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Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Epidemiology and Prevention".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11659

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Special Issue Editors

Dr. Ling-Zhi Liu

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Guest Editor

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Interests: carcinogenesis; angiogenesis; cancer resistance
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Binghua Jiang

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Guest Editor

Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Interests: cancer development; cancer therapeutic resistance; carcinogenesis; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Environmental metal pollution can be found in water, air, landfills, and industrial processing, as well as in agricultural products. Metals such as hexavalent chromium (Cr(VI)), arsenic, cadmium, and nickel are environmental carcinogens and long-term exposure to these metals is associated with the development of various types of cancer. Non-coding RNAs and epigenetic alterations have recently been demonstrated to be important in metal-induced malignant transformation, angiogenesis, and cancer development. Non-coding RNAs (ncRNAs)—especially micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs)—have been intensively investigated regarding their roles in cancer development and drug resistance. A list of evidence shows that ncRNAs play important roles in metal-induced carcinogenesis and angiogenesis. This Special Issue will focus on new research findings in elucidating roles and mechanisms of ncRNAs in regulating carcinogenesis. Epigenetic regulations such as DNA methylation, RNA methylation, and histone modifications are other networks mediating carcinogenesis and cancer development. Thus, recent information and study are important to understand the roles and mechanisms of ncRNAs and epigenetic alterations in metal-induced malignant transformation, carcinogenesis, angiogenesis, and cellular programs. A better understanding of the complex networks of ncRNAs and epigenetic regulations would provide the opportunity to identify new biomarkers and to design new options to prevent metal-induced carcinogenesis in the future.

Dear Colleagues,

We are pleased to invite you to contribute a research article or a review paper for this Special Issue, entitled “Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis”.

Growing evidence has demonstrated that ncRNAs and epigenetic alterations such as DNA and RNA methylation and histone modification play important roles in metal-induced carcinogenesis through multiple processes such as malignant transformation, tumor initiation, development, and angiogenesis. Micro-RNAs (miRNAs) are the first class of non-coding RNAs that were discovered in cancer, and have been the most extensively investigated. Long ncRNAs (lncRNAs) represent the largest class of non-coding RNAs with more than 55,000 genes in the human genome, and lncRNAs may regulate gene expression through their interactions with proteins, miRNAs, DNA, and mRNAs. NcRNAs may regulate multiple molecular and cellular processes such as RNA stability, protein translation, post-transcriptional regulations, DNA methylation, chromatin remodeling, and signal transduction. DNA methylation is a regulatory modification that elicits a cascade of events resulting in chromatin condensation and gene silencing. N⁶-methyladenosine (m⁶A) is the most common, abundant, and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). m⁶A exerts diverse effects on gene expression such as mRNA stability, mRNA splicing, mRNA structure, mRNA export, translation efﬁciency, and miRNA biogenesis, and m⁶A RNA methylation participates in the pathogenesis of multiple diseases including metal-induced carcinogenesis. Histone modifications regulate gene transcription through directly disrupting DNA–nucleosome contacts or recruiting and binding to non-histone proteins and additional histone modifiers. The changes of histone modifications may impact differential gene and subsequent protein expression. Recent studies have demonstrated that metals alter the DNA and RNA methylation and histone modification profiles, which are involved in metal-induced carcinogenesis. We would like to invite you to submit a research or review article in the area of your interest in any aspect of these fields.

This Special Issue aims to focus on recent complementary information or research findings to understand roles and mechanisms of ncRNAs and other epigenetic alterations induced by metal exposure and leading to malignant transformation, carcinogenesis, angiogenesis, and/or cellular programs.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:
1) ncRNAs including miRNAs and lncRNAs in metal-induced carcinogenesis and angiogenesis;
2) DNA methylation in metal-induced carcinogenesis and angiogenesis;
3) RNA methylation in metal-induced carcinogenesis and angiogenesis;
4) histone modifications in metal-induced carcinogenesis and angiogenesis.

We look forward to your contributions to this Special Issue.

Dr. Ling-Zhi Liu
Prof. Dr. Binghua Jiang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

LnRNA
NcRNA
miRNA
lncRNA
metal
carcinogenesis
angiogenesis
epigenetic regulation
histone modifications
DNA methylation
RNA methylation

Published Papers (5 papers)

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Research

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15 pages, 2656 KiB

Open AccessArticle

MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis

by Ranakul Islam, Lei Zhao, Xiujuan Zhang and Ling-Zhi Liu

Cancers 2023, 15(4), 1204; https://doi.org/10.3390/cancers15041204 - 14 Feb 2023

Cited by 4 | Viewed by 1911

Abstract

Background: Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear. Methods: RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling. Results: EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3′-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR. Conclusion: Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future. Full article

(This article belongs to the Special Issue Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis)

