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Saranya I, Dharshini VS, Akshaya RL, Subhashini PS, Selvamurugan N. Regulatory and therapeutic implications of competing endogenous RNA network in breast cancer progression and metastasis: A review. Int J Biol Macromol 2024; 266:131075. [PMID: 38531528 DOI: 10.1016/j.ijbiomac.2024.131075] [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: 01/30/2024] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 03/28/2024]
Abstract
Breast cancer (BC) is a global health concern, and development of diagnostic tools and targeted treatments for BC remains challenging. Therapeutic approaches for BC often involve a combination of surgery, radiation therapy, chemotherapy, targeted therapy, and hormone therapy. In recent years, there has been a growing interest in the role of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), in BC and their therapeutic implications. Various biological processes such as cell proliferation, migration, and apoptosis rely on the activities of these ncRNAs, and their dysregulation has been implicated in BC progression. The regulatory function of the competitive endogenous RNA (ceRNA) network, which comprises lncRNAs, miRNAs, and mRNAs, has been the subject of extensive pathophysiological research. Most lncRNAs serve as molecular sponges for miRNAs and sequester their activities, thereby regulating the expression of target mRNAs and contributing to the promotion or inhibition of BC progression. This review summarizes recent findings on the role of ceRNA networks in BC progression, metastasis, and therapeutic resistance, and highlights the association of ceRNA networks with transcription factors and signaling pathways. Understanding the ceRNA network can lead to the discovery of biomarkers and targeted treatment methods to prevent the spread and metastasis of BC.
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Affiliation(s)
- I Saranya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - V Sowfika Dharshini
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - R L Akshaya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - P Sakthi Subhashini
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India
| | - N Selvamurugan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India.
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Huang ML, Shen GT, Li NL. Emerging potential of ubiquitin-specific proteases and ubiquitin-specific proteases inhibitors in breast cancer treatment. World J Clin Cases 2022; 10:11690-11701. [PMID: 36405275 PMCID: PMC9669866 DOI: 10.12998/wjcc.v10.i32.11690] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/30/2022] [Accepted: 10/17/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most frequently diagnosed cancer in women, accounting for 30% of new diagnosing female cancers. Emerging evidence suggests that ubiquitin and ubiquitination played a role in a number of breast cancer etiology and progression processes. As the primary deubiquitinases in the family, ubiquitin-specific peptidases (USPs) are thought to represent potential therapeutic targets. The role of ubiquitin and ubiquitination in breast cancer, as well as the classification and involvement of USPs are discussed in this review, such as USP1, USP4, USP7, USP9X, USP14, USP18, USP20, USP22, USP25, USP37, and USP39. The reported USPs inhibitors investigated in breast cancer were also summarized, along with the signaling pathways involved in the investigation and its study phase. Despite no USP inhibitor has yet been approved for clinical use, the biological efficacy indicated their potential in breast cancer treatment. With the improvements in phenotypic discovery, we will know more about USPs and USPs inhibitors, developing more potent and selective clinical candidates for breast cancer.
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Affiliation(s)
- Mei-Ling Huang
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Guang-Tai Shen
- Department of Breast Surgery, Xing'an League People's Hospital, Ulanhot 137400, Inner Mongolia Autonomous Region, China
| | - Nan-Lin Li
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
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Liu P, Yang F, Zhang L, Hu Y, Chen B, Wang J, Su L, Wu M, Chen W. Emerging role of different DNA methyltransferases in the pathogenesis of cancer. Front Pharmacol 2022; 13:958146. [PMID: 36091786 PMCID: PMC9453300 DOI: 10.3389/fphar.2022.958146] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/26/2022] [Indexed: 11/18/2022] Open
Abstract
DNA methylation is one of the most essential epigenetic mechanisms to regulate gene expression. DNA methyltransferases (DNMTs) play a vital role in DNA methylation in the genome. In mammals, DNMTs act with some elements to regulate the dynamic DNA methylation patterns of embryonic and adult cells. Conversely, the aberrant function of DNMTs is frequently the hallmark in judging cancer, including total hypomethylation and partial hypermethylation of tumor suppressor genes (TSGs), which improve the malignancy of tumors, aggravate the ailment for patients, and significantly exacerbate the difficulty of cancer therapy. Since DNA methylation is reversible, currently, DNMTs are viewed as an important epigenetic target for drug development. However, the impression of DNMTs on cancers is still controversial, and therapeutic methods targeting DNMTs remain under exploration. This review mainly summarizes the relationship between the main DNMTs and cancers as well as regulatory mechanisms and clinical applications of DNMTs in cancer and highlights several forthcoming strategies for targeting DNMTs.
