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Chen Y, Yu W, Huang Y, Jiang Z, Deng J, Qi Y. Causal associations between sleep traits, sleep disorders, and glioblastoma: a two-sample bidirectional Mendelian randomization study. J Neurophysiol 2025; 133:513-521. [PMID: 39740798 DOI: 10.1152/jn.00338.2024] [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: 07/31/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/02/2025] Open
Abstract
Glioblastoma (GBM), a highly aggressive brain tumor predominantly affecting individuals over 40, often co-occurs with sleep disorders. However, the causal relationship remains unclear. This study employed a bidirectional Mendelian randomization (MR) approach to investigate the causal links between sleep traits/disorders and GBM. Sleep trait and disorder data were obtained from the IEU Open GWAS Project, while GBM data came from the Finn cohort. Primary analysis utilized the inverse-variance weighted (IVW) method, complemented by MR-Egger, weighted median, and weighted mode methods. MR pleiotropy residual sum and outlier (MR-PRESSO) was applied to detect potential outliers, and MR-Egger regression explored horizontal pleiotropy, with Cochran's Q test assessing heterogeneity. IVW analysis indicated a significant negative association between sleep duration and GBM risk [odds ratio (OR) = 0.13; 95% confidence interval (CI) = 0.02-0.80; P = 0.027). Conversely, GBM was positively associated with evening chronotype (OR = 1.0094; 95% CI = 1.0034-1.0154; P = 0.002). No significant associations were found for other sleep traits or disorders. Midday napping showed potential pleiotropy, and significant heterogeneity was noted in the reverse analysis. MR-PRESSO identified no outliers. Shorter sleep duration may elevate GBM risk, and GBM might influence circadian preference toward eveningness. Further studies are warranted to validate these findings.NEW & NOTEWORTHY This study employs a bidirectional Mendelian randomization approach to explore the causal relationship between various sleep traits, sleep disorders, and glioblastoma (GBM). We found that shorter sleep duration may increase GBM risk, while GBM may shift individuals toward an evening chronotype. No significant relationships were observed for other sleep traits or any of the sleep disorders. These findings illuminate the complex interplay between sleep and GBM, highlighting the need for further investigation into their correlations.
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Affiliation(s)
- Yuan Chen
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wenjun Yu
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yang Huang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zijuan Jiang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Juan Deng
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yujuan Qi
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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Mi S, Hu J, Chen W, Chen J, Xu Z, Xue M. m1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19. Clin Exp Metastasis 2025; 42:10. [PMID: 39843730 PMCID: PMC11754336 DOI: 10.1007/s10585-024-10323-0] [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: 06/12/2024] [Accepted: 10/04/2024] [Indexed: 01/24/2025]
Abstract
BACKGROUND In recent years, the emphasis has shifted to understanding the role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and its role in the metastasis of colorectal cancer (CRC). METHODS We performed methylated RNA immunoprecipitation sequencing of tumor tissues and tumor-adjacent normal tissues from three patients with CRC to determine the m1A profile of mRNA in CRC. The expression of diaphanous-related formin 3 (DIAPH3) and its correlation with clinicopathological characteristics of CRC were evaluated using immunohistochemistry and online datasets. The role of DIAPH3 in the migration and invasion of CRC cells was evaluated using wound healing assay, Transwell assay and xenograft metastatic model. The downstream targets of DIAPH3 were screened using mass spectrometry. By co-transfecting DIAPH3 siRNA and a keratin 19 (KRT19) ectopic plasmid into CRC cells, the role of DIAPH3-KRT19 signaling axis was confirmed. RESULTS The mRNA level of DIAPH3 and its m1A modifications increased simultaneously in the CRC tissues. In addition, high DIAPH3 expression in CRC tissues is significantly associated with metastasis and progression to an advanced stage. After the knockdown of DIAPH3, the migration and invasion capabilities of CRC cells suffered a notable decline, which could be rescued by overexpressing KRT19. In addition, the proteasome inhibitor MG132 could block the degradation of KRT19 induced by DIAPH3 silencing. CONCLUSIONS Our study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.
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Affiliation(s)
- Shuyi Mi
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Jie Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China
- Department of Gastroenterology, Jiande First People's Hospital, Jiande, Hangzhou, China
| | - Wenwen Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Jingyu Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Zhipeng Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China.
| | - Meng Xue
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
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Ding M, Wang W, Huo K, Song Y, Chen X, Xiang Z, Chen P, Liu L. The Role of lncRNA FEZF1-AS1 in Colorectal Cancer Progression Via the P53 Signaling Pathway. DNA Cell Biol 2025; 44:32-45. [PMID: 39503758 DOI: 10.1089/dna.2024.0184] [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] [Indexed: 01/30/2025] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical regulators in the development of colorectal cancer (CRC). Previous studies indicate that lncRNA FEZF1-AS1 is highly expressed in CRC, but its role in modulating CRC via the P53 signaling pathway remains unclear. In this study, we found that FEZF1-AS1 promotes the growth of the CRC cell line (HCT116) and drives epithelial-mesenchymal transition (EMT) through the P53 signaling pathway. Our data showed that FEZF1-AS1 expression is significantly upregulated in HCT116, and elevated levels of FEZF1-AS1 are associated with poor prognosis in patients with CRC. In addition, the knockdown of FEZF1-AS1 markedly inhibited the proliferation of HCT116 by inducing cell cycle arrest. Knockdown of FEZF1-AS1 depletion also led to apoptosis in CRC cells by suppressing the P53 signaling pathway and EMT, thereby reducing their viability, proliferation, migration, and invasion. In summary, this study confirmed that FEZF1-AS1 regulates the growth of junction HCT116 through P53 signaling pathway and inhibiting EMT, providing new insights for the potential therapeutic strategies against CRC.
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Affiliation(s)
- Minglu Ding
- Mudanjiang Medical University, Mudanjiang, China
| | - Wanyao Wang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Keyuan Huo
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Yidan Song
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaojie Chen
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Zihan Xiang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Lantao Liu
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
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Feng Y, Wang K, Fan J, Wu X, Li T, Yang Z. Mindfulness intervention, homogeneous medical concept, and concentrated solution nursing for colorectal cancer patients: a retrospective study. BMC Cancer 2024; 24:1055. [PMID: 39192195 DOI: 10.1186/s12885-024-12508-y] [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: 02/09/2024] [Accepted: 06/12/2024] [Indexed: 08/29/2024] Open
Abstract
OBJECTIVE We aim to explore the differences of the psychological distress of postoperative chemotherapy patients with colorectal cancer between mindfulness intervention combined with homogeneous medical concepts and mindfulness intervention only. METHODS One hundred patients with colorectal cancer undergoing chemotherapy after surgery from Sep 2020 to Sep 2022 were enrolled and divided into active control group (Solution centered nursing interventions; homogenized medical and nursing professional teams; dedicated personnel responsible for "admission notices"; Regular follow-up after discharge) and mindfulness group (homogeneous medical concept + and concentrated solution + Mindfulness intervention) with 50 cases in each group according to different nursing methods. RESULTS After nursing, the physical function, emotional function, cognitive function, and social function of the patients in the mindfulness group were significantly higher than those in the active control group. However, the overall life and economic difficulties of the patients in the mindfulness group were significantly lower than those in the active control group (P < 0.05). After nursing, the observation score, description score, action score, intrinsic experience score, non-judgment score and non-reaction score of the mindfulness group were significantly higher than those of the active control group (P < 0.05). CONCLUSION The implementation of mindfulness intervention in colorectal cancer patients undergoing chemotherapy can alleviate the patients' negative emotions, improve the level of mindfulness, and improve the quality of life of patients.
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Affiliation(s)
- Yaning Feng
- Physical Examination Center, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China
| | - Kuanlei Wang
- Hospital Office, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China
| | - Jianchun Fan
- Graduate School, Hebei North University, Zhangjiakou, 075000, China
| | - Xueliang Wu
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, 12 Changqing Rd, Zhangjiakou, 075000, China.
- Tumor Research Institute, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China.
| | - Tian Li
- School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Zhili Yang
- Department of General Surgery, The First Affiliated Hospital of Hebei North University, 12 Changqing Rd, Zhangjiakou, 075000, China.
- Department of Anorectal Surgery, Xinchang Country People's Hospital, 117 Gushan Middle Road, Xinchang, Zhejiang Province, 312500, China.
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Zhao B, Wang J, Sheng G, Wang Y, Yang T, Meng K. Identifying a Risk Signature of Methylation-Driven Genes as a Predictor of Survival Outcome for Colon Cancer Patients. Appl Biochem Biotechnol 2024; 196:4156-4165. [PMID: 37906409 DOI: 10.1007/s12010-023-04751-z] [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] [Accepted: 10/17/2023] [Indexed: 11/02/2023]
Abstract
Aberrant expression of gene is driven by its promoter methylation and is the key molecular basis of carcinogenic processes. This study aimed at identifying a risk signature of methylation-driven (MD) genes and evaluating its prognostic value for colon cancer (CC) patients. The expression profiles of methylation and mRNA in CC samples were obtained from the TCGA database, and the MethylMix algorithm was used to identify MD genes. The relationships between their expression levels and overall survival (OS) of CC patients were analyzed, and a prognostic signature of MD genes was established. The risk score of gene signature was calculated, and the median was used to divide all patients into high (H) and low (L) risk groups. The prognostic value of gene signature was tested by the TCGA cohort and an independent validation cohort (GSE17538 dataset). In total, 69 MD genes were identified, and 7 were associated with OS of CC patients. Ultimately, 4 (TWIST1, LDOC1, EPHX3, and STC2) were screened out to establish a risk signature. The H-risk patients (>0.923) had a worse OS than L-risk patients (≤0.923) in both the TCGA (5-year cumulative survival: 52.9% vs 72.0%, P=0.005) and GSE17538 cohort (49.4% vs 69.3%, P=0.004). The AUC values of MD genes signature for the prediction of 3- and 5-year OS were 0.648 and 0.643 in the TCGA dataset and 0.634 and 0.624 in the GSE17538 dataset, respectively. The risk signature of four MD genes was identified as an independent predictor of OS for CC patients (HR for TCGA dataset: 2.071, 95% CI=1.196-3.586, P=0.009; HR for GSE17538 dataset: 2.021, 95% CI=1.290-3.166, P=0.002). The risk signature of four MD genes might be a useful prognostic tool and help doctors improve the clinical management of CC patients.
