|
1
|
Dai C, Qianjiang H, Fu R, Yang H, Shi A, Luo H. Epigenetic and epitranscriptomic role of lncRNA in carcinogenesis (Review). Int J Oncol 2025; 66:29. [PMID: 40017127 PMCID: PMC11900940 DOI: 10.3892/ijo.2025.5735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Long non‑coding RNAs (lncRNAs) are key players in the regulation of gene expression by mediating epigenetic and epitranscriptomic modification. Dysregulation of lncRNAs is implicated in tumor initiation, progression and metastasis. lncRNAs modulate chromatin structure and gene transcription by recruiting epigenetic regulators, including DNA‑ or histone‑modifying enzymes. Additionally, lncRNAs mediate chromatin remodeling and enhancer‑promoter long‑range chromatin interactions to control oncogene expression by recruiting chromatin organization‑associated proteins, thereby promoting carcinogenesis. Furthermore, lncRNAs aberrantly induce oncogene expression by mediating epitranscriptomic modifications, including RNA methylation and RNA editing. The present study aimed to summarize the regulatory mechanisms of lncRNAs in cancer to unravel the complex interplay between lncRNAs and epigenetic/epitranscriptomic regulators in carcinogenesis. The present review aimed to provide a novel perspective on the epigenetic and epitranscriptomic roles of lncRNAs in carcinogenesis to facilitate identification of potential biomarkers and therapeutic targets for cancer diagnosis and treatment.
Collapse
Affiliation(s)
- Chunfei Dai
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
| | - Haoyue Qianjiang
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
| | - Ruishuang Fu
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Huimin Yang
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Aiqin Shi
- Xianghu Laboratory, Hangzhou, Zhejiang 311231, P.R. China
| | - Huacheng Luo
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| |
Collapse
|
|
2
|
Poma P, Rigogliuso S, Labbozzetta M, Nicosia A, Costa S, Ragusa MA, Notarbartolo M. Epigenetic and Cellular Reprogramming of Doxorubicin-Resistant MCF-7 Cells Treated with Curcumin. Int J Mol Sci 2024; 25:13416. [PMID: 39769180 PMCID: PMC11679585 DOI: 10.3390/ijms252413416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
The MCF-7R breast cancer cell line, developed by treating the parental MCF-7 cells with increasing doses of doxorubicin, serves as a model for studying acquired multidrug resistance (MDR). MDR is a major challenge in cancer therapy, often driven by overexpression of the efflux pump P-glycoprotein (P-gp) and epigenetic modifications. While many P-gp inhibitors show promise in vitro, their nonspecific effects on the efflux pump limit in vivo application. Curcumin, a natural compound with pleiotropic action, is a nontoxic P-gp inhibitor capable of modulating multiple pathways. To explore curcumin's molecular effects on MCF-7R cells, we analyzed the expression of genes involved in DNA methylation and transcription regulation, including ABCB1/MDR1. Reduced representation bisulfite sequencing further unveiled key epigenetic changes induced by curcumin. Our findings indicate that curcumin treatment not only modulates critical cellular processes, such as ribosome biogenesis and cytoskeletal dynamics, but also reverses the resistant phenotype, toward that of sensitive cells. This study highlights curcumin's potential as an adjuvant therapy to overcome chemoresistance, offering new avenues for pharmacological strategies targeting epigenetic regulation to re-sensitize resistant cancer cells.
Collapse
Affiliation(s)
- Paola Poma
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| | - Salvatrice Rigogliuso
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| | - Manuela Labbozzetta
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| | - Aldo Nicosia
- Institute for Biomedical Research and Innovation—National Research Council (IRIB-CNR), 90146 Palermo, Italy;
| | - Salvatore Costa
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| | - Maria Antonietta Ragusa
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| | - Monica Notarbartolo
- Department of Biological Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy; (P.P.); (S.R.); (M.L.); (S.C.); (M.N.)