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22 pages, 8435 KiB

Open AccessArticle

HDAC2- and EZH2-Mediated Histone Modifications Induce PDK1 Expression through miR-148a Downregulation in Breast Cancer Progression and Adriamycin Resistance

by Yunxia Xie, Zhumei Shi, Yingchen Qian, Chengfei Jiang, Wenjing Liu, Bingjie Liu and Binghua Jiang

Cancers 2022, 14(15), 3600; https://doi.org/10.3390/cancers14153600 - 23 Jul 2022

Cited by 8 | Viewed by 2302

Abstract

Background: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. Methods: Gene set enrichment analysis (GSEA) and Pearson’s correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. Results: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a—including miR-148a’s ability to increase cell sensitivity to Adriamycin (ADR) treatment—inhibiting cell glycolysis, invasion and epithelial–mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. Conclusion: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future. Full article

(This article belongs to the Special Issue Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis)

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Review

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12 pages, 898 KiB

Open AccessReview

MicroRNA–Gene Interactions Impacted by Toxic Metal(oid)s during EMT and Carcinogenesis

by Franklin Tran, Eunji Lee, Suresh Cuddapah, Byeong Hyeok Choi and Wei Dai

Cancers 2022, 14(23), 5818; https://doi.org/10.3390/cancers14235818 - 25 Nov 2022

Cited by 4 | Viewed by 1562

Abstract

Chronic environmental exposure to toxic metal(loid)s significantly contributes to human cancer development and progression. It is estimated that approximately 90% of cancer deaths are a result of metastasis of malignant cells, which is initiated by epithelial–mesenchymal transition (EMT) during early carcinogenesis. EMT is regulated by many families of genes and microRNAs (miRNAs) that control signaling pathways for cell survival, death, and/or differentiation. Recent mechanistic studies have shown that toxic metal(loid)s alter the expression of miRNAs responsible for regulating the expression of genes involved in EMT. Altered miRNA expressions have the potential to be biomarkers for predicting survival and responses to treatment in cancers. Significantly, miRNAs can be developed as therapeutic targets for cancer patients in the clinic. In this mini review, we summarize key findings from recent studies that highlight chemical–miRNA–gene interactions leading to the perturbation of EMT after exposure to toxic metal(loid)s including arsenic, cadmium, nickel, and chromium. Full article

(This article belongs to the Special Issue Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis)

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43 pages, 1297 KiB

Open AccessReview

Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis

by Lei Zhao, Ranakul Islam, Yifang Wang, Xiujuan Zhang and Ling-Zhi Liu

Cancers 2022, 14(23), 5768; https://doi.org/10.3390/cancers14235768 - 23 Nov 2022

Cited by 13 | Viewed by 1947

Abstract

Environmental and occupational exposure to heavy metals, such as hexavalent chromium, nickel, and cadmium, are major health concerns worldwide. Some heavy metals are well-documented human carcinogens. Multiple mechanisms, including DNA damage, dysregulated gene expression, and aberrant cancer-related signaling, have been shown to contribute to metal-induced carcinogenesis. However, the molecular mechanisms accounting for heavy metal-induced carcinogenesis and angiogenesis are still not fully understood. In recent years, an increasing number of studies have indicated that in addition to genotoxicity and genetic mutations, epigenetic mechanisms play critical roles in metal-induced cancers. Epigenetics refers to the reversible modification of genomes without changing DNA sequences; epigenetic modifications generally involve DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. Epigenetic regulation is essential for maintaining normal gene expression patterns; the disruption of epigenetic modifications may lead to altered cellular function and even malignant transformation. Therefore, aberrant epigenetic modifications are widely involved in metal-induced cancer formation, development, and angiogenesis. Notably, the role of epigenetic mechanisms in heavy metal-induced carcinogenesis and angiogenesis remains largely unknown, and further studies are urgently required. In this review, we highlight the current advances in understanding the roles of epigenetic mechanisms in heavy metal-induced carcinogenesis, cancer progression, and angiogenesis. Full article

(This article belongs to the Special Issue Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis)

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24 pages, 740 KiB

Open AccessReview

Epigenetic Dysregulations in Arsenic-Induced Carcinogenesis

by Ranakul Islam, Lei Zhao, Yifang Wang, Grace Lu-Yao and Ling-Zhi Liu

Cancers 2022, 14(18), 4502; https://doi.org/10.3390/cancers14184502 - 16 Sep 2022

Cited by 9 | Viewed by 2845

Abstract

Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced epigenetic modifications in carcinogenesis and angiogenesis. Importantly, we highlight the possible mechanisms underlying epigenetic reprogramming through arsenic exposure that cause changes in cell signaling and dysfunctions of different epigenetic elements. Full article

(This article belongs to the Special Issue Non-coding RNAs and Epigenetic Alterations in Metal-Induced Carcinogenesis)

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