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Affiliation(s)
- Bochao Zhao
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China.
| | - Jingchao Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China
| | - Guannan Sheng
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China
| | - Yiming Wang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China
| | - Tao Yang
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China
| | - Kewei Meng
- Department of Gastrointestinal Surgery, Tianjin First Central Hospital, No.24 Fukang Road, Nankai District, Tianjin, 300190, People's Republic of China.
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Yu F, Li L, Gu Y, Wang S, Zhou L, Cheng X, Jiang H, Huang Y, Zhang Y, Qian W, Li X, Liu Z. Lysine demethylase 5C inhibits transcription of prefoldin subunit 5 to activate c-Myc signal transduction and colorectal cancer progression. Mol Med 2024; 30:9. [PMID: 38216914 PMCID: PMC10785505 DOI: 10.1186/s10020-023-00775-7] [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: 11/09/2023] [Accepted: 12/22/2023] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Lysine demethylase 5C (KDM5C) has been implicated in the development of several human cancers. This study aims to investigate the role of KDM5C in the progression of colorectal cancer (CRC) and explore the associated molecular mechanism. METHODS Bioinformatics tools were employed to predict the target genes of KDM5C in CRC. The expression levels of KDM5C and prefoldin subunit 5 (PFDN5) in CRC cells were determined by RT-qPCR and western blot assays. The interaction between KDM5C, H3K4me3, and PFDN5 was validated by chromatin immunoprecipitation. Expression and prognostic values of KDM5C and PFDN5 in CRC were analyzed in a cohort of 72 patients. The function of KDM5C/PFDN5 in c-Myc signal transduction was analyzed by luciferase assay. Silencing of KDM5C and PFDN5 was induced in CRC cell lines to analyze the cell malignant phenotype in vitro and tumorigenic activity in nude mice. RESULTS KDM5C exhibited high expression, while PFDN5 displayed low expression in CRC cells and clinical CRC samples. High KDM5C levels correlated with poor survival and unfavorable clinical presentation, whereas elevated PFDN5 correlated with improved patient outcomes. KDM5C mediated demethylation of H3K4me3 on the PFDN5 promoter, suppressing its transcription and thereby enhancing the transcriptional activity of c-Myc. KDM5C knockdown in CRC cells suppressed cell proliferation, migration and invasion, epithelial-mesenchymal transition, and tumorigenic activity while increasing autophagy and apoptosis rates. However, the malignant behavior of cells was restored by the further silencing of PFDN5. CONCLUSION This study demonstrates that KDM5C inhibits PFDN5 transcription, thereby activating c-Myc signal transduction and promoting CRC progression.
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Affiliation(s)
- Fulong Yu
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, People's Republic of China
| | - Liang Li
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, People's Republic of China
| | - Yimei Gu
- Emergency ICU, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, Anhui, People's Republic of China
| | - Song Wang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Lianbang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Xiaohu Cheng
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Heng Jiang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Yang Huang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Yingfeng Zhang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China
| | - Wenbao Qian
- Department of Molecular Pathology, Hefei Da'an Medical Laboratory Co., Ltd., Hefei, 230012, Anhui, People's Republic of China
| | - Xianghua Li
- Department of Molecular Pathology, Hefei Da'an Medical Laboratory Co., Ltd., Hefei, 230012, Anhui, People's Republic of China.
| | - Zhining Liu
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Hefei, 230601, Anhui, People's Republic of China.
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Manogaran P, Anandan A, Vijaya Padma V. Isoliensinine augments the therapeutic potential of paclitaxel in multidrug-resistant colon cancer stem cells and induced mitochondria-mediated cell death. J Biochem Mol Toxicol 2023; 37:e23395. [PMID: 37424111 DOI: 10.1002/jbt.23395] [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: 11/01/2021] [Revised: 04/03/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023]
Abstract
Previously we have reported the isoliensinine (ISO) potentates the therapeutic potential of cisplatin in cisplatin resistant colorectal cancer stem cells. The present study evaluates the chemo-sensitizing potential of the combinatorial regimen of ISO and Paclitaxcel (PTX) on multidrug-resistant (MDR)-HCT-15 cells to reduce the dose requirement of both ISO and PTX. The results of the present study suggest that treatment with the combinatorial regimen of ISO and PTX enhanced the cytotoxic effect with resultant increase in apoptosis in MDR-HCT-15 cells as evident from the altered cellular morphology, G2/M cell cycle arrest, propidium iodide uptake, Annexin V, increased intracellular Ca2+ accumulation, decreased mitochondrial membrane potential, diminished ATP production, PARP-1 cleavage, altered expression of ERK1/2, and apoptotic proteins. Treatment with combinatorial regimen of ISO and PTX also modulated the expression of the transcription factors SOX2, OCT4 which determine the stemness of cancer cells. Thus, results of the present study suggest that ISO and PTX combination regimen induces apoptosis in MDR-HCT-15 in a synergistic manner.
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Affiliation(s)
- Prasath Manogaran
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Aparna Anandan
- Department of Biotechnology, Bharathiar University, Coimbatore, India
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Prognostic Nomogram for Colorectal Cancer Patients After Surgery. Indian J Surg 2023. [DOI: 10.1007/s12262-023-03712-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023] Open
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Sirtuin1 (SIRT1) is involved in the anticancer effect of black raspberry anthocyanins in colorectal cancer. Eur J Nutr 2023; 62:395-406. [PMID: 36056948 DOI: 10.1007/s00394-022-02989-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/11/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE Abnormal acetylation modification is a common epigenetic change in tumorigenesis and is closely related to the progression of colorectal cancer (CRC). Our previous studies have suggested that black raspberry (BRB) anthocyanins have a significant chemopreventive effect against CRC. This study investigated whether protein acetylation plays an important role in BRB anthocyanins-mediated regulation of CRC progression. METHODS We used the AOM-induced CRC mouse model and the CRC cell lines SW480 and Caco-2 to explore the potential role of acetylation of histone H4 and NF-κB signaling pathway-related proteins (non-histone proteins) in the antitumor process mediated by BRB anthocyanins. The expression of related proteins was detected by western blot. ROS level was detected by immunofluorescence. RESULTS BRB anthocyanins affected the acetylation level by down-regulating the expression of Sirtuin1 (SIRT1) and up-regulating the expression of MOF and EP300. The acetylation level of lysine sites on histone H4 (H4K5, H4K12 and H4K16) was increased. Furthermore, following BRB anthocyanins treatment, the expression of ac-p65 was significantly up-regulated and the NF-κB signal pathway was activated, which in turn up-regulated Bax expression and inhibited Bcl-2, cyclin-D1, c-myc and NLRP3 expression to promote CRC cell cycle arrest, apoptosis and relieve inflammation. CONCLUSION The findings suggested that protein acetylation could play a critical role in BRB anthocyanins-regulated CRC development.
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Tumor-augmenting Effect of Histone Methyltransferase WHSC1 on Colorectal Cancer Via Epigenetic Upregulation of TACC3 and PI3K/Akt Activation. Arch Med Res 2022; 53:658-665. [DOI: 10.1016/j.arcmed.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 09/14/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
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Construction of Nomogram-Based Prediction Model for Clinical Prognosis of Patients with Stage II and III Colon Cancer Who Underwent Xelox Chemotherapy after Laparoscopic Radical Resection. JOURNAL OF ONCOLOGY 2022; 2022:7742035. [PMID: 36213840 PMCID: PMC9546684 DOI: 10.1155/2022/7742035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/23/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022]
Abstract
Objective To construct a nomogram-based prediction model for the clinical prognosis of patients with stage II and III colon cancer who underwent Xelox chemotherapy after laparoscopic radical resection based on large data sets. Methods A total of 7,832 patients with colorectal cancer who received postoperative Xelox-based chemotherapy were screened from the Surveillance, Epidemiology, and End Results database (USA) as the training data set. In addition, 348 domestic patients were screened as the validation data set. Multivariate Cox regression analysis was performed to identify variables for inclusion in the nomogram-based prediction model. The predictive accuracy of the model was assessed using C-index and calibration curve. Results Age, cell differentiation, nerve invasion, T and N stages of tumours, number of dissected lymph nodes, and carcinoembryonic antigen (CEA) level were found to influence the efficacy of postoperative chemotherapy. The nomogram-based prediction model was successfully constructed. The C-index of both the training set and validation set were higher than those of the 7th edition of TNM staging system published by the American Joint Commission on Cancer (C − index of training data set = 0.728, C − index of validation data set = 0.734). The prediction results of the model in the calibration curve showed a good fit with the actual situation. Conclusion We successfully constructed a nomogram-based model to predict the clinical prognosis of patients with colorectal cancer receiving postoperative Xelox-based chemotherapy after laparoscopic radical resection, which showed good clinical application value for predicting the efficacy of postoperative Xelox-based chemotherapy in patients with colorectal cancer.