| |
Collapse
|
|
3
|
Bolkent S. Cellular and molecular mechanisms of asymmetric stem cell division in tissue homeostasis. Genes Cells 2024; 29:1099-1110. [PMID: 39379096 PMCID: PMC11609605 DOI: 10.1111/gtc.13172] [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: 02/15/2024] [Revised: 09/09/2024] [Accepted: 09/25/2024] [Indexed: 10/10/2024]
Abstract
The asymmetric cell division determines cell diversity and distinct sibling cell fates by mechanisms linked to mitosis. Many adult stem cells divide asymmetrically to balance self-renewal and differentiation. The process of asymmetric cell division involves an axis of polarity and, second, the localization of cell fate determinants at the cell poles. Asymmetric division of stem cells is achieved by intrinsic and extrinsic fate determinants such as signaling molecules, epigenetics factors, molecules regulating gene expression, and polarized organelles. At least some stem cells perform asymmetric and symmetric cell divisions during development. Asymmetric division ensures that the number of stem cells remains constant throughout life. The asymmetric division of stem cells plays an important role in biological events such as embryogenesis, tissue regeneration and carcinogenesis. This review summarizes recent advances in the regulation of asymmetric stem cell division in model organisms.
Collapse
Affiliation(s)
- Sema Bolkent
- Cerrahpaşa Faculty of Medicine, Department of Medical BiologyIstanbul University‐CerrahpaşaCerrahpaşaIstanbulTurkey
| |
Collapse
|
|
4
|
Niebora J, Woźniak S, Domagała D, Data K, Farzaneh M, Zehtabi M, Dari MAG, Pour FK, Bryja A, Kulus M, Mozdziak P, Dzięgiel P, Kempisty B. The role of ncRNAs and exosomes in the development and progression of endometrial cancer. Front Oncol 2024; 14:1418005. [PMID: 39188680 PMCID: PMC11345653 DOI: 10.3389/fonc.2024.1418005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/26/2024] [Indexed: 08/28/2024] Open
Abstract
Endometrial cancer (EC) is one of the most common gynecologic cancers. In recent years, research has focused on the genetic characteristics of the tumors to detail their prognosis and tailor therapy. In the case of EC, genetic mutations have been shown to underlie their formation. It is very important to know the mechanisms of EC formation related to mutations induced by estrogen, among other things. Noncoding RNAs (ncRNAs), composed of nucleotide transcripts with very low protein-coding capacity, are proving to be important. Their expression patterns in many malignancies can inhibit tumor formation and progression. They also regulate protein coding at the epigenetic, transcriptional, and posttranscriptional levels. MicroRNAs (miRNAs), several varieties of which are associated with normal endometrium as well as its tumor, also play a particularly important role in gene expression. MiRNAs and long noncoding RNAs (lncRNAs) affect many pathways in EC tissues and play important roles in cancer development, invasion, and metastasis, as well as resistance to anticancer drugs through mechanisms such as suppression of apoptosis and progression of cancer stem cells. It is also worth noting that miRNAs are highly precise, sensitive, and robust, making them potential markers for diagnosing gynecologic cancers and their progression. Unfortunately, as the incidence of EC increases, treatment becomes challenging and is limited to invasive tools. The prospect of using microRNAs as potential candidates for diagnostic and therapeutic use in EC seems promising. Exosomes are extracellular vesicles that are released from many types of cells, including cancer cells. They contain proteins, DNA, and various types of RNA, such as miRNAs. The noncoding RNA components of exosomes vary widely, depending on the physiology of the tumor tissue and the cells from which they originate. Exosomes contain both DNA and RNA and have communication functions between cells. Exosomal miRNAs mediate communication between EC cells, tumor-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) and play a key role in tumor cell proliferation and tumor microenvironment formation. Oncogenes carried by tumor exosomes induce malignant transformation of target cells. During the synthesis of exosomes, various factors, such as genetic and proteomic data are upregulated. Thus, they are considered an interesting therapeutic target for the diagnosis and prognosis of endometrial cancer by analyzing biomarkers contained in exosomes. Expression of miRNAs, particularly miR-15a-5p, was elevated in exosomes derived from the plasma of EC patients. This may suggest the important utility of this biomarker in the diagnosis of EC. In recent years, researchers have become interested in the topic of prognostic markers for EC, as there are still too few identified markers to support the limited treatment of endometrial cancer. Further research into the effects of ncRNAs and exosomes on EC may allow for cancer treatment breakthroughs.
