). In higher eukaryotes, the Pol III transcriptome has expanded to include additional, recently evolved ncRNA species that effectively broaden the footprint of Pol III transcription to additional cellular activities. Newly evolved ncRNAs function as riboregulators of autophagy (vault), immune signaling cascades (nc886), and translation (Alu, BC200, snaR). Notably, upregulation of Pol III transcription is frequently observed in cancer, and multiple ncRNA species are linked to both cancer progression and poor survival outcomes among cancer patients. In this review, we outline the basic features and functions of the Pol III transcriptome, and the evidence for dysregulation and dysfunction for each ncRNA in cancer. When taken together, recurrent patterns emerge, ranging from shared functional motifs that include molecular scaffolding and protein sequestration, overlapping protein interactions, and immunostimulatory activities, to the biogenesis of analogous small RNA fragments and noncanonical miRNAs, augmenting the function of the Pol III transcriptome and further broadening its role in cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Processing of Small RNAs RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Sihang Zhou
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Kevin Van Bortle
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
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Han XY, Li X, Zhao RY, Ma HZ, Yu M, Niu XD, Jin HJ, Wang YF, Liu DM, Cai H. Comprehensive analysis of prognostic value and immunotherapy prospect of brain cytoplasmic RNA1 in hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:644-664. [PMID: 37123057 PMCID: PMC10134208 DOI: 10.4251/wjgo.v15.i4.644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/18/2023] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND The expression of brain cytoplasmic RNA1 (BCYRN1) is linked to the clinicopathology and prognosis of several types of cancers, among which hepatocellular carcinoma (HCC) is one of the most frequent types of cancer worldwide.
AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.
METHODS Information was obtained from the Cancer Genome Atlas database. First, the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored. Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis. Secondly, potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes. The relationships between BCYRN1 expression and tumor microenvironment, immune cell infiltration, immune checkpoint, drug sensitivity and immunotherapy effect were also investigated. Finally, three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.
RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics. Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules, participates in the metabolism of nutrients, such as proteins, and participates in tumor-related pathways. BCYRN1 expression was linked to the tumor microenvironment, immune cell infiltration, drug sensitivity and the efficacy of immunotherapy. Furthermore, the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.
CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.
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Affiliation(s)
- Xiao-Yong Han
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiong Li
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Rang-Yin Zhao
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hai-Zhong Ma
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Miao Yu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiang-Dong Niu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hao-Jie Jin
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yong-Feng Wang
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - De-Ming Liu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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Clinicopathological Significance and Prognostic Values of Long Noncoding RNA BCYRN1 in Cancer Patients: A Meta-Analysis and Bioinformatics Analysis. JOURNAL OF ONCOLOGY 2022; 2022:8903265. [PMID: 35874631 PMCID: PMC9303157 DOI: 10.1155/2022/8903265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/14/2022] [Indexed: 12/24/2022]
Abstract
Background Although combination therapies have substantially improved the clinical outcomes of cancer patients, the prognosis and early diagnosis remain unsatisfactory. As a result, it is critical to look for novel indicators linked to cancer. Despite a number of recent studies indicating that the lncRNA brain cytoplasmic RNA1(BCYRN1) may be a potential predictive biomarker in cancer patients, BCYRN1's prognostic value is still being debated. Methods We utilized PubMed, Embase, Web of Science, and the Cochrane Library to search for studies related to BCYRN1 until October 2021. Valid data were extracted after determining the articles according to the inclusion and exclusion criteria, and forest plots were made using Stata software. We used hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals to evaluate the relationship between abnormal BCYRN1 expression and patient prognosis and clinicopathological characteristics. Results Meta-analysis revealed that increased BCYRN1 expression was associated with both overall tumor survival (OS; HR = 1.84, 95% CI 1.51–2.25, p < 0.0001) and disease-free survival (DFS; HR = 1.65, 95% CI 1.20–2.26, p=0.002). Furthermore, a strong association was discovered between increased BCYRN1 expression and tumor invasion depth (OR = 2.11, 95% CI 1.49–2.99, p=0.000), clinical stage (OR = 2.52, 95% CI 1.18–5.37, p=0.017), and distant tumor metastasis (OR = 4.19, 95% CI 1.45–12.05, p=0.008). Conclusions We found that high BCYRN1 expression was associated with poor survival prognosis and aggressive clinicopathological characteristics in various cancers, indicating that it is a potential prognostic indicator as well as a therapeutic target. Further research is needed on pan-cancer cohorts to determine the clinical relevance of BCYRN1 in distinct cancer types.