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Zheng Q, Zhang W, Rao GW. Protein Lysine Methyltransferase SMYD2: A Promising Small Molecule Target for Cancer Therapy. J Med Chem 2022; 65:10119-10132. [PMID: 35914250 DOI: 10.1021/acs.jmedchem.2c00325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In epigenetic research, the abnormality of protein methylation modification is closely related to the occurrence and development of tumors, which stimulates the interest of researchers in protein methyltransferase research and the efforts to develop corresponding specific small molecule inhibitors. Currently, the protein lysine methyltransferase SMYD2 has been identified as a promising new small molecule target for cancer therapy. But its biological functions have not been fully studied and relatively few inhibitors have been reported, thus this field needs to be further explored. This perspective provides a comprehensive and systematic review of the available resources in this field, including its research status, biological structure, related substrates and methylation mechanisms, and research status of inhibitors. In addition, this perspective elaborates in detail the current challenges in this field, our insights into what needs to be done next, rational drug design of novel SMYD2 inhibitors, and foreseeable development directions in the future.
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Affiliation(s)
- Quan Zheng
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China
| | - Wen Zhang
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China
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Alagia A, Gullerova M. The Methylation Game: Epigenetic and Epitranscriptomic Dynamics of 5-Methylcytosine. Front Cell Dev Biol 2022; 10:915685. [PMID: 35721489 PMCID: PMC9204050 DOI: 10.3389/fcell.2022.915685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
DNA and RNA methylation dynamics have been linked to a variety of cellular processes such as development, differentiation, and the maintenance of genome integrity. The correct deposition and removal of methylated cytosine and its oxidized analogues is pivotal for cellular homeostasis, rapid responses to exogenous stimuli, and regulated gene expression. Uncoordinated expression of DNA/RNA methyltransferases and demethylase enzymes has been linked to genome instability and consequently to cancer progression. Furthermore, accumulating evidence indicates that post-transcriptional DNA/RNA modifications are important features in DNA/RNA function, regulating the timely recruitment of modification-specific reader proteins. Understanding the biological processes that lead to tumorigenesis or somatic reprogramming has attracted a lot of attention from the scientific community. This work has revealed extensive crosstalk between epigenetic and epitranscriptomic pathways, adding a new layer of complexity to our understanding of cellular programming and responses to environmental cues. One of the key modifications, m5C, has been identified as a contributor to regulation of the DNA damage response (DDR). However, the various mechanisms of dynamic m5C deposition and removal, and the role m5C plays within the cell, remains to be fully understood.
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Affiliation(s)
| | - Monika Gullerova
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
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14
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Pan L, Fan Y, Zhou L. SMYD2
epigenetically activates
MEX3A
and suppresses
CDX2
in colorectal cancer cells to augment cancer growth. Clin Exp Pharmacol Physiol 2022; 49:959-969. [PMID: 35637161 DOI: 10.1111/1440-1681.13679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Lizhen Pan
- Department of Gastroenterology Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu P.R. China
| | - Yuejuan Fan
- Department of Gastroenterology Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu P.R. China
| | - Lei Zhou
- Department of Gastroenterology Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou Jiangsu P.R. China
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15
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Fu L, Shi Z, Chen B. Deleted in lymphocytic leukemia 2 induces retinoic acid receptor beta promoter methylation and mitogen activated kinase-like protein activation to enhance viability and mobility of colorectal cancer cells. Bioengineered 2022; 13:12847-12862. [PMID: 35611845 PMCID: PMC9275910 DOI: 10.1080/21655979.2022.2076482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Abnormal expression of long non-coding RNAs (lncRNAs) is frequently linked to the pathogenesis of colorectal cancer (CRC). This work explored the function of lncRNA deleted in lymphocytic leukemia 2 (DLEU2) in CRC and the epigenetic mechanism. Candidate oncogenes in CRC were predicted using a GSE146587 dataset. DLEU2 was highly expressed in CRC according to the bioinformatic analysis and its high expression was detected in CRC cells compared to the normal colon epithelial cells (FHC). Downregulation of DLEU2 in CRC SW480 and HT29 cells suppressed viability, migration, invasiveness, and resistance to apoptosis of cells. The mRNA microarray analysis was performed to explore the key molecules mediated by DLEU2. Retinoic acid receptor beta (RARB) expression was elevated in cells after DLEU2 downregulation. The promoter methylation of RARB was enhanced in CRC cells compared to normal FHC cells. DLEU2 induced promoter methylation of RARB to downregulate its expression. Further silencing of RARB restored proliferation and invasiveness of cells blocked by sh-DLEU2. Upregulation of DLEU2 activated the mitogen activated kinase-like protein (MAPK) signaling pathway to trigger CRC progression. In conclusion, this study demonstrates that DLEU2 enhances viability and mobility of CRC cells by inducing RARB promoter methylation and activating the MAPK signaling pathway.
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Affiliation(s)
- Liang Fu
- Department of Anorectal Surgery, Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Zhitao Shi
- Department of General Surgery, Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi. P.R. China
| | - Bingxue Chen
- Department of General Surgery, Changzhou No. 2 Peoples' Hospital, Changzhou, P.R. China
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16
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Jin Y, Liu T, Luo H, Liu Y, Liu D. Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development. Front Oncol 2022; 12:848221. [PMID: 35419278 PMCID: PMC8995554 DOI: 10.3389/fonc.2022.848221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Dysregulation of the epigenetic enzyme-mediated transcription of oncogenes or tumor suppressor genes is closely associated with the occurrence, progression, and prognosis of tumors. Based on the reversibility of epigenetic mechanisms, small-molecule compounds that target epigenetic regulation have become promising therapeutics. These compounds target epigenetic regulatory enzymes, including DNA methylases, histone modifiers (methylation and acetylation), enzymes that specifically recognize post-translational modifications, chromatin-remodeling enzymes, and post-transcriptional regulators. Few compounds have been used in clinical trials and exhibit certain therapeutic effects. Herein, we summarize the classification and therapeutic roles of compounds that target epigenetic regulatory enzymes in cancer treatment. Finally, we highlight how the natural compounds berberine and ginsenosides can target epigenetic regulatory enzymes to treat cancer.
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Affiliation(s)
- Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Tianjia Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Haoming Luo
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yangyang Liu
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Da Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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17
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Molecular Landscape of Small Bowel Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14051287. [PMID: 35267592 PMCID: PMC8909755 DOI: 10.3390/cancers14051287] [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: 01/23/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and poor overall prognosis compared to other cancers of the gastrointestinal tract. Owing to the rarity of the disease along with the paucity of high-quality tissue samples and preclinical models, little is known about the molecular alterations characteristic of SBA. This is reflected by the fact that the clinical management of SBA is primarily extrapolated from colorectal cancer (CRC). Recent advances in genomic profiling have highlighted key differences between these tumors, establishing SBA as a molecularly unique intestinal cancer. Moreover, comprehensive molecular analysis has identified a relatively high incidence of potentially targetable genomic alterations in SBA, predictive of response to targeted and immunotherapies. Further advances in our knowledge of the mutational and transcriptomic landscape of SBA, guided by an increased understanding of the molecular drivers of SBA, will provide opportunities to develop novel diagnostic tools and personalized therapeutic strategies.
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18
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Cheng T, Zhu X, Lu J, Teng X. MiR-532-3p suppresses cell proliferation, migration and invasion of colon adenocarcinoma via targeting FJX1. Pathol Res Pract 2022; 232:153835. [DOI: 10.1016/j.prp.2022.153835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 02/14/2022] [Accepted: 03/05/2022] [Indexed: 12/19/2022]
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19
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Su JQ, Lai PY, Hu PH, Hu JM, Chang PK, Chen CY, Wu JJ, Lin YJ, Sun CA, Yang T, Hsu CH, Lin HC, Chou YC. Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan. World J Gastroenterol 2022; 28:825-839. [PMID: 35317099 PMCID: PMC8900576 DOI: 10.3748/wjg.v28.i8.825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/24/2021] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) undergo surgery, as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor–node– metastasis (TNM) cancer staging system. However, treatment responses and prognostic outcomes of patients within the same stage vary markedly. The potential use of novel biomarkers can improve prognostication and shared decision making before implementation into certain therapies.
AIM To investigate whether SUMF2, ADAMTS5, and PXDN methylation status could be associated with CRC prognosis.
METHODS We conducted a Taiwan region cohort study involving 208 patients with CRC recruited from Tri-Service General Hospital and applied the candidate gene approach to identify three genes involved in oncogenesis pathways. A methylation-specific polymerase chain reaction (MS-PCR) and EpiTYPER DNA methylation analysis were employed to detect methylation status and to quantify the methylation level of candidate genes in tumor tissue and adjacent normal tissue from participants. We evaluated SUMF2, ADAMTS5, and PXDN methylation as predictors of prognosis, including recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS), using a Cox regression model and Kaplan–Meier analysis.