Collapse
Affiliation(s)
- Julia Niebora
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Sławomir Woźniak
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Dominika Domagała
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Krzysztof Data
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Clinical Research Development Unit, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Zehtabi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahrokh Abouali Gale Dari
- Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fatemeh Khojasteh Pour
- Department of Obstetrics and Gynecology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Artur Bryja
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC, United States
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Bartosz Kempisty
- Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, Poland
- Physiology Graduate Program, North Carolina State University, Raleigh, NC, United States
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Brno, Czechia
| |
Collapse
|
|
5
|
Larue AEM, Atlasi Y. The epigenetic landscape in intestinal stem cells and its deregulation in colorectal cancer. Stem Cells 2024; 42:509-525. [PMID: 38597726 PMCID: PMC11177158 DOI: 10.1093/stmcls/sxae027] [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: 10/08/2023] [Accepted: 03/25/2024] [Indexed: 04/11/2024]
Abstract
Epigenetic mechanisms play a pivotal role in controlling gene expression and cellular plasticity in both normal physiology and pathophysiological conditions. These mechanisms are particularly important in the regulation of stem cell self-renewal and differentiation, both in embryonic development and within adult tissues. A prime example of this finely tuned epigenetic control is observed in the gastrointestinal lining, where the small intestine undergoes renewal approximately every 3-5 days. How various epigenetic mechanisms modulate chromatin functions in intestinal stem cells (ISCs) is currently an active area of research. In this review, we discuss the main epigenetic mechanisms that control ISC differentiation under normal homeostasis. Furthermore, we explore the dysregulation of these mechanisms in the context of colorectal cancer (CRC) development. By outlining the main epigenetic mechanisms contributing to CRC, we highlight the recent therapeutics development and future directions for colorectal cancer research.
Collapse
Affiliation(s)
- Axelle E M Larue
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, United Kingdom
| | - Yaser Atlasi
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT9 7AE, United Kingdom
| |
Collapse
|
|
6
|
Gao W, Zhou J, Morshedi M. MicroRNA-34 and gastrointestinal cancers: a player with big functions. Cancer Cell Int 2024; 24:163. [PMID: 38725047 PMCID: PMC11084024 DOI: 10.1186/s12935-024-03338-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.
Collapse
Affiliation(s)
- Wei Gao
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Jianping Zhou
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
7
|
Buss JH, Begnini KR, Lenz G. The contribution of asymmetric cell division to phenotypic heterogeneity in cancer. J Cell Sci 2024; 137:jcs261400. [PMID: 38334041 DOI: 10.1242/jcs.261400] [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] [Indexed: 02/10/2024] Open
Abstract
Cells have evolved intricate mechanisms for dividing their contents in the most symmetric way during mitosis. However, a small proportion of cell divisions results in asymmetric segregation of cellular components, which leads to differences in the characteristics of daughter cells. Although the classical function of asymmetric cell division (ACD) in the regulation of pluripotency is the generation of one differentiated daughter cell and one self-renewing stem cell, recent evidence suggests that ACD plays a role in other physiological processes. In cancer, tumor heterogeneity can result from the asymmetric segregation of genetic material and other cellular components, resulting in cell-to-cell differences in fitness and response to therapy. Defining the contribution of ACD in generating differences in key features relevant to cancer biology is crucial to advancing our understanding of the causes of tumor heterogeneity and developing strategies to mitigate or counteract it. In this Review, we delve into the occurrence of asymmetric mitosis in cancer cells and consider how ACD contributes to the variability of several phenotypes. By synthesizing the current literature, we explore the molecular mechanisms underlying ACD, the implications of phenotypic heterogeneity in cancer, and the complex interplay between these two phenomena.
Collapse
Affiliation(s)
- Julieti Huch Buss
- Departamento de Biofísica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
- Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
| | - Karine Rech Begnini
- Departamento de Biofísica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
- Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
- Instituto do Cérebro (INSCER), Pontifícia Universidade Católica RS (PUCRS), Porto Alegre, RS 90610-000, Brazil
| | - Guido Lenz
- Departamento de Biofísica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
- Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS 91509-900, Brazil
| |
Collapse
|
|
8
|
Chao S, Yan H, Bu P. Asymmetric division of stem cells and its cancer relevance. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:5. [PMID: 38411768 PMCID: PMC10897644 DOI: 10.1186/s13619-024-00188-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/30/2024] [Indexed: 02/28/2024]
Abstract
Asymmetric division is a fundamental process for generating cell diversity and maintaining the stem cell population. During asymmetric division, proteins, organelles, and even RNA are distributed unequally between the two daughter cells, determining their distinct cell fates. The mechanisms orchestrating this process are extremely complex. Dysregulation of asymmetric division can potentially trigger cancer progression. Cancer stem cells, in particular, undergo asymmetric division, leading to intra-tumoral heterogeneity, which contributes to treatment refractoriness. In this review, we delve into the cellular and molecular mechanisms that govern asymmetric division and explore its relevance to tumorigenesis.