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Affiliation(s)
- Pengcheng Liu
- Department of Human Resources, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fan Yang
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Lizhi Zhang
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Bangjie Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianpeng Wang
- The First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Lei Su
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mingyue Wu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenjian Chen
- Department of Orthopaedics, Anhui Provincial Children’s Hospital, Hefei, China
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Man X, Li Q, Wang B, Zhang H, Zhang S, Li Z. DNMT3A and DNMT3B in Breast Tumorigenesis and Potential Therapy. Front Cell Dev Biol 2022; 10:916725. [PMID: 35620052 PMCID: PMC9127442 DOI: 10.3389/fcell.2022.916725] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 04/21/2022] [Indexed: 01/15/2023] Open
Abstract
Breast cancer has become a leading cause of cancer-related deaths in women worldwide. DNA methylation has been revealed to play an enormously important role in the development and progression of breast cancer. DNA methylation is regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT2, and DNMT3. DNMT3 family has three members: DNMT3A, DNMT3B, and DNMT3L. The roles and functions of DNMT1 in breast cancer have been well reviewed. In this article, the roles of DNMT3A and DNMT3B in breast tumorigenesis and development are reviewed. We also discuss the SNP and mutations of DNMT3A and DNMT3B in breast cancer. In addition, we summarize how DNMT3A and DNMT3B are regulated by non-coding RNAs and signaling pathways in breast cancer, and targeting the expression levels of DNMT3A and DNMT3B may be a promising therapeutic approach for breast cancer. This review will provide reference for further studies on the biological functions and molecular mechanisms of DNMT3A and DNMT3B in breast cancer.
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Affiliation(s)
- Xiaxia Man
- Department of Oncologic Gynecology, the First Hospital of Jilin University, Jilin, China
| | - Qi Li
- State and Local Joint Engineering Laboratory for Animal Models of Human Diseases, Academy of Translational Medicine, the First Hospital of Jilin University, Jilin, China
| | - Baogang Wang
- Department of Cardiac Surgery, the First Hospital of Jilin University, Jilin, China
| | - He Zhang
- Department of Oncologic Gynecology, the First Hospital of Jilin University, Jilin, China
| | - Songling Zhang
- Department of Oncologic Gynecology, the First Hospital of Jilin University, Jilin, China
| | - Ziyi Li
- State and Local Joint Engineering Laboratory for Animal Models of Human Diseases, Academy of Translational Medicine, the First Hospital of Jilin University, Jilin, China
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+HOXA10-AS Promotes Malignant Phenotypes of Gastric Cancer via Upregulating HOXA10. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1846687. [PMID: 35222681 PMCID: PMC8866012 DOI: 10.1155/2022/1846687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/16/2021] [Accepted: 12/29/2021] [Indexed: 12/07/2022]
Abstract
Objective To study the role of long noncoding RNA HOXA10-AS in gastric cancer (GC) and its underlying mechanism which is one of the most common and fetal malignancies. Long noncoding RNA HOXA10-AS is highly expressed and acts in an oncogenic role in cancers. However, its roles in GC are still unknown. Methods The expression of HOXA10-AS and HOXA10 in GC tissues from the TCGA database was analyzed. Western blot and qRT-PCR assays were applied to examine the expression of HOXA10-AS and HOXA10. Cell proliferation was evaluated with CCK-8 and EdU incorporation assays. Cell apoptosis was analyzed by flow cytometry. Migratory and invasive capacities were evaluated with wound healing and transwell assays. Results HOXA10-AS and HOXA10 were upregulated in GC, and their expressions were positively correlated. Knockdown of HOXA10-AS inhibited HOXA10 expression in GC cells. Furthermore, knockdown of HOXA10-AS restrained GC cell proliferation, migration, and invasion but promoted apoptosis. In addition, overexpression of HOXA10-AS promoted malignant phenotypes of GC cells, but all these effects could be reversed by knockdown of HOXA10. Conclusion HOXA10-AS promoted GC cell proliferation, migration and invasion and enhanced apoptosis via upregulating HOXA10. Our study implies a novel regulatory mechanism of malignant phenotypes and provides potential therapeutic targets for GC.