RESULTS We revealed various outcomes related to methylation and prognosis. Significantly shorter PFS and OS were associated with the CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue compared with CpG_3+CpG_7 hypomethylation [hazard ratio (HR) = 2.24, 95% confidence interval (CI) = 1.03-4.85 for PFS, HR = 2.56 and 95%CI = 1.08-6.04 for OS]. By contrast, a significantly longer RFS was associated with CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue compared with CpG_2 and CpG_13 hypomethylation [HR (95%CI) = 0.15 (0.03-0.71) for CpG_2 and 0.20 (0.04-0.97) for CpG_13]. The relationship between the methylation status of PXDN and the prognosis of CRC did not reach statistical significance.
CONCLUSION Our study found that CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue was associated with significantly shorter PFS and OS compared with CpG_3+CpG_7 hypomethylation. CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue was associated with a significantly longer RFS compared with CpG_2 and CpG_13 hypomethylation. These methylation-related biomarkers which have implications for CRC prognosis prediction may aid physicians in clinical decision-making.
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Affiliation(s)
- Jing-Quan Su
- School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Pin-Yu Lai
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Pei-Hsuan Hu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Je-Ming Hu
- Division of Colorectal Surgery, Department of surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Pi-Kai Chang
- Division of Colorectal Surgery, Department of surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chao-Yang Chen
- Division of Colorectal Surgery, Department of surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Jia-Jheng Wu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Jyun Lin
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
- Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
| | - Tsan Yang
- Department of Health Business Administration, Meiho University, Pingtung County 912, Taiwan
| | - Chih-Hsiung Hsu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Hua-Ching Lin
- Division of Colorectal Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei 112, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
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20
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Huang Y, Huang C, Jiang X, Yan Y, Zhuang K, Liu F, Li P, Wen Y. Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis. Front Genet 2022; 13:816173. [PMID: 35281843 PMCID: PMC8908034 DOI: 10.3389/fgene.2022.816173] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.
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Affiliation(s)
- Yuancheng Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chaoyuan Huang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaotao Jiang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanhua Yan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kunhai Zhuang
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Liu
- Department of Gastroenterology, Baiyun Branch of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Peiwu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
| | - Yi Wen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Peiwu Li, ; Yi Wen,
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21
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Yun Z, Yue M, Kang Z, Zhang P. Reduced expression of microRNA-432-5p by DNA methyltransferase 3B leads to development of colorectal cancer through upregulation of CCND2. Exp Cell Res 2022; 410:112936. [PMID: 34801563 DOI: 10.1016/j.yexcr.2021.112936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND The tumor suppressive function of microRNA-432-5p (miR-432-5p) has been reported in several human malignances. This study aimed to probe the expression profile and role of miR-432-5p in colorectal cancer (CRC) and the molecular mechanism. METHODS Differentially expressed miRNAs between CRC and healthy samples were screened using a miRNA expression dataset GSE136020. The related molecules were identified by integrated bioinformatic analyses. A murine model of primary CRC was established and xenograft tumors were induced in mice. Altered expression of DNMT3B, miR-432-5p and cyclin D2 (CCND2) were introduced in CRC cells to determine their roles in the development of CRC. RESULTS miR-432-5p was downregulated in CRC according to the GSE136020 dataset. CCND2 mRNA was confirmed as a target of miR-432-5p. miR-432-5p was downregulated, whereas CCND2 was abundantly expressed in CRC tissues and cells. DNA methyltransferase 3B (DNMT3B) induced DNA methylation at the CpG island of miR-432-5p to inhibit its expression. miR-432-5p mimic significantly suppressed tumorigenesis of primary CRC in mice. Downregulation of DNMT3B weakened viability, invasiveness, blocked the cell cycle progression of CRC cells in vitro, and inhibited xenograft tumor growth and metastasis in nude mice. However, additional downregulation of miR-432-5p or upregulation of CCND2 restored the malignant behaviors of CRC cells. CONCLUSION This study showed that DNMT3B induced DNA methylation and downregulation of miR-432-5p to promote development of CRC by upregulating CCND2.
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Affiliation(s)
- Zhennan Yun
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China
| | - Meng Yue
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China
| | - Zhenhua Kang
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China.
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22
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Qiu Z, Wang Q, Liu L, Li G, Hao Y, Ning S, Zhang L, Zhang X, Chen Y, Wu J, Wang X, Yang S, Lin Y, Xu S. Riddle of the Sphinx: Emerging Role of Transfer RNAs in Human Cancer. Front Pharmacol 2021; 12:794986. [PMID: 34975491 PMCID: PMC8714751 DOI: 10.3389/fphar.2021.794986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/10/2021] [Indexed: 01/16/2023] Open
Abstract
The dysregulation of transfer RNA (tRNA) expression contributes to the diversity of proteomics, heterogeneity of cell populations, and instability of the genome, which may be related to human cancer susceptibility. However, the relationship between tRNA dysregulation and cancer susceptibility remains elusive because the landscape of cancer-associated tRNAs has not been portrayed yet. Furthermore, the molecular mechanisms of tRNAs involved in tumorigenesis and cancer progression have not been systematically understood. In this review, we detail current knowledge of cancer-related tRNAs and comprehensively summarize the basic characteristics and functions of these tRNAs, with a special focus on their role and involvement in human cancer. This review bridges the gap between tRNAs and cancer and broadens our understanding of their relationship, thus providing new insights and strategies to improve the potential clinical applications of tRNAs for cancer diagnosis and therapy.
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Affiliation(s)
- Zhilin Qiu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qin Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lei Liu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guozheng Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yi Hao
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shipeng Ning
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lei Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Zhang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yihai Chen
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiale Wu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xinheng Wang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shuai Yang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yaoxin Lin
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China
- *Correspondence: Yaoxin Lin, ; Shouping Xu,
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Yaoxin Lin, ; Shouping Xu,
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23
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Yeoh Y, Low TY, Abu N, Lee PY. Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance. PeerJ 2021; 9:e12338. [PMID: 34733591 PMCID: PMC8544255 DOI: 10.7717/peerj.12338] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.
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Affiliation(s)
- Yeelon Yeoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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24
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Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021; 14:101174. [PMID: 34243011 PMCID: PMC8273208 DOI: 10.1016/j.tranon.2021.101174] [Citation(s) in RCA: 1213] [Impact Index Per Article: 303.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence of CRC is higher in highly developed countries, and it is increasing in middle- and low-income countries due to westernization. Moreover, a rising incidence of early-onset CRC is also emerging. The large number of CRC cases poses a growing global public health challenge. Raising awareness of CRC is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing CRC morbidity and mortality in the future. CRC is a heterogeneous disease, and its subtype affiliation influences prognosis and therapeutic response. An accurate CRC subtype classification system is of great significance for basic research and clinical outcome. Here, we present the global epidemiology of CRC in 2020 and projections for 2040, review the major CRC subtypes to better understand CRC molecular basis, and summarize current risk factors, prevention, and screening strategies for CRC.
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Affiliation(s)
- Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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25
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Sadoughi F, Mirhashemi SM, Asemi Z. Epigenetic roles of PIWI proteins and piRNAs in colorectal cancer. Cancer Cell Int 2021; 21:328. [PMID: 34193172 PMCID: PMC8243752 DOI: 10.1186/s12935-021-02034-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 06/19/2021] [Indexed: 12/24/2022] Open
Abstract
Small non‐coding RNAs (sncRNAs) are a subgroup of non‐coding RNAs, with less than 200 nucleotides length and no potential for coding proteins. PiRNAs, a member of sncRNAs, were first discovered more than a decade ago and have attracted researcher’s attention because of their gene regulatory function both in the nucleus and in the cytoplasm. Recent investigations have found that the abnormal expression of these sncRNAs is involved in many human diseases, including cancers. Colorectal cancer (CRC), as a common gastrointestinal malignancy, is one of the important causes of cancer‐related deaths through the entire world and appears to be a consequence of mutation in the genome and epigenetic alterations. The aim of this review is to realize whether there is a relationship between CRC and piRNAs or not.
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Affiliation(s)
- Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. of Iran
| | - Seyyed Mehdi Mirhashemi
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. of Iran.
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26
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Perillo A, Agbaje Olufemi MV, De Robbio J, Mancuso RM, Roscigno A, Tirozzi M, Scognamiglio IR. Liquid biopsy in NSCLC: a new challenge in radiation therapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:156-173. [PMID: 36046142 PMCID: PMC9400754 DOI: 10.37349/etat.2021.00038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 02/23/2021] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide. To date, tissue biopsy has been the gold standard for the diagnosis and the identification of specific molecular mutations, to guide choice of therapy. However, this procedure has several limitations. Liquid biopsy could represent a solution to the intrinsic limits of traditional biopsy. It can detect cancer markers such as circulating tumor DNA or RNA (ctDNA, ctRNA), and circulating tumor cells, in plasma, serum or other biological fluids. This procedure is minimally invasive, reproducible and can be used repeatedly. The main clinical applications of liquid biopsy in non-small cell lung cancer (NSCLC) patients are the early diagnosis, stratification of the risk of relapse, identification of mutations to guide application of targeted therapy and the evaluation of the minimum residual disease. In this review, the current role of liquid biopsy and associated markers in the management of NSCLC patients was analyzed, with emphasis on ctDNA and CTCs, and radiotherapy.