Collapse
Affiliation(s)
- Shanshan Chao
- Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing, 100101, China
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Huiwen Yan
- Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing, 100101, China
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Pengcheng Bu
- Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing, 100101, China.
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
9
|
Mohammadpour S, Noukabadi FN, Esfahani AT, Kazemi F, Esmaeili S, Zafarjafarzadeh N, Sarpash S, Nazemalhosseini-Mojarad E. Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation. Curr Mol Med 2024; 24:565-575. [PMID: 37226783 DOI: 10.2174/1566524023666230523155719] [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: 09/08/2022] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 05/26/2023]
Abstract
Colorectal cancer (CRC) is one of the world's most common types of malignancy. The proliferation of precancerous lesions causes this type of cancer. Two distinct pathways for CRC carcinogenesis have been identified: the conventional adenoma-carcinoma pathway and the serrated neoplasia pathway. Recently, evidence has demonstrated the regulatory roles of noncoding RNAs (ncRNAs) in the initiation and progression of precancerous lesions, especially in the adenoma-carcinoma pathway and serrated neoplasia pathway. By expanding the science of molecular genetics and bioinformatics, several studies have identified dysregulated ncRNAs that function as oncogenes or tumor suppressors in cancer initiation and formation by diverse mechanisms via intracellular signaling pathways known to act on tumor cells. However, many of their roles are still unclear. This review summarizes the functions and mechanisms of ncRNAs (such as long non-coding RNAs, microRNAs, long intergenic non-coding RNAs, small interfering RNAs, and circRNAs) in the initiation and formation of precancerous lesions.
Collapse
Affiliation(s)
- Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Naderi Noukabadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Amir Torshizi Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Kazemi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Sahar Esmaeili
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Nikta Zafarjafarzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - SeyedKasra Sarpash
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
10
|
Roy L, Chatterjee O, Bose D, Roy A, Chatterjee S. Noncoding RNA as an influential epigenetic modulator with promising roles in cancer therapeutics. Drug Discov Today 2023; 28:103690. [PMID: 37379906 DOI: 10.1016/j.drudis.2023.103690] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 05/11/2023] [Accepted: 06/21/2023] [Indexed: 06/30/2023]
Abstract
The epigenetic landscape has an important role in cellular homeostasis and its deregulation leads to cancer. Noncoding (nc)RNA networks function as major regulators of cellular epigenetic hallmarks via regulation of vital processes, such as histone modification and DNA methylation. They are integral intracellular components affecting multiple oncogenic pathways. Thus, it is important to elucidate the effects of ncRNA networks on epigenetic programming that lead to the initiation and progression of cancer. In this review, we summarize the effects of epigenetic modification influenced by ncRNA networks and crosstalk between diverse classes of ncRNA, which could aid the development of patient-specific cancer therapeutics targeting ncRNAs, thereby altering cellular epigenetics.
Collapse
Affiliation(s)
- Laboni Roy
- Department of Biophysics, Bose Institute, Kolkata 700091, India
| | | | - Debopriya Bose
- Department of Biophysics, Bose Institute, Kolkata 700091, India
| | - Ananya Roy
- Department of Biophysics, Bose Institute, Kolkata 700091, India
| | | |
Collapse
|
|
11
|
Bhattacharjee R, Prabhakar N, Kumar L, Bhattacharjee A, Kar S, Malik S, Kumar D, Ruokolainen J, Negi A, Jha NK, Kesari KK. Crosstalk between long noncoding RNA and microRNA in Cancer. Cell Oncol (Dordr) 2023; 46:885-908. [PMID: 37245177 PMCID: PMC10356678 DOI: 10.1007/s13402-023-00806-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2023] [Indexed: 05/29/2023] Open
Abstract
miRNAs and lncRNAs play a central role in cancer-associated gene regulations. The dysregulated expression of lncRNAs has been reported as a hallmark of cancer progression, acting as an independent prediction marker for an individual cancer patient. The interplay of miRNA and lncRNA decides the variation of tumorigenesis that could be mediated by acting as sponges for endogenous RNAs, regulating miRNA decay, mediating intra-chromosomal interactions, and modulating epigenetic components. This paper focuses on the influence of crosstalk between lncRNA and miRNA on cancer hallmarks such as epithelial-mesenchymal transition, hijacking cell death, metastasis, and invasion. Other cellular roles of crosstalks, such as neovascularization, vascular mimicry, and angiogenesis were also discussed. Additionally, we reviewed crosstalk mechanism with specific host immune responses and targeting interplay (between lncRNA and miRNA) in cancer diagnosis and management.