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Long Noncoding RNA BCYRN1 Recruits BATF to Promote TM4SF1 Upregulation and Enhance HCC Cell Proliferation and Invasion. DISEASE MARKERS 2022; 2022:1561607. [PMID: 35730016 PMCID: PMC9206761 DOI: 10.1155/2022/1561607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/29/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common form of cancer for which a subset of reliable clinical biomarkers has been defined. However, other factors including long noncoding RNAs (lncRNAs) can also regulate HCC development. This study was thus designed to understand how the lncRNA Brain cytoplasmic RNA 1 (BCYRN1) modulates HCC progression. Bioinformatics approaches were used to identify genes, lncRNAs, and transcription factors that were differentially expressed in the context of HCC, after which the relative expression of BCYRN1 in HCC and control tissues was assessed via qPCR. The ability of BCYRN1 to bind the transcription factor BATF was further evaluated in an RNA immunoprecipitation (RIP) assay, while chromatin immunoprecipitation (ChIP) was used to gauge the binding of the TM4SF1 promoter by BATF. Luciferase reporter assays were also used to assess the association between BCYRN1 and the TM4SF1 promoter. Subsequent loss- and gain-of-function assays were then conducted to explore the effects of altering BCYRN1 expression levels on the proliferative, invasive, and migratory activity of HCC cells. BCYRN1 upregulation was associated with poorer clinical outcomes in HCC patients, and knocking down this lncRNA impaired HCC cell migration and invasion. From a mechanistic perspective, BATF was recruited to the TM4SF1 promoter by BCYRN1, and reducing the expression of this lncRNA was sufficient to constrain xenograft tumor growth in mice. These results highlight BCYRN1 as a putative therapeutic target in HCC tumors.
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Akhbari MH, Zafari Z, Sheykhhasan M. Competing Endogenous RNAs (ceRNAs) in Colorectal Cancer: A Review. Expert Rev Mol Med 2022; 24:e27. [PMID: 35748050 DOI: 10.1017/erm.2022.21] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Colorectal cancer (CRC) is a common type of cancer and the second leading cause of cancer-related deaths worldwide. Competing endogenous RNAs (ceRNAs) that contain microRNA response elements (MREs) are involved in CRC progression. They can compete with microRNAs (miRNAs) via their MREs, which can combine non-coding and coding RNAs via complex ceRNA networks. This molecular interaction has the potential to affect a wide variety of biological processes, and many cancers can occur as a result of an imbalanced ceRNA network. Recent research indicates that numerous dysregulated RNAs in CRC may function as ceRNAs, regulating multiple biological functions of the tumour, including proliferation, apoptosis, metastasis, invasion and migration. In this review, we discuss the role of protein-coding and non-coding RNAs, such as long non-coding RNAs, circular RNAs and pseudogenes, in the occurrence of ceRNA networks in CRC, and their function in cancer-related pathways, such as Wnt/β-catenin, mitogen-activated protein kinase and transforming growth factor-β signalling pathways. Additionally, we discuss validated ceRNAs associated with CRC biological functions and their potential role as novel prognostic and diagnostic biomarkers. Examining the role of ceRNAs in CRC sheds new light on cancer treatment and pathogenesis.