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Affiliation(s)
- Annarita Perillo
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Mohamed Vincenzo Agbaje Olufemi
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Jacopo De Robbio
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Rossella Margherita Mancuso
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Anna Roscigno
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Maddalena Tirozzi
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Ida Rosalia Scognamiglio
- Department of Advanced Biomedical Sciences, University “Federico II” School of Medicine, Via Sergio Pansini 5, 80131 Napoli, Italy
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27
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Wang H, Xing J, Wang W, Lv G, He H, Lu Y, Sun M, Chen H, Li X. Molecular Characterization of the Oncogene BTF3 and Its Targets in Colorectal Cancer. Front Cell Dev Biol 2021; 8:601502. [PMID: 33644029 PMCID: PMC7905040 DOI: 10.3389/fcell.2020.601502] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/26/2020] [Indexed: 01/12/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide, and the prognosis of patients with CRC remains unsatisfactory. Basic transcription factor 3 (BTF3) is an oncogene and hazardous prognosticator in CRC. Although two distinct functional mechanisms of BTF3 in different cancer types have been reported, its role in CRC is still unclear. In this study, we aimed to molecularly characterize the oncogene BTF3 and its targets in CRC. Here, we first identified the transcriptional targets of BTF3 by applying combined RNA-Seq and ChIP-Seq analysis, identifying CHD1L as a transcriptional target of BTF3. Thereafter, we conducted immunoprecipitation (IP)-MS and E3 ubiquitin ligase analysis to identify potential interacting targets of BTF3 as a subunit of the nascent-polypeptide-associated complex (NAC). The analysis revealed that BTF3 might also inhibit E3 ubiquitin ligase HERC2-mediated p53 degradation. Finally, miRNAs targeting BTF3 were predicted and validated. Decreased miR-497-5p expression is responsible for higher levels of BTF3 post-transcriptionally. Collectively, we concluded that BTF3 is an oncogene, and there may exist a transcription factor and NAC-related proteolysis mechanism in CRC. This study provides a comprehensive basis for understanding the oncogenic mechanisms of BTF3 in CRC.
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Affiliation(s)
- Hantao Wang
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
| | - Junjie Xing
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
| | - Wei Wang
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
| | - Guifen Lv
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
| | - Haiyan He
- Department of Digestive Endoscopy, Changhai Hospital, Shanghai, China
| | - Yeqing Lu
- Department of Anesthesiology, Changhai Hospital, Shanghai, China
| | - Mei Sun
- Department of Anesthesiology, Changhai Hospital, Shanghai, China
| | - Haiyan Chen
- Department of Endocrinology, Changzheng Hospital, Shanghai, China
| | - Xu Li
- Department of Colorectal Surgery, Changhai Hospital, Shanghai, China
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28
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Viralippurath Ashraf J, Sasidharan Nair V, Saleh R, Elkord E. Role of circular RNAs in colorectal tumor microenvironment. Biomed Pharmacother 2021; 137:111351. [PMID: 33550046 DOI: 10.1016/j.biopha.2021.111351] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) are a class of endogenous noncoding RNA, which were previously considered as a byproduct of RNA splicing error. Numerous studies have demonstrated the altered expression of circRNAs in organ tissues during pathological conditions and their involvements in disease pathogenesis and progression, including cancers. In colorectal cancer (CRC), multiple circRNAs have been identified and characterized as "oncogenic", given their involvements in the downregulation of tumor suppressor genes and induction of tumor initiation, progression, invasion, and metastasis. Additionally, other circRNAs have been identified in CRC and characterized as "tumor suppressive" based on their ability of inhibiting the expression of oncogenic genes and suppressing tumor growth and proliferation. circRNAs could serve as potential diagnostic and prognostic biomarkers, and therapeutic targets or vectors to be utilized in cancer therapies. This review briefly describes the dynamic changes of the tumor microenvironment inducing immunosuppression and tumorigenesis, and outlines the biogenesis and characteristics of circRNAs and recent findings indicating their roles and functions in the CRC tumor microenvironment. It also discusses strategies and technologies, which could be employed in the future to overcome current cancer therapy challenges associated with circRNAs.
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Affiliation(s)
| | - Varun Sasidharan Nair
- Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Reem Saleh
- Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Eyad Elkord
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar; Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
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29
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Yan G, Li S, Yue M, Li C, Kang Z. Lysine demethylase 5B suppresses CC chemokine ligand 14 to promote progression of colorectal cancer through the Wnt/β-catenin pathway. Life Sci 2021; 264:118726. [PMID: 33160990 DOI: 10.1016/j.lfs.2020.118726] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022]
Abstract
AIMS Epigenetic and genetic alterations are crucial events in the onset and progression of human cancers including colorectal cancer (CRC). This work aims to probe the relevance of lysine demethylase 5B (KDM5B) to the progression of CRC and the possible molecules involved. MATERIALS AND METHODS KDM5B expression in CRC tissues and cells was determined. The association between KDM5B and the prognosis of patients was analyzed. Gain- and loss-of function studies of KDM5B were performed in HT-29 and KDM5B cells to explore the impact of KDM5B on cell behaviors. Expression of CC chemokine ligand 14 (CCL14) in CRC tissues and cells and its correlation with KDM5B were analyzed. Altered expression of CCL14 was introduced in CRC cells, and a Wnt/β-catenin-specific antagonist KYA1797K was induced in cells as well. KEY FINDINGS KDM5B was abundantly expressed while CCL14 was poorly expressed in CRC tissues and cells. High KDM5B expression was relevant to poor prognosis of patients. Downregulation of KDM5B suppressed proliferation and aggressiveness of HT-29 cells, and reduced the growth of xenograft tumors in mice, while upregulation of KDM5B in SW480 cells led to reverse results. KDM5B reduced CCL14 expression through demethylation modification of H3K4me3. Upregulation of CCL14 suppressed colony formation and invasiveness of CRC cells. KDM5B downregulated CCL14 to activate the Wnt/β-catenin. Inhibition of β-catenin by KYA1797K blocked the oncogenic roles of KDM5B in cells and in xenograft tumors. SIGNIFICANCE This study suggested that KDM5B suppresses CCL14 through demethylation modification of H3K4me3, leading to activation of the Wnt/β-catenin and the CRC progression.
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Affiliation(s)
- Guoqiang Yan
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China
| | - Shiquan Li
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China
| | - Meng Yue
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China
| | - Chenyao Li
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China
| | - Zhenhua Kang
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China.
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30
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Klutstein M. Cause and effect in epigenetics - where lies the truth, and how can experiments reveal it?: Epigenetic self-reinforcing loops obscure causation in cancer and aging. Bioessays 2020; 43:e2000262. [PMID: 33236359 DOI: 10.1002/bies.202000262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/19/2022]
Abstract
Epigenetic changes are implicated in aging and cancer. Sometimes, it is clear whether the causing agent of the condition is a genetic factor or epigenetic. In other cases, the causative factor is unclear, and could be either genetic or epigenetic. Is there a general role for epigenetic changes in cancer and aging? Here, I present the paradigm of causative roles executed by epigenetic changes. I discuss cases with clear roles of the epigenome in cancer and aging, and other cases showing involvement of other factors. I also present the possibility that sometimes causality is difficult to assign because of the presence of self-reinforcing loops in epigenetic regulation. Such loops hinder the identification of the causative factor. I provide an experimental framework by which the role of the epigenome can be examined in a better setting and where the presence of such loops could be investigated in more detail.
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Affiliation(s)
- Michael Klutstein
- Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
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31
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Lin Y, Meng Y, Zhang J, Ma L, Jiang L, Zhang Y, Yuan M, Ren A, Zhu W, Li S, Shu Y, Du M, Zhu L. Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer. J Cell Mol Med 2020; 24:14160-14170. [PMID: 33118286 PMCID: PMC7754038 DOI: 10.1111/jcmm.16026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression‐free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual‐luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40‐3.22, P = 4.03 × 10−4; PFS, HR = 1.64, 95% CI = 1.11‐2.44, P = 1.35 × 10−2), of which T allele could increase HSD17B12 expression (P = 1.78 × 10−11). Subsequently, the functional experiments indicated that rs10838164 T allele could not only enhance the binding affinity of transcription factor YY1 to HSD17B12 region harbouring rs10838164 but also promote the transcriptional activity of HSD17B12, which was significantly up‐regulated in colorectal tumour tissues. Our findings suggest that genetic variants in fatty acid biosynthesis pathway play an important role in CRC outcome.
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Affiliation(s)
- Yu Lin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yixuan Meng
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jinying Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Ma
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lu Jiang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ming Yuan
- Department of Oncology, The Jiangyin People's Hospital, Wuxi, China
| | - Anjing Ren
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiyou Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuwei Li
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lingjun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Oncology, The Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
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32
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Wang X, Wang Z, Wang K, Gao M, Zhang H, Xu X. Metabolomics analysis of multidrug resistance in colorectal cancer cell and multidrug resistance reversal effect of verapamil. Biomed Chromatogr 2020; 35:e4976. [PMID: 32852057 DOI: 10.1002/bmc.4976] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/19/2020] [Accepted: 08/23/2020] [Indexed: 12/20/2022]
Abstract
Multidrug resistance remains a huge challenge in the chemotherapy of cancer and numerous studies have reported that P-glycoprotein is the most common mechanism of multidrug resistance. Verapamil has been shown to be able to reverse development of multidrug resistance mediated by P-glycoprotein. However, the mechanism of action for verapamil in reversing multidrug resistance at the metabolic level has been rarely reported. In this research, we report the reversal effect of verapamil on multidrug resistance and its mechanisms of action using metabolomics. The results show that the P-glycoprotein-mediated chemotherapy drug resistance was significantly reversed by verapamil in resistant SW620/Ad300 cells. In-depth studies demonstrated that verapamil at reversal concentration had no effect on the P-glycoprotein expression level, but increased intramolecular accumulation of paclitaxel in SW620/Ad300 cells. Metabolomics revealed that the multidrug resistance of SW620/Ad300 cells was related to changes in glycerophospholipid metabolism, sphingolipid metabolism and citric acid cycle, and verapamil could antagonize the multidrug resistance by reversing the above-mentioned glycerophospholipid metabolism and sphingolipid metabolism. This research shows the multidrug resistance reversal mechanism of verapamil at the metabolic level, which helps in understanding the exact multidrug resistance mechanism of verapamil and might be potentially useful to find new multidrug resistance reversal agents. The combination of verapamil (VRP) and paclitaxel (PTX) yielded synergistic effects. VRP had no effect on the expression of P-gp, but increased intramolecular accumulation of PTX. VRP antagonized the MDR by regulating glycerophospholipid metabolism and sphingolipid metabolism.