Collapse
Affiliation(s)
- Rahul Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Neeraj Prabhakar
- Centre for Structural System Biology, Department of Physics, University of Hamburg, c/o DESY, Building 15, Notkestr. 852267, Hamburg, Germany
- Pharmacy, Abo Akademi University, Tykistökatu 6A, Turku, Finland
| | - Lamha Kumar
- School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, India
| | - Arkadyuti Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Sulagna Kar
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Sumira Malik
- Amity Institute of Biotechnology, Amity University Jharkhand, Ranchi, Jharkhand, 834001, India
| | - Dhruv Kumar
- School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand, India
| | - Janne Ruokolainen
- Department of Applied Physics, School of Science, Aalto University, Espoo, 00076, Finland
| | - Arvind Negi
- Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University, Espoo, 00076, Finland.
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, 201310, UP, India.
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, 144411, India.
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India.
| | - Kavindra Kumar Kesari
- Department of Applied Physics, School of Science, Aalto University, Espoo, 00076, Finland.
- Faculty of Biological and Environmental Sciences, University of Helsinki, Biocentre 3, Helsinki, Finland.
| |
Collapse
|
|
12
|
Wei M, Nurjanah U, Li J, Luo X, Hosea R, Li Y, Zeng J, Duan W, Song G, Miyagishi M, Kasim V, Wu S. YY2-DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207349. [PMID: 37300334 PMCID: PMC10427375 DOI: 10.1002/advs.202207349] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 04/24/2023] [Indexed: 06/12/2023]
Abstract
Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross-omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem-like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor-initiating capacity. Meanwhile, YY2 knock-out in stem-like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin-related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic-mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.
Collapse
Affiliation(s)
- Mankun Wei
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Uli Nurjanah
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Juan Li
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Xinxin Luo
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Rendy Hosea
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Yanjun Li
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Jianting Zeng
- Department of Hepatobiliary and Pancreatic OncologyChongqing University Cancer HospitalChongqing UniversityChongqing400030P. R. China
| | - Wei Duan
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Guanbin Song
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
| | - Makoto Miyagishi
- Life Science InnovationSchool of Integrative and Global MajorsUniversity of TsukubaTsukubaIbaraki305‐0006Japan
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized TreatmentChongqing University Cancer HospitalChongqing UniversityChongqing400030P. R. China
| | - Shourong Wu
- Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- The 111 Project Laboratory of Biomechanics and Tissue RepairCollege of BioengineeringChongqing UniversityChongqing400044P. R. China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized TreatmentChongqing University Cancer HospitalChongqing UniversityChongqing400030P. R. China
| |
Collapse
|
|
13
|
Qi A, Lamont L, Liu E, Murray SD, Meng X, Yang S. Essential Protein PHB2 and Its Regulatory Mechanisms in Cancer. Cells 2023; 12:cells12081211. [PMID: 37190120 DOI: 10.3390/cells12081211] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 05/17/2023] Open
Abstract
Prohibitins (PHBs) are a highly conserved class of proteins and have an essential role in transcription, epigenetic regulation, nuclear signaling, mitochondrial structural integrity, cell division, and cellular membrane metabolism. Prohibitins form a heterodimeric complex, consisting of two proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2). They have been discovered to have crucial roles in regulating cancer and other metabolic diseases, functioning both together and independently. As there have been many previously published reviews on PHB1, this review focuses on the lesser studied prohibitin, PHB2. The role of PHB2 in cancer is controversial. In most human cancers, overexpressed PHB2 enhances tumor progression, while in some cancers, it suppresses tumor progression. In this review, we focus on (1) the history, family, and structure of prohibitins, (2) the essential location-dependent functions of PHB2, (3) dysfunction in cancer, and (4) the promising modulators to target PHB2. At the end, we discuss future directions and the clinical significance of this common essential gene in cancer.