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Affiliation(s)
| | - Zahra Zafari
- Department of Biology, Shahed University, Tehran, Iran
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
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Wang K, Huang D, Zhou P, Su X, Yang R, Shao C, Wu J. Bisphenol A exposure triggers the malignant transformation of prostatic hyperplasia in beagle dogs via cfa-miR-204/KRAS axis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 235:113430. [PMID: 35325610 DOI: 10.1016/j.ecoenv.2022.113430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/02/2022] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
The prostatic toxicity of bisphenol A (BPA) exposure is mainly associated with hormonal disturbances, thus interfering with multiple signal pathways and increasing the susceptibility to prostatic lesions. This study concentrates predominantly on the potential effect and mechanisms of low-dose BPA exposure on prostates in adult beagle dogs. The dogs were orally given BPA (2, 6, 18 μg/kg/day) and vehicle for 8 weeks, followed by blood collection and dissection. The ascended organ coefficient and volume of prostates, thickened epithelium, as well as histopathological observation have manifested that BPA exposure could trigger the aberrant prostatic hyperplasia in beagle dogs. Hormone level detection revealed that the ratios of estradiol (E2) to testosterone (T) (E2/T) and prolactin (PRL) to T (PRL/T) were up-regulated in the serum from BPA group. Based on microRNA (miRNA) microarray screening and functional enrichment analysis, BPA might facilitate the progression of prostate tumorigenesis in beagle dogs via cfa-miR-204 and its downstream target KRAS oncogene. Subsequently, the overexpression of KRAS, CDKN1A, MAPK1, VEGFA, BCL2 and PTGS2 was validated. These findings provide a series of underlying targets for preventing the initiation and metastasis of BPA-induced prostatic hyperplasia and tumorigenesis, while the regulatory relationship headed with KRAS requires further investigation.
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Affiliation(s)
- Kaiyue Wang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Dongyan Huang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Ping Zhou
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Xin Su
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Rongfu Yang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Congcong Shao
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Jianhui Wu
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Pharmacy School of Fudan University, Shanghai 200032, China; Department of Pharmacology & Toxicology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China.
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Zhao SY, Wang Z, Wu XB, Zhang S, Chen Q, Wang DD, Tan QF. CERS6-AS1 contributes to the malignant phenotypes of colorectal cancer cells by interacting with miR-15b-5p to regulate SPTBN2. Kaohsiung J Med Sci 2022; 38:403-414. [PMID: 35146902 DOI: 10.1002/kjm2.12503] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/17/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) act as tumor promoters or suppressors in various types of cancer. Previous investigations suggest that ceramide synthase 6 (CERS6) antisense RNA 1 (CERS6-AS1) acts as an oncogene in breast cancer; however, its role in colorectal cancer is unknown. This study aimed to explore the molecular mechanism of CERS6-AS1 in colorectal cancer. Gene expression in colorectal cancer was examined using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The viability and proliferation of colorectal cancer cells were measured by Cell Counting Kit-8 assays and colony formation assays. The migratory and invasive capacities of the colorectal cancer cells were assessed by Transwell assay. Cell stemness was examined by sphere-formation assay. Mechanistically, RNA pull-down assays, RNA immunoprecipitation assays, and luciferase reporter assays were performed to explore the relationship among CERS6-AS1, miR-15b-5p and spectrin beta, non-erythrocytic 2 (SPTBN2). Moreover, a xenograft tumor model was established to investigate the role of CERS6-AS1 in vivo. We found that CERS6-AS1 and SPTBN2 were highly expressed in colorectal cancer tissues and cells. CERS6-AS1 depletion inhibited cell viability, proliferation, migration, and invasion; the epithelial-mesenchymal transition process and stemness. It suppressed xenograft tumor growth in colorectal cancer. Moreover, SPTBN2 levels were positively regulated by CERS6-AS1 and negatively regulated by miR-15b-5p in colorectal cancer cells. Rescue assays revealed that SPTBN2 reversed the inhibitory effect of CERS6-AS1 deficiency on the malignant behaviors of colorectal cancer cells. Overall, the lncRNA CERS6-AS1 facilitates malignant phenotypes of colorectal cancer cells by targeting miR-15b-5p to upregulate SPTBN2.