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Affiliation(s)
- Xinying Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Zihan Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Kaili Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Ming Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hang Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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33
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Taheri Z, Asadzadeh Aghdaei H, Irani S, Modarressi MH, Zahra N. Evaluation of the Epigenetic Demethylation of NRF2, a Master Transcription Factor for Antioxidant Enzymes, in Colorectal Cancer. Rep Biochem Mol Biol 2020; 9:33-39. [PMID: 32821749 DOI: 10.29252/rbmb.9.1.33] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Epigenetic changes in CpG islands of the promoter regions of homeostasis-related genes, including nuclear factor erythroid 2-related factor 2 (NRF2), have been shown to hold a significant role in the development of colorectal cancer. Therefore, we aimed to examine the DNA demethylation pattern of the NRF2 promoter region in cancerous lesions from patients with colorectal cancer and the association of methylation status with clinicopathological features in the Iranian population. Methods In this cross-sectional study, 114 colorectal tissue samples were collected. These samples included: 34 tumour tissue samples, 60 precancerous polyps, and 20 normal tissue samples. The promoter methylation status of the NRF2 gene was examined using methylation-specific PCR. Additionally, the relationship between the methylation status and the clinicopathological features was investigated. Results The frequency of NRF2 demethylation in the tumour samples was significantly higher compared to the polyp tissues (p= 0.003) and normal tissue (p= 0.009), indicating that cancerous colorectal tissues exhibit increased demethylation of the NRF2 promoter. After examining the demethylation status of tissue samples, the clinicopathological features were compared to the demethylation results. No significant association was found between NRF2 promoter demethylation and the clinicopathological features of patient samples. Conclusion Our findings suggest that the epigenetic modifications leading to NRF2 demethylation found in colorectal tumour samples may contribute to cancer progression from precancerous polyps to cancerous lesions.
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Affiliation(s)
- Zahra Taheri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Noormohammadi Zahra
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
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34
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Lin K, Huang J, Luo H, Luo C, Zhu X, Bu F, Xiao H, Xiao L, Zhu Z. Development of a prognostic index and screening of potential biomarkers based on immunogenomic landscape analysis of colorectal cancer. Aging (Albany NY) 2020; 12:5832-5857. [PMID: 32235004 PMCID: PMC7185108 DOI: 10.18632/aging.102979] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/03/2020] [Indexed: 12/26/2022]
Abstract
Background: Colorectal cancer (CRC) accounts for the highest fatality rate among all malignant tumors. Immunotherapy has shown great promise in management of many malignant tumors, necessitating the need to explore its role in CRC. Results: Our analysis revealed a total of 71 differentially expressed IRGs, that were associated with prognosis of CRC patients. Ten IRGs (FABP4, IGKV1-33, IGKV2D-40, IGLV6-57, NGF, RETNLB, UCN, VIP, NGFR, and OXTR) showed high prognostic performance in predicting CRC outcomes, and were further associated with tumor burden, metastasis, tumor TNM stage, gender, age, and pathological stage. Interestingly, the IRG-based prognostic index (IRGPI) reflected infiltration of multiple immune cell types. Conclusions: This model provides an effective approach for stratification and characterization of patients using IRG-based immunolabeling tools to monitor prognosis of CRC. Methods: We performed a comprehensive analysis of expression profiles for immune-related genes (IRGs) and overall survival time in 437 CRC patients from the TCGA database. We employed computational algorithms and Cox regression analysis to estimate the relationship between differentially expressed IRGs and survival rates in CRC patients. Furthermore, we investigated the mechanisms of action of the IRGs involved in CRC, and established a novel prognostic index based on multivariate Cox models.
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Affiliation(s)
- Kang Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Jun Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Hongliang Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Chen Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Xiaojian Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Fanqin Bu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Han Xiao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Li Xiao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
| | - Zhengming Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, P.R. China
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Hsu CH, Hsiao CW, Sun CA, Wu WC, Yang T, Hu JM, Huang CH, Liao YC, Chen CY, Lin FH, Chou YC. Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan. World J Gastroenterol 2020; 26:154-167. [PMID: 31988582 PMCID: PMC6962436 DOI: 10.3748/wjg.v26.i2.154] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/14/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC).
AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.
METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival.
RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.
CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.
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Affiliation(s)
- Chih-Hsiung Hsu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
- Teaching Office, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Cheng-Wen Hsiao
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
- Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
| | - Wen-Chih Wu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
- Department of Surgery, Suao and Yuanshan Branches of Taipei Veterans General Hospital, Yilan County 264, Taiwan
| | - Tsan Yang
- Department of Health Business Administration, Meiho University, Pingtung County 912, Taiwan
| | - Je-Ming Hu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Adjunct Instructor, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Chi-Hua Huang
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Chan Liao
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Chao-Yang Chen
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Adjunct Instructor, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Ching Chou
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
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36
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Li R, Yin YH, Jin J, Liu X, Zhang MY, Yang YE, Qu YQ. Integrative analysis of DNA methylation-driven genes for the prognosis of lung squamous cell carcinoma using MethylMix. Int J Med Sci 2020; 17:773-786. [PMID: 32218699 PMCID: PMC7085273 DOI: 10.7150/ijms.43272] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/16/2020] [Indexed: 12/18/2022] Open
Abstract
Background: DNA methylation acts as a key component in epigenetic modifications of genomic function and functions as disease-specific prognostic biomarkers for lung squamous cell carcinoma (LUSC). This present study aimed to identify methylation-driven genes as prognostic biomarkers for LUSC using bioinformatics analysis. Materials and Methods: Differentially expressed RNAs were obtained using the edge R package from 502 LUSC tissues and 49 adjacent non-LUSC tissues. Differentially methylated genes were obtained using the limma R package from 504 LUSC tissues and 69 adjacent non-LUSC tissues. The methylation-driven genes were obtained using the MethylMix R package from 500 LUSC tissues with matched DNA methylation data and gene expression data and 69 non-LUSC tissues with DNA methylation data. Gene ontology and ConsensusPathDB pathway analysis were performed to analyze the functional enrichment of methylation-driven genes. Univariate and multivariate Cox regression analyses were performed to identify the independent effect of differentially methylated genes for predicting the prognosis of LUSC. Results: A total of 44 methylation-driven genes were obtained. Univariate and multivariate Cox regression analyses showed that twelve aberrant methylated genes (ATP6V0CP3, AGGF1P3, RP11-264L1.4, HIST1H4K, LINC01158, CH17-140K24.1, CTC-523E23.14, ADCYAP1, COX11P1, TRIM58, FOXD4L6, CBLN1) were entered into a Cox predictive model associated with overall survival in LUSC patients. Methylation and gene expression combined survival analysis showed that the survival rate of hypermethylation and low-expression of DQX1 and WDR61 were low. The expression of DQX1 had a significantly negatively correlated with the methylation site cg02034222. Conclusion: Methylation-driven genes DQX1 and WDR61 might be potential biomarkers for predicting the prognosis of LUSC.
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Affiliation(s)
- Rui Li
- Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yun-Hong Yin
- Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Jia Jin
- Department of Cardiology, Zhangqiu District People's Hospital of Jinan, 250200, Shandong, China
| | - Xiao Liu
- Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Meng-Yu Zhang
- Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yi-E Yang
- Department of Clinical Laboratory, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan 250014, China
| | - Yi-Qing Qu
- Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
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He K, Zhang S, Shao LL, Yin JC, Wu X, Shao YW, Yuan S, Yu J. Developing more sensitive genomic approaches to detect radioresponse in precision radiation oncology: From tissue DNA analysis to circulating tumor DNA. Cancer Lett 2019; 472:108-118. [PMID: 31837443 DOI: 10.1016/j.canlet.2019.12.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/02/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023]
Abstract
Despite the common application and considerable efforts to achieve precision radiotherapy (RT) in several types of cancer, RT has not yet entered the era of precision medicine; the ability to predict radiosensitivity and treatment responses in tumors and normal tissues is lacking. Therefore, development of genome-based methods for individual prognosis in radiation oncology is urgently required. Traditional DNA sequencing requires tissue samples collected during invasive operations; therefore, repeated tests are nearly impossible. Intra- and inter-tumoral heterogeneity may undermine the predictive power of a single assay from tumor samples. In contrast, analysis of circulating tumor DNA (ctDNA) allows for non-invasive and near real-time sampling of tumors. By investigating the genetic composition of tumors and monitoring dynamic changes during treatment, ctDNA analysis may potentially be clinically valuable in prediction of treatment responses prior to RT, surveillance of responses during RT, and evaluation of residual disease following RT. As a biomarker for RT response, ctDNA profiling may guide personalized treatments. In this review, we will discuss approaches of tissue DNA sequencing and ctDNA detection and summarize their clinical applications in both traditional RT and in combination with immunotherapy.