Collapse
Affiliation(s)
- Amanda Qi
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Lillie Lamont
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Evelyn Liu
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Sarina D Murray
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Xiangbing Meng
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Shujie Yang
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| |
Collapse
|
|
14
|
Chuang YT, Shiau JP, Tang JY, Farooqi AA, Chang FR, Tsai YH, Yen CY, Chang HW. Connection of Cancer Exosomal LncRNAs, Sponging miRNAs, and Exosomal Processing and Their Potential Modulation by Natural Products. Cancers (Basel) 2023; 15:cancers15082215. [PMID: 37190145 DOI: 10.3390/cancers15082215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Cancerous exosomes contain diverse biomolecules that regulate cancer progression. Modulating exosome biogenesis with clinical drugs has become an effective strategy for cancer therapy. Suppressing exosomal processing (assembly and secretion) may block exosomal function to reduce the proliferation of cancer cells. However, the information on natural products that modulate cancer exosomes lacks systemic organization, particularly for exosomal long noncoding RNAs (lncRNAs). There is a gap in the connection between exosomal lncRNAs and exosomal processing. This review introduces the database (LncTarD) to explore the potential of exosomal lncRNAs and their sponging miRNAs. The names of sponging miRNAs were transferred to the database (miRDB) for the target prediction of exosomal processing genes. Moreover, the impacts of lncRNAs, sponging miRNAs, and exosomal processing on the tumor microenvironment (TME) and natural-product-modulating anticancer effects were then retrieved and organized. This review sheds light on the functions of exosomal lncRNAs, sponging miRNAs, and exosomal processing in anticancer processes. It also provides future directions for the application of natural products when regulating cancerous exosomal lncRNAs.
Collapse
Affiliation(s)
- Ya-Ting Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jun-Ping Shiau
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ammad Ahmad Farooqi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 54000, Pakistan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Hong Tsai
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Yu Yen
- School of Dentistry, Taipei Medical University, Taipei 11031, Taiwan
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan 71004, Taiwan
| | - Hsueh-Wei Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| |
Collapse
|
|
15
|
Wang X, Zheng Y, Chai Z, Li J, Zhu C, Peng Y, Qiu J, Xu J, Liu C. Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway. Mol Carcinog 2023; 62:293-302. [PMID: 36342357 DOI: 10.1002/mc.23486] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022]
Abstract
Dihydroartemisinin (DHA) has recently attracted increasing attention for its low toxicity and high antitumor activity. DHA has been reported to have synergistic anticancer effects with a variety of drugs in the clinic; however, the molecular mechanism by which DHA inhibits tumorigenesis and improves oxaliplatin cytotoxicity in colon cancer cells is still not well understood. In this study, we found that DHA can inhibit cell proliferation and colony formation in a dose-dependent manner. Prohibitin 2 (PHB2) is a potential target by which DHA exerts its antitumor and cytotoxic effects. The function and molecular mechanism of PHB2 in colon cancer tumorigenesis were fully studied to determine the regulatory mechanism between DHA and PHB2. We found that PHB2, a mitochondrial inner membrane scaffold protein, has a higher expression level in colon cancer tissues than in adjacent nontumor tissues and is mainly localized in mitochondria. Overexpression of PHB2 can promote cell proliferation and colony formation in vitro and accelerate tumor growth in vivo. We also found that the expression level of PHB2 was inversely related to the cytotoxicity of DHA and oxaliplatin in colon cancer cells. The molecular mechanism of PHB2 in tumorigenesis and cancer therapy was further studied. The results showed that 20 μM DHA can downregulate PHB2 expression in a ubiquitylation-dependent manner and subsequently block PHB2-induced RCHY1 upregulation and p53 and p21 downregulation. In this process, RCHY1 is necessary for PHB2 to play a tumor-promoting role. Thus, PHB2 and RCHY1 are effective targets for colon cancer therapy, and DHA has synergistic anticancer effects with oxaliplatin via promoting PHB2 degradation in colon cancer cells.