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Combination of the 6-thioguanine and disulfiram/Cu synergistically inhibits proliferation of triple-negative breast cancer cells by enhancing DNA damage and disrupting DNA damage checkpoint. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119169. [PMID: 34763028 DOI: 10.1016/j.bbamcr.2021.119169] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/18/2021] [Accepted: 11/01/2021] [Indexed: 11/22/2022]
Abstract
Because of the lack of specific molecular targeted therapies, triple-negative breast cancer (TNBC) has high tumour recurrence and metastasis rates. It is urgent to develop novel chemotherapeutic strategies to improve patient survival. DNA damaging agents have been shown to sensitize cancer to genotoxic chemotherapies. We first found that 6-thioguanine (6-TG) can activate the NF-кB signalling pathway. Our results showed that NF-кB signalling was reduced when cells were treated with 6-TG/disulfiram (DSF)/Cu. DSF/Cu enhanced the 6-TG-mediated inhibition of proliferation. 6-TG/DSF/Cu inhibited cell cycle progression, causing cell cycle arrest in the S phase and G2/M phase. Moreover, the combined effect of 6-TG and DSF/Cu induced apoptosis, and either agent alone was able to induce apoptosis. The accumulation of γH2A indicated that DSF/Cu increased the DNA damage induced by 6-TG. Combined treatment with 6-TG and DSF/Cu synergistically reduced the levels of both phosphorylated and total ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR), suggesting that DSF/Cu promoted 6-TG-induced DNA damage by suppressing ATR protein kinases, therefore enhancing cell apoptosis. In conclusion, we demonstrate that the combination of 6-TG and DSF/Cu exerted a significant synergistic antitumour effect on human TNBC in vitro and in vivo by enhancing DNA damage and disrupting DNA damage checkpoints. We propose that this combination therapy could be a novel strategy for the treatment of TNBC.
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The regulatory effect of 6-TG on lncRNA-miRNA-mRNA ceRNA network in triple-negative breast cancer cell line. Biosci Rep 2021; 41:227631. [PMID: 33470407 PMCID: PMC7859320 DOI: 10.1042/bsr20203890] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/30/2020] [Accepted: 01/18/2021] [Indexed: 01/07/2023] Open
Abstract
Breast cancer is one of the most prevalent and recurring cancer types that leads to deaths in women. Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of therapeutic targets. Many studies have focused on identifying drugs for use as alternative treatments for breast cancer. Thioguanine (6-TG) exerts antitumor effects in cancer. Increasing evidence has demonstrated that competitive endogenous ribonucleic acids (ceRNAs) are involved in cancer processes. However, the mechanism by which 6-TG regulates lncRNA-miRNA-mRNAs has not been elucidated. We evaluated the antitumor effect of 6-TG in MDA-MB-231 cells and comprehensively analyzed the RNA-Seq data of MDA-MB-231 cells treated with 6-TG. Our results showed that most tumor pathways were blocked by 6-TG. The hub genes were FN1, FLNA, FLNB, VCL, GSN, MYH10, ACTN4, KDR and EREG, and they were all down-regulated after 6-TG treatment. The coexpression network consisted of 18 microRNAs (miRNAs), 9 long noncoding RNAs (lncRNAs) and 20 mRNAs. Hsa-mir-16-5p and Hsa-mir-335-5p targeted the greatest number of mRNAs in the network. These molecules could bind to PAX8-AS1 and eliminate the inhibition of target mRNA expression. We showed that PAX8-AS1 is the main lncRNA affected by 6-TG and that PAX8-AS1 regulates the hub genes in tumor pathways by competitively binding with miR-16-5p and miR-335-5p.
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Li H, An X, Li Q, Yu H, Li Z. Construction and analysis of competing endogenous RNA network of MCF-7 breast cancer cells based on the inhibitory effect of 6-thioguanine on cell proliferation. Oncol Lett 2020; 21:104. [PMID: 33376537 PMCID: PMC7751352 DOI: 10.3892/ol.2020.12365] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/24/2020] [Indexed: 12/24/2022] Open
Abstract
Previous research has proven that 6-thioguanine (6-TG) inhibits the growth of MCF-7 breast cancer cells. Accumulating evidence indicates that long non-coding (lnc)RNAs are involved in the development of various cancer types as competitive endogenous (ce)RNA molecules. The present study was conducted to investigate the regulatory mechanism underlying the function of lncRNAs as ceRNA molecules in MCF-7 cells and to identify more effective prognostic biomarkers for breast cancer treatment. The expression profiles of lncRNAs in untreated MCF-7 cells and 6-TG-treated MCF-7 cells were compared by RNA-seq. The regulatory associations among lncRNAs, micro (mi)RNAs and mRNAs were analyzed and verified by the TargetScan, miRDB and miRTarBas databases. The ceRNA networks were constructed by Cytoscape. The expression levels of two lncRNAs and two miRNAs in the ceRNA network were measured by reverse transcription-quantitative PCR. The OncoLnc and Kaplan-Meier plotter network databases were utilized to determine the effects of lncRNA and miRNA expression on the survival of patients with breast cancer. A ceRNA network was constructed for MCF-7 breast cancer cells treated with 6-TG, and this network may provide valuable information for further research elucidating the molecular mechanism underlying the effects of 6-TG on breast cancer. Moreover, LINC00324, MIR22HG, miR-370-3p and miR-424-5p were identified as potential prognostic and therapeutic biomarkers for breast cancer.
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Affiliation(s)
- Hao Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xinglan An
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Qi Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hao Yu
- College of Animal Sciences, Jilin University, Changchun, Jilin 130062, P.R. China
| | - Ziyi Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
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