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Affiliation(s)
- Kewen He
- Department of Radiology, Shandong Cancer Hospital affiliated to Shandong University, Jinan, Shandong, 250117, People's Republic of China; Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People's Republic of China
| | - Shaotong Zhang
- Department of Cardiology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, 250013, People's Republic of China
| | - Liang L Shao
- Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada
| | - Jiani C Yin
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, People's Republic of China
| | - Xue Wu
- Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada
| | - Yang W Shao
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, People's Republic of China; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Shuanghu Yuan
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People's Republic of China.
| | - Jinming Yu
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People's Republic of China.
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38
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Zhang N, Shi S, Jia TZ, Ziegler A, Yoo B, Yuan X, Li W, Zhang S. A general LC-MS-based RNA sequencing method for direct analysis of multiple-base modifications in RNA mixtures. Nucleic Acids Res 2019; 47:e125. [PMID: 31504795 PMCID: PMC6847078 DOI: 10.1093/nar/gkz731] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/07/2019] [Accepted: 08/15/2019] [Indexed: 12/31/2022] Open
Abstract
A complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and non-canonical bases; this in turn requires advances in current sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these non-standard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via introduction of a 2-dimensional hydrophobic end-labeling strategy into traditional mass spectrometry-based sequencing (2D HELS MS Seq) to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA versus its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site in the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification type and can also be used in the quality control of modified therapeutic RNAs.
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Affiliation(s)
- Ning Zhang
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Shundi Shi
- Department of Chemical Engineering, Columbia University, New York, NY 10027, USA
| | - Tony Z Jia
- Earth-Life Science Institute, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8550, Japan
- Blue Marble Space Institute of Science, Seattle, WA 98154, USA
| | - Ashley Ziegler
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA
| | - Barney Yoo
- Department of Chemistry, Hunter College, City University of New York, New York, NY 10065, USA
| | - Xiaohong Yuan
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA
| | - Wenjia Li
- Department of Computer Science, New York Institute of Technology, New York, NY 10023, USA
| | - Shenglong Zhang
- Department of Biological and Chemical Sciences, New York Institute of Technology, New York, NY 10023, USA
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Zhang P, Li R, Xiao H, Liu W, Zeng X, Xie G, Yang W, Shi L, Yin Y, Tao K. BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor. Int J Biol Sci 2019; 15:1942-1954. [PMID: 31523195 PMCID: PMC6743290 DOI: 10.7150/ijbs.34162] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/24/2019] [Indexed: 01/06/2023] Open
Abstract
Background: Bromodomain-containing protein 4(BRD4) is reported to play a vital role in the development of numerous malignant diseases, which is considered as a promising target for cancer therapy. AZD5153, a novel specific BRD4 inhibitor, showed potent anticancer effects in several cancer types, but its therapeutic potential has not been fully evaluated in colorectal cancer cells. Objective: We sought to evaluate the therapeutic potential of BRD4 inhibition of by AZD5153 and its combined anticancer cancer effect with PARP inhibitor BMN673 in vitro and in vivo in colorectal cancer. Methods: We analyzed The Cancer Genome Atlas (TCGA) database to investigate BRD4 expression in colorectal cancer patient. Clonogenic assays 、MTT assays and PI/Annexin V staining were used to determine the effect of AZD5153 and BMN673 and combination therapy on cell viability and apoptosis induction. Western blotting was applied to detect relevant molecules changes. Propidium iodide staining was performed to examine cell cycle distributions after monotherapy or combination therapy. Nude mice xenograft model was generated to confirm the therapeutic effect of AZD5153 and BMN673 combination in vivo, and IHC staining was used to detect the expression level of BRD4 and related markers in colorectal patient and xenograft. Results: Analysis of TCGA database indicated that BRD4 was overexpressed in colorectal cancer patient. The clonogenic and MTT assays and PI/Annexin V staining demonstrated that AZD5153 significantly suppressed cell proliferation and induced apoptosis in colorectal cancer cells HCT116 and LoVo. Western blotting showed that AZD5153 inhibited the expression of c-Myc and increased expression of the apoptosis markers, cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), besides, we found that BRD4 knockdown could also inhibited cell proliferation and induced cell apoptosis. Moreover, AZD5153 inhibited the expression of Wee1 and impaired G2M cell cycle checkpoint, thus sensitized the anticancer effect of BMN673 in vitro and in vivo. Conclusion: Our data revealed that AZD5153suppressed the proliferation of colorectal cancer cells and sensitized them to the anticancer effect of the PARP inhibitor BMN673 via Wee1 inhibition in vitro and in vivo. This suggested that targeting BRD4 might be a valuable strategy for colorectal cancer treatment.
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Affiliation(s)
- Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ruidong Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hua Xiao
- Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, No. 283 Tongzipo Road, Changsha, Hunan Province 410013, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiangyu Zeng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Genchen Xie
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wenchang Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liang Shi
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuping Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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40
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Patnaik S, Anupriya. Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer. Front Pharmacol 2019; 10:588. [PMID: 31244652 PMCID: PMC6563763 DOI: 10.3389/fphar.2019.00588] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/08/2019] [Indexed: 12/14/2022] Open
Abstract
Genetic variations along with epigenetic modifications of DNA are involved in colorectal cancer (CRC) development and progression. CRC is the fourth leading cause of cancer-related deaths worldwide. Initiation and progression of CRC is the cumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Colorectal carcinogenesis is associated with epigenetic aberrations including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Recently, epigenetic modifications have been identified like association of hypermethylated gene Claudin11 (CLDN11) with metastasis and prognosis of poor survival of CRC. DNA methylation of genes CMTM3, SSTR2, MDF1, NDRG4 and TGFB2 are potential epigenetic biomarkers for the early detection of CRC. Tumor suppressor candidate 3 (TUSC3) mRNA expression is silenced by promoter methylation, which promotes epidermal growth factor receptor (EGFR) signaling and rescues the CRC cells from apoptosis and hence leading to poor survival rate. Previous scientific evidences strongly suggest epigenetic modifications that contribute to anticancer drug resistance. Recent research studies emphasize development of drugs targeting histone deacetylases (HDACs) and DNA methyltransferase inhibitors as an emerging anticancer strategy. This review covers potential epigenetic modification targeting chemotherapeutic drugs and probable implementation for the treatment of CRC, which offers a strong rationale to explore therapeutic strategies and provides a basis to develop potent antitumor drugs.
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Epigenetic Influences in the Obesity/Colorectal Cancer Axis: A Novel Theragnostic Avenue. JOURNAL OF ONCOLOGY 2019; 2019:7406078. [PMID: 31007685 PMCID: PMC6441533 DOI: 10.1155/2019/7406078] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/21/2019] [Indexed: 12/25/2022]
Abstract
The World Health Organization (WHO) considers that obesity has reached proportions of pandemic. Experts also insist on the importance of considering obesity as a chronic disease and one of the main contributors to the worldwide burden of other nontransmissible chronic diseases, which have a great impact on health, lifestyle, and economic cost. One of the most current challenges of biomedical science faces is to understand the origin of the chronic nontransmissible diseases, such as obesity and cancer. There is a large evidence, both in epidemiological studies in humans and in animal models, of the association between obesity and an increased risk of cancer incidence. In the last years, the initial discovery of epigenetic mechanisms represents the most relevant finding to explain how the genome interacts with environmental factors and the ripple effects on disease pathogeneses. Since then, all epigenetic process has been investigated by the scientific communities for nearly two decades to determine which components are involved in this process. DNA/RNA methylation and miRNA are classified as two of the most important representative classes of such epigenetic mechanisms and dysregulated activity of such mechanism can certainly contribute to disease pathogenesis and/or progression especially in tumors. This review article serves to highlight the impact of DNA/RNA methylation and miRNA-based epigenetic mechanism activities in the interplay between obesity and the development and clinical significance of colorectal cancer.
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Murillo-Rodríguez E, Arankowsky-Sandoval G, Barros JA, Rocha NB, Yamamoto T, Machado S, Budde H, Telles-Correia D, Monteiro D, Cid L, Veras AB. Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status. Front Neurosci 2019; 13:237. [PMID: 30930741 PMCID: PMC6428769 DOI: 10.3389/fnins.2019.00237] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 02/27/2019] [Indexed: 12/24/2022] Open
Abstract
Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.