Collapse
Affiliation(s)
- Xiwei Wang
- Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China
| | - Yingying Zheng
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China.,Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China
| | - Zhengbin Chai
- Department of Clinical Laboratory Medicine, Shandong Public Health Clinical Center, Jinan, People's Republic of China
| | - Ji Li
- Department of AIDS Control and Prevention, Center for Disease Control and Prevention of Jining, Jining, Shandong, People's Republic of China
| | - Changhui Zhu
- School of Basic Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Yanling Peng
- Shandong First Medical University & Shandong First Medical University, Jinan, People's Republic of China
| | - Juanjuan Qiu
- Shandong First Medical University & Shandong First Medical University, Jinan, People's Republic of China
| | - Jiajun Xu
- Shandong First Medical University & Shandong First Medical University, Jinan, People's Republic of China
| | - Chunyan Liu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China
| |
Collapse
|
|
16
|
Wu Y, Xu X. Long non-coding RNA signature in colorectal cancer: research progression and clinical application. Cancer Cell Int 2023; 23:28. [PMID: 36797749 PMCID: PMC9936661 DOI: 10.1186/s12935-023-02867-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/05/2023] [Indexed: 02/18/2023] Open
Abstract
Colorectal cancer is one of the top-ranked human malignancies. The development and progression of colorectal cancer are associated with aberrant expression of multiple coding and non-coding genes. Long non-coding RNAs (lncRNAs) have an important role in regulating gene stability as well as gene expression. Numerous current studies have shown that lncRNAs are promising biomarkers and therapeutic targets for colorectal cancer. In this review, we have searched the available literature to list lncRNAs involved in the pathogenesis and regulation of colorectal cancer. We focus on the role of lncRNAs in cancer promotion or suppression, their value in tumor diagnosis, and their role in treatment response and prognosis prediction. In addition, we will discuss the signaling pathways that these lncRNAs are mainly associated with in colorectal cancer. We also summarize the role of lncRNAs in colorectal precancerous lesions and colorectal cancer consensus molecular subgroups. We hope this review article will bring you the latest research progress and outlook on lncRNAs in colorectal cancer.
Collapse
Affiliation(s)
- Yudi Wu
- grid.33199.310000 0004 0368 7223GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China ,grid.33199.310000 0004 0368 7223Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 People’s Republic of China
| | - Xiangshang Xu
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China. .,Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| |
Collapse
|
|
17
|
Akbari A, Abbasi S, Borumandnia N, Eshkiki ZS, Sedaghat M, Tabaeian SP, Kashani AF, Talebi A. Epigenetic regulation of gastrointestinal cancers mediated by long non-coding RNAs. Cancer Biomark 2022; 35:359-377. [PMID: 36404536 DOI: 10.3233/cbm-220142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Long noncoding RNAs (lncRNAs), as well-known modulator of the epigenetic processes, have been shown to contribute to normal cellular physiological and pathological conditions such as cancer. Through the interaction with epigenetic regulators, an aberrant regulation of gene expression can be resulted due to their dysregulation, which in turn, can be involved in tumorigenesis. In the present study, we reviewed the lncRNAs' function and mechanisms that contributed to aberrant epigenetic regulation, which is directly related to gastrointestinal cancer (GI) development and progression. Findings indicated that epigenetic alterations may involve in tumorigenesis and are valuable biomarkers in case of diagnosing, assessing of risk factors, and predicting of GI cancers. This review summarized the accumulated evidence for biological and clinical application to use lncRNAs in GI cancers, including colorectal, gastric, oral, liver, pancreatic and oesophageal cancer.