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Affiliation(s)
- Shi-Yu Zhao
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Zhi Wang
- Department of Gastrointestinal Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, China
| | - Xiang-Bai Wu
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Shuai Zhang
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Qiao Chen
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Dong-Dong Wang
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Qiong-Feng Tan
- Department of Colorectal Anal Surgery, China Three Gorges University Colorectal Disease Research Institute, Yichang Key Laboratory of Precise Diagnosis and Treatment of Colorectal Cancer, The Second Hospital of China Three Gorges University, Yichang, Hubei, China
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10
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KRAS-related long noncoding RNAs in human cancers. Cancer Gene Ther 2022; 29:418-427. [PMID: 34489556 PMCID: PMC9113938 DOI: 10.1038/s41417-021-00381-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/29/2021] [Accepted: 08/11/2021] [Indexed: 02/08/2023]
Abstract
KRAS is one of the most widely prevalent proto-oncogenes in human cancers. The constitutively active KRAS oncoprotein contributes to both tumor onset and cancer development by promoting cell proliferation and anchorage-independent growth in a MAPK pathway-dependent manner. The expression of microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, while long noncoding RNAs (lncRNAs) can act as regulators of the miRNAs targeting KRAS oncogene in different cancers and have gradually become a focus of research in recent years. In this review article, we summarize recent advances in the research on lncRNAs that have sponging effects on KRAS-targeting miRNAs as crucial mediators of KRAS expression in different cell types and organs. A deeper understanding of lncRNA function in KRAS-driven cancers is of major fundamental importance and will provide a valuable clinical tool for the diagnosis, prognosis, and eventual treatment of cancers.
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11
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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12
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Abi Zamer B, Abumustafa W, Hamad M, Maghazachi AA, Muhammad JS. Genetic Mutations and Non-Coding RNA-Based Epigenetic Alterations Mediating the Warburg Effect in Colorectal Carcinogenesis. BIOLOGY 2021; 10:847. [PMID: 34571724 PMCID: PMC8472255 DOI: 10.3390/biology10090847] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) development is a gradual process defined by the accumulation of numerous genetic mutations and epigenetic alterations leading to the adenoma-carcinoma sequence. Despite significant advances in the diagnosis and treatment of CRC, it continues to be a leading cause of cancer-related deaths worldwide. Even in the presence of oxygen, CRC cells bypass oxidative phosphorylation to produce metabolites that enable them to proliferate and survive-a phenomenon known as the "Warburg effect". Understanding the complex glucose metabolism in CRC cells may support the development of new diagnostic and therapeutic approaches. Here we discuss the most recent findings on genetic mutations and epigenetic modulations that may positively or negatively regulate the Warburg effect in CRC cells. We focus on the non-coding RNA (ncRNA)-based epigenetics, and we present a perspective on the therapeutic relevance of critical molecules and ncRNAs mediating the Warburg effect in CRC cells. All the relevant studies were identified and assessed according to the genes and enzymes mediating the Warburg effect. The findings summarized in this review should provide a better understanding of the relevance of genetic mutations and the ncRNA-based epigenetic alterations to CRC pathogenesis to help overcome chemoresistance.
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Affiliation(s)
- Batoul Abi Zamer
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
| | - Wafaa Abumustafa
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Azzam A. Maghazachi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; (B.A.Z.); (W.A.)
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; (M.H.); (A.A.M.)
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13
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Jebelli A, Baradaran B, Mosafer J, Baghbanzadeh A, Mokhtarzadeh A, Tayebi L. Recent developments in targeting genes and pathways by RNAi-based approaches in colorectal cancer. Med Res Rev 2020; 41:395-434. [PMID: 32990372 DOI: 10.1002/med.21735] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 08/16/2020] [Accepted: 09/16/2020] [Indexed: 12/18/2022]
Abstract
A wide spectrum of genetic and epigenetic variations together with environmental factors has made colorectal cancer (CRC), which involves the colon and rectum, a challenging and heterogeneous cancer. CRC cannot be effectively overcomed by common conventional therapies including surgery, chemotherapy, targeted therapy, and hormone replacement which highlights the need for a rational design of novel anticancer therapy. Accumulating evidence indicates that RNA interference (RNAi) could be an important avenue to generate great therapeutic efficacy for CRC by targeting genes that are responsible for the viability, cell cycle, proliferation, apoptosis, differentiation, metastasis, and invasion of CRC cells. In this review, we underline the documented benefits of small interfering RNAs and short hairpin RNAs to target genes and signaling pathways related to CRC tumorigenesis. We address the synergistic effects of RNAi-mediated gene knockdown and inhibitors/chemotherapy agents to increase the sensitivity of CRC cells to common therapies. Finally, this review points new delivery systems/materials for improving the cellular uptake efficiency and reducing off-target effects of RNAi.
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Affiliation(s)
- Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Mosafer
- Research Center of Advanced Technologies in Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, Wisconsin, USA
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