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Affiliation(s)
- Eric Murillo-Rodríguez
- Laboratorio de Neurociencias Moleculares e Integrativas, Escuela de Medicina División Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, Mexico.,Intercontinental Neuroscience Research Group, Mérida, Mexico
| | - Gloria Arankowsky-Sandoval
- Centro de Investigaciones Regionales "Dr. Hideyo Noguchi" Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Jorge Aparecido Barros
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Post-graduation Program of Psychology of Health, NACNeuro, Dom Bosco Catholic University, Campo Grande, Mato Grosso del Sur, Brazil
| | - Nuno Barbosa Rocha
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,School of Health, Polytechnic Institute of Porto, Porto, Portugal
| | - Tetsuya Yamamoto
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan
| | - Sérgio Machado
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Laboratory of Physical Activity Neuroscience, Physical Activity Sciences Postgraduate Program, Salgado de Oliveira University, Niterói, Brazil
| | - Henning Budde
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Faculty of Human Sciences, Medical School Hamburg, Hamburg, Germany.,Institute of Sport Science and Innovations, Lithuanian Sports University, Kaunas, Lithuania
| | - Diogo Telles-Correia
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,University of Lisbon, Faculty of Medicine, Lisbon, Portugal
| | - Diogo Monteiro
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Sport Science School of Rio Maior- Polytechnic Institute of Santarém, Rio Maior, Portugal.,Research Center in Sport, Health and Human Development-CIDESD, Vila Real, Portugal
| | - Luis Cid
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Sport Science School of Rio Maior- Polytechnic Institute of Santarém, Rio Maior, Portugal.,Research Center in Sport, Health and Human Development-CIDESD, Vila Real, Portugal
| | - André Barciela Veras
- Intercontinental Neuroscience Research Group, Mérida, Mexico.,Post-graduation Program of Psychology of Health, NACNeuro, Dom Bosco Catholic University, Campo Grande, Mato Grosso del Sur, Brazil
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43
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Chen H, Xu Z, Liu D. Small non-coding RNA and colorectal cancer. J Cell Mol Med 2019; 23:3050-3057. [PMID: 30801950 PMCID: PMC6484298 DOI: 10.1111/jcmm.14209] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 01/07/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignance. Although great efforts have been made to understand the pathogenesis of CRC, the underlying mechanisms are still unclear. It is now clear that more than 90% of the total genome is actively transcribed, but lack of protein‐coding potential. The massive amount of RNA can be classified as housekeeping RNAs (such as ribosomal RNAs, transfer RNAs) and regulatory RNAs (such as microRNAs [miRNAs], PIWI‐interacting RNA [piRNAs], tRNA‐derived stress‐induced RNA, tRNA‐derived small RNA [tRFs] and long non‐coding RNAs [lncRNAs]). Small non‐coding RNAs are a group of ncRNAs with the length no more than 200 nt and they have been found to exert important regulatory functions under many pathological conditions. In this review, we summarize the biogenesis and functions of regulatory sncRNAs, such as miRNAs, piRNA and tRFs, and highlight their involvements in cancers, particularly in CRC.
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Affiliation(s)
- Hui Chen
- Department of Gastroenterology, People's Hospital of Taizhou, Taizhou, Jiangsu, China
| | - Zhiying Xu
- Department of Gastroenterology, People's Hospital of Taizhou, Taizhou, Jiangsu, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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44
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Wu Q, Li P, Wu M, Liu Q. Deregulation of Circular RNAs in Cancer From the Perspectives of Aberrant Biogenesis, Transport and Removal. Front Genet 2019; 10:16. [PMID: 30774645 PMCID: PMC6367250 DOI: 10.3389/fgene.2019.00016] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 01/14/2019] [Indexed: 12/28/2022] Open
Abstract
CircRNAs (circular RNAs) are a class of RNAs generated from circularization with multiple novel functions. Recent studies have revealed the aberrant expression and aberrant functions of circRNAs in various tumors; thus, circRNAs have been recognized as promising cancer biomarkers. However, the underlying mechanisms behind their aberrant expression and functions remain unclear. In this review, we discuss at length the cancer-specific deregulation of circRNAs and the potential underlying aberrant events in circRNA biogenesis, localization and removal in cancer cells.
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Affiliation(s)
- Qiongqiong Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Peiyao Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, China
| | - Minghua Wu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Qiang Liu
- Third Xiangya Hospital, Central South University, Changsha, China
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45
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Dinescu S, Ignat S, Lazar AD, Constantin C, Neagu M, Costache M. Epitranscriptomic Signatures in lncRNAs and Their Possible Roles in Cancer. Genes (Basel) 2019; 10:genes10010052. [PMID: 30654440 PMCID: PMC6356509 DOI: 10.3390/genes10010052] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/09/2019] [Accepted: 01/09/2019] [Indexed: 12/16/2022] Open
Abstract
In contrast to the amazing exponential growth in knowledge related to long non-coding RNAs (lncRNAs) involved in cell homeostasis or dysregulated pathological states, little is known so far about the links between the chemical modifications occurring in lncRNAs and their function. Generally, ncRNAs are post-transcriptional regulators of gene expression, but RNA modifications occurring in lncRNAs generate an additional layer of gene expression control. Chemical modifications that have been reported in correlation with lncRNAs include m⁶A, m⁵C and pseudouridylation. Up to date, several chemically modified long non-coding transcripts have been identified and associated with different pathologies, including cancers. This review presents the current level of knowledge on the most studied cancer-related lncRNAs, such as the metastasis associated lung adenocarcinoma transcript 1 (MALAT1), the Hox transcript antisense intergenic RNA (HOTAIR), or the X-inactive specific transcript (XIST), as well as more recently discovered forms, and their potential roles in different types of cancer. Understanding how these RNA modifications occur, and the correlation between lncRNA changes in structure and function, may open up new therapeutic possibilities in cancer.
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Affiliation(s)
- Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Simona Ignat
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Andreea Daniela Lazar
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Carolina Constantin
- Immunology Department, "Victor Babes" National Institute of Pathology, 050096 Bucharest, Romania.
| | - Monica Neagu
- Immunology Department, "Victor Babes" National Institute of Pathology, 050096 Bucharest, Romania.
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
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Riefolo M, Porcellini E, Dika E, Broseghini E, Ferracin M. Interplay between small and long non-coding RNAs in cutaneous melanoma: a complex jigsaw puzzle with missing pieces. Mol Oncol 2019; 13:74-98. [PMID: 30499222 PMCID: PMC6322194 DOI: 10.1002/1878-0261.12412] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/20/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022] Open
Abstract
The incidence of cutaneous melanoma (CM) has increased in the past few decades. The biology of melanoma is characterized by a complex interaction between genetic, environmental and phenotypic factors. A greater understanding of the molecular mechanisms that promote melanoma cell growth and dissemination is crucial to improve diagnosis, prognostication, and treatment of CM. Both small and long non-coding RNAs (lncRNAs) have been identified to play a role in melanoma biology; microRNA and lncRNA expression is altered in transformed melanocytes and this in turn has functional effects on cell proliferation, apoptosis, invasion, metastasis, and immune response. Moreover, specific dysregulated ncRNAs were shown to have a diagnostic or prognostic role in melanoma and to drive the establishment of drug resistance. Here, we review the current literature on small and lncRNAs with a role in melanoma, with the aim of putting into some order this complex jigsaw puzzle.
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Affiliation(s)
- Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES)University of BolognaItaly
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES)University of BolognaItaly
| | - Emi Dika
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES)University of BolognaItaly
| | - Elisabetta Broseghini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES)University of BolognaItaly
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES)University of BolognaItaly
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47
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The Emerging Role of Epitranscriptomics in Cancer: Focus on Urological Tumors. Genes (Basel) 2018; 9:genes9110552. [PMID: 30428628 PMCID: PMC6265908 DOI: 10.3390/genes9110552] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/27/2018] [Accepted: 11/08/2018] [Indexed: 12/11/2022] Open
Abstract
Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs. m6A has been demonstrated to play important roles in many physiological processes and several disease states, including various cancer models (from solid to liquid tumors). Tumor cells’ epitranscriptome is indeed disrupted in a way to promote cancer-prone features, by means of up/downregulating m6A-related players: the so-called writers, readers and erasers. These proteins modulate m6A establishment, removal and determine mRNAs fate, acting in a context-dependent manner, so that a single player may act as an oncogenic signal in one tumor model (methyltransferase like 3 (METTL3) in lung cancer) and as a tumor suppressor in another context (METTL3 in glioblastoma). Despite recent advances, however, little attention has been directed towards urological cancer. By means of a thorough analysis of the publicly available TCGA (The Cancer Genome Atlas) database, we disclosed the most relevant players in four major urogenital neoplasms—kidney, bladder, prostate and testicular cancer—for prognostic, subtype discrimination and survival purposes. In all tumor models assessed, the most promising player was shown to be Vir like m6A methyltransferase associated (VIRMA), which could constitute a potential target for personalized therapies.
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48
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Coppedè F, Stoccoro A, Lazzarotti A, Spisni R, Migliore L. Investigation of GHSR and GHRL methylation in colorectal cancer. Epigenomics 2018; 10:1525-1539. [PMID: 29963901 DOI: 10.2217/epi-2018-0030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AIM To investigate GHSR and GHRL methylation in 73 pairs of colorectal cancer (CRC) tissues and healthy adjacent mucosa. METHODS Methylation was assessed with methylation-sensitive high-resolution melting. RESULTS GHSR was significantly hypermethylated in CRC tissues than in healthy mucosa (p < 1 × 10-5), but no significant changes of GHRL methylation were observed. GHSR hypermethylation was already detectable at the adenoma stage and maintained in later stages independently of age, gender, anatomical location, histological grading, MLH1 deficiency, as well as of major polymorphisms in folate-pathway genes, yielding an area under the curve of 0.824 for discriminating cancers from respective non-neoplastic mucosa specimens. CONCLUSION GHSR hypermethylation occurs early in CRC, but is not paralleled by significant changes of GHRL methylation.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Andrea Stoccoro
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Alessandro Lazzarotti
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Roberto Spisni
- Department of Surgery, Medical, Molecular, & Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Lucia Migliore
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
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