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Zhai Z, Li H. Identification of CircRNAs that promote cancer and their potential contribution to hepatocellular carcinoma (HCC) pathogenesis. Clin Exp Med 2025; 25:60. [PMID: 39961942 PMCID: PMC11832687 DOI: 10.1007/s10238-025-01585-3] [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: 11/29/2024] [Accepted: 02/02/2025] [Indexed: 02/20/2025]
Abstract
The critical involvement of circRNAs in tumour progression and development is becoming increasingly evident. This study aimed to identify novel cancer-promoting circRNAs and explore their potential contribution to the pathogenesis of hepatocellular carcinoma (HCC). Expression profiles of circRNAs, miRNAs, and mRNAs associated with HCC were predicted through interaction analysis using data from the GEO and TCGA databases. A circRNA-miRNA-mRNA network was constructed, and the biological functions of the target mRNAs were predicted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was generated to identify important hub genes. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to determine the key modules related to cancer-promoting circRNAs. OncomiR and GEPIA were used to investigate the correlation between miRNAs, mRNAs, and clinicopathological features, while TIMER was utilized to explore the relationship between gene expression and immune cell infiltration. A network of 18 cancer-promoting circRNAs in HCC was identified, which enhanced the expression of 141 downstream mRNAs through competitive binding with 10 miRNAs. GO, KEGG, and PPI network analyses revealed that E2F1, H2AFX, TOP2A, and RAD51 are key hub genes within the competitive endogenous RNA (ceRNA) network, primarily involved in cell cycle regulation, cancer-related pathways, and angiogenesis. WGCNA identified the "HCC DUcircRNA Module". Moreover, these core genes and key modules were closely associated with pathological stage, patient survival, and B-cell immune infiltration. We constructed a ceRNA network related to cancer-promoting circRNAs. The genes and key modules involved in this network may serve as potential therapeutic targets.
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Affiliation(s)
- Zhensheng Zhai
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, NO.99 Longcheng Road, Xiaodian District, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Huiyu Li
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, NO.99 Longcheng Road, Xiaodian District, Taiyuan, 030032, Shanxi, People's Republic of China.
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Ghaderi-Zefrehi H, Rezaei M, Sadeghi F, Heiat M. Genetic polymorphisms in DNA repair genes and hepatocellular carcinoma risk. DNA Repair (Amst) 2021; 107:103196. [PMID: 34416543 DOI: 10.1016/j.dnarep.2021.103196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 05/23/2021] [Accepted: 07/26/2021] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent types of tumors worldwide. Its occurrence and development have been related to various risk factors, such as chronic infection with hepatitis B or C viruses and alcohol addiction. DNA repair systems play a critical role in maintaining the integrity of the genome. Defects in these systems have been related to increased susceptibility to various types of cancer. Multiple genetic polymorphisms in genes of DNA repair systems have been reported that may affect DNA repair capacity (DRC) and modulate risk to cancer. Several studies have been conducted to assess the role of polymorphisms of DNA repair genes on the HCC risk. Identifying these polymorphisms and their association with HCC risk may help to improve prevention and treatment strategies. In this study, we review investigations that evaluated the association between genetic polymorphisms of DNA repair genes and risk of HCC.
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Affiliation(s)
- Hossein Ghaderi-Zefrehi
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Rezaei
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farzin Sadeghi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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CD44, IL-33, and ST2 Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility in the Chinese Population. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2918517. [PMID: 33062675 PMCID: PMC7538256 DOI: 10.1155/2020/2918517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/24/2020] [Accepted: 09/17/2020] [Indexed: 01/27/2023]
Abstract
The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant (p < 0.05). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers (p = 0.007, odds ratio (OR) = 1.429, 95% confidence interval (CI): 1.102-1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes (p ≤ 0.001, OR = 1.647, 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.
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Baz M, Ibrahim T. Role of microRNAs in the predisposition to gastrointestinal malignancies. World J Clin Cases 2020; 8:1580-1585. [PMID: 32420299 PMCID: PMC7211524 DOI: 10.12998/wjcc.v8.i9.1580] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/26/2020] [Accepted: 04/24/2020] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs (miRNAs) are highly deregulated in cancer and play a role in the initiation of tumorigenesis. Recently, miRNAs have attracted attention in gastrointestinal (GI) cancers. Single nucleotide polymorphisms (SNPs) could affect the genes involved in each step of miRNA biosynthesis. Several meta-analyses of case-control studies have assessed the association between miRNA “pathway” gene-SNPs (including biosynthesis regulators and binding sites) and susceptibility to GI cancers. We present in this mini-review the current knowledge on the association between miRNAs “pathway” genes and GI cancer predisposition. The interaction between miRNA/regulators/binding site-SNPs and environmental as well as genomic factors is an interesting field that should be exploited in future studies.
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Affiliation(s)
- Maria Baz
- Department of Tumor Molecular Biology, Gustave Roussy Cancer Campus, Villfejuif 94805, France
| | - Tony Ibrahim
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villfejuif 94805, France
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Association between Single-Nucleotide Polymorphism in MicroRNA Target Site of DDB2 and Risk of Hepatocellular Carcinoma in a Southern Chinese Population. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8528747. [PMID: 32090112 PMCID: PMC7031712 DOI: 10.1155/2020/8528747] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/26/2019] [Accepted: 12/18/2019] [Indexed: 01/27/2023]
Abstract
Damage-specific DNA-binding protein 2 (DDB2) is a DNA repair protein mainly involved in nucleotide excision repair, which plays a pivotal role in maintaining genomic stability. In this study, we evaluated the association of single-nucleotide polymorphism (SNP) rs1050244 in miRNA target site of DDB2 gene with risk of hepatocellular carcinoma (HCC) among 1073 HCC patients and 1119 cancer-free controls in a southern Chinese population. Our results showed that no statistically significant association was found between DDB2 rs1050244 and HCC risk. In further analysis stratified by age, sex, smoking, alcohol drinking, and HBV infection status, we found that individuals carrying the CT/TT genotypes of SNP rs1050244 had a significantly decreased risk of HCC compared with those with the CC genotype among non-HBV infected population (adjusted OR = 0.31, 95% CI = 0.13–0.72), and a significant interaction was found between this SNP and HBV infection (Pinteraction=0.002). Our results suggested that the DDB2 rs1050244 C>T polymorphism was associated with the decreased risk of HCC among non-HBV infected population. Further studies with larger sample sizes are needed to validate our findings.
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Dai J, Chen Y, Gong Y, Gu D, Chen J. Association of microRNA-27a rs895819 polymorphism with the risk of cancer: An updated meta-analysis. Gene 2019; 728:144185. [PMID: 31838252 DOI: 10.1016/j.gene.2019.144185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND MiR-27a rs895819 polymorphism is considered as a tumor- related susceptibility gene. Previous meta-analyses evaluated the association the association between miR-27a rs895819 and cancer risk, but the results were inconsistent. The present meta-analysis was carried out to better estimate the correlation of rs895819 and cancer susceptibility. METHODS We searched several databases to identify relevant studies, including PubMed, EMBASE and the Cochrane Controlled Trials Register. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the association between miR-27a rs895819 and cancer risk. RESULTS The overall analysis showed the miR-27a rs895819 was not associated with cancer susceptibility in all models (dominant model: OR = 1.02, 95% CI:0.94-1.10, p = 0.632; recessive model: OR = 1.05, 95% CI: 0.92-1.76, p = 0.474; homozygote model: OR = 1.06, 95% CI: 0.91-1.23, p = 0.439; heterozygote model: OR = 1.00, 95% CI: 0.93-1.08, p = 0.934; and allele model: OR = 1.02, 95% CI: 0.96-1.09, p = 0.486). Interestingly, rs895819 A > G was significantly associated with colorectal cancer risk in recessive model (OR = 1.54, 95% CI: 1.29-1.83, p < 0.001), homozygote model (OR = 1.59, 95% CI: 1.31-1.92, p < 0.001), and allele model (OR = 1.22, 95% CI: 1.10-1.34, p < 0.001). In addition, rs895819 polymorphism was correlated with increased risk of breast cancer in the recessive model (OR = 0.81, 95% CI: 0.66-1.00, p = 0.046) and allele model (OR = 0.89, 95% CI: 0.80-0.98, p = 0.021). CONCLUSIONS Our results suggested that rs895819 polymorphism was correlated with increased risk of colorectal cancer and breast cancer, but not all types of cancer.
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Affiliation(s)
- Jiali Dai
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yuetong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Gong
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dongying Gu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
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Thyagarajan A, Tsai KY, Sahu RP. MicroRNA heterogeneity in melanoma progression. Semin Cancer Biol 2019; 59:208-220. [PMID: 31163254 PMCID: PMC6885122 DOI: 10.1016/j.semcancer.2019.05.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/31/2019] [Indexed: 01/27/2023]
Abstract
The altered expression of miRNAs has been linked with neocarcinogenesis or the development of human malignancies including melanoma. Of significance, multiple clinical studies have documented that distinct sets of microRNAs (miRNAs) could be utilized as prognostic biomarkers for cancer development or predict the outcomes of treatment responses. To that end, an in-depth validation of such differentially expressed miRNAs is necessary in diverse settings of cancer patients in order to devise novel approaches to control tumor growth and/or enhance the efficacy of clinically-relevant therapeutic options. Moreover, considering the heterogeneity and sophisticated regulation of miRNAs, the precise delineation of their cellular targets could also be explored to design personalized medicine. Given the significance of miRNAs in regulating several key cellular processes of tumor cells including cell cycle progression and apoptosis, we review the findings of such miRNAs implicated in melanoma tumorigenesis. Understanding the novel mechanistic insights of such miRNAs will be useful for developing diagnostic or prognostic biomarkers or devising future therapeutic intervention for malignant melanoma.
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Affiliation(s)
- Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA
| | - Kenneth Y Tsai
- Departments of Anatomic Pathology & Tumor Biology at H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA.
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Jiang YJ, Zhong JH, Zhou ZH, Qiu MQ, Zhou XG, Liu YC, Huo RR, Liang XM, Chen Z, Lin QL, Yu XY, Yu HP. Association between polymorphisms in MicroRNA target sites of RAD51D genes and risk of hepatocellular carcinoma. Cancer Med 2019; 8:2545-2552. [PMID: 30883040 PMCID: PMC6536933 DOI: 10.1002/cam4.2068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/10/2019] [Accepted: 02/12/2019] [Indexed: 01/27/2023] Open
Abstract
RAD51D (RAD51L3) is a member of the RAD51 gene family which plays important roles in maintaining genomic stability and preventing DNA damage. This study is aimed to investigate the associations between RAD51D polymorphisms and the hereditary susceptibility of hepatocellular carcinoma (HCC). In this study we conducted a hospital–based case‐control study including 805 cases (HCC patients) and 846 controls (nontumor patients) in Guangxi, China. A total of two Single–nucleotide polymorphisms (SNPs) rs12947947 and rs28363292 of RAD51D were selected and genotyped. Although we did not find two SNPs individually that had any significant main effect on risk of HCC, We found that the combined genotypes with 1‐2 risk genotypes were associated with significantly increased overall risk of HCC (OR = 1.462, 95% CI = 1.050‐2.036). According to the results of further stratification analysis, GT/GG genotype of rs28363292 increased HCC risk in zhuang people (OR = 3.913, 95% CI = 1.873‐8.175) and nonhepatitis B virus (HBV) infection population (OR = 1.774, 95% CI = 1.060‐2.969), the combined 1‐2 risk genotypes increased the risk of HCC in zhuang people (OR = 2.817, 95% CI = 1.532‐5.182) and non‐HBV infected population (OR = 1.567, 95% CI = 1.042‐2.358). Our results suggest that rs12947947 and rs28363292 polymorphisms may jointly contribute to the risk of HCC. Further large studies and functional studies are required to validate our findings.
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Affiliation(s)
- Yan-Ji Jiang
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.,School of Public Health, Guangxi Medical University, Guangxi, China
| | - Jian-Hong Zhong
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Zi-Han Zhou
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.,School of Public Health, Guangxi Medical University, Guangxi, China
| | - Mo-Qin Qiu
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.,School of Public Health, Guangxi Medical University, Guangxi, China
| | - Xian-Guo Zhou
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Ying-Chun Liu
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Rong-Rui Huo
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Xiu-Mei Liang
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Zhu Chen
- Affiliated Hospital of Guilin Medical University, Guangxi, China
| | - Qiu-Ling Lin
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.,School of Public Health, Guangxi Medical University, Guangxi, China
| | - Xiang-Yuan Yu
- School of Public Health, Guilin Medical University, Guangxi, China
| | - Hong-Ping Yu
- Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.,School of Public Health, Guangxi Medical University, Guangxi, China
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