Collapse
Affiliation(s)
- Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.,Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Abbasi
- Department of Mathematics, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Nasrin Borumandnia
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Meghdad Sedaghat
- Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seidamir Pasha Tabaeian
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
18
|
Yang Z, Xu F, Teschendorff AE, Zhao Y, Yao L, Li J, He Y. Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation. Front Mol Biosci 2022; 9:1067406. [PMID: 36533073 PMCID: PMC9755597 DOI: 10.3389/fmolb.2022.1067406] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/17/2022] [Indexed: 09/12/2023] Open
Abstract
DNA methylation is one of the most important epigenetic mechanisms that governing regulation of gene expression, aberrant DNA methylation patterns are strongly associated with human malignancies. Long non-coding RNAs (lncRNAs) have being discovered as a significant regulator on gene expression at the epigenetic level. Emerging evidences have indicated the intricate regulatory effects between lncRNAs and DNA methylation. On one hand, transcription of lncRNAs are controlled by the promoter methylation, which is similar to protein coding genes, on the other hand, lncRNA could interact with enzymes involved in DNA methylation to affect the methylation pattern of downstream genes, thus regulating their expression. In addition, circular RNAs (circRNAs) being an important class of noncoding RNA are also found to participate in this complex regulatory network. In this review, we summarize recent research progress on this crosstalk between lncRNA, circRNA, and DNA methylation as well as their potential functions in complex diseases including cancer. This work reveals a hidden layer for gene transcriptional regulation and enhances our understanding for epigenetics regarding detailed mechanisms on lncRNA regulatory function in human cancers.
Collapse
Affiliation(s)
- Zhen Yang
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Feng Xu
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Andrew E. Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yi Zhao
- Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Lei Yao
- Experiment Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jian Li
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yungang He
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
19
|
Li W(J, Liu X, Dougherty EM, Tang DG. MicroRNA-34a, Prostate Cancer Stem Cells, and Therapeutic Development. Cancers (Basel) 2022; 14:4538. [PMID: 36139695 PMCID: PMC9497236 DOI: 10.3390/cancers14184538] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Prostate cancer (PCa) is a highly heterogeneous disease and typically presents with multiple distinct cancer foci. Heterogeneity in androgen receptor (AR) expression levels in PCa has been observed for decades, from untreated tumors to castration-resistant prostate cancer (CRPC) to disseminated metastases. Current standard-of-care therapies for metastatic CRPC can only extend life by a few months. Cancer stem cells (CSCs) are defined as a subpopulation of cancer cells that exists in almost all treatment-naive tumors. Additionally, non-CSCs may undergo cellular plasticity to be reprogrammed to prostate cancer stem cells (PCSCs) during spontaneous tumor progression or upon therapeutic treatments. Consequently, PCSCs may become the predominant population in treatment-resistant tumors, and the "root cause" for drug resistance. microRNA-34a (miR-34a) is a bona fide tumor-suppressive miRNA, and its expression is dysregulated in PCa. Importantly, miR-34a functions as a potent CSC suppressor by targeting many molecules essential for CSC survival and functions, which makes it a promising anti-PCSC therapeutic. Here, we conducted a comprehensive literature survey of miR-34a in the context of PCa and especially PCSCs. We provided an updated overview on the mechanisms of miR-34a regulation followed by discussing its tumor suppressive functions in PCa. Finally, based on current advances in miR-34a preclinical studies in PCa, we offered potential delivery strategies for miR-34a-based therapeutics for treating advanced PCa.
Collapse
Affiliation(s)
- Wen (Jess) Li
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY 14263, USA
| | - Xiaozhuo Liu
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Emily M. Dougherty
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Genetics & Genomics Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY 14263, USA
| | - Dean G. Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY 14263, USA
| |
Collapse
|
|
20
|
Regulation of the Cancer Stem Phenotype by Long Non-Coding RNAs. Cells 2022; 11:cells11152352. [PMID: 35954194 PMCID: PMC9367355 DOI: 10.3390/cells11152352] [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: 07/04/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer stem cells are a cell population within malignant tumors that are characterized by the ability to self-renew, the presence of specific molecules that define their identity, the ability to form malignant tumors in vivo, resistance to drugs, and the ability to invade and migrate to other regions of the body. These characteristics are regulated by various molecules, such as lncRNAs, which are transcripts that generally do not code for proteins but regulate multiple biological processes through various mechanisms of action. LncRNAs, such as HOTAIR, H19, LncTCF7, LUCAT1, MALAT1, LINC00511, and FMR1-AS1, have been described as key regulators of stemness in cancer, allowing cancer cells to acquire this phenotype. It has been proposed that cancer stem cells are clinically responsible for the high recurrence rates after treatment and the high frequency of metastasis in malignant tumors, so understanding the mechanisms that regulate the stem phenotype could have an impact on the improvement of cancer treatments.
Collapse
|
|
21
|
Hussen BM, Kheder RK, Abdullah ST, Hidayat HJ, Rahman HS, Salihi A, Taheri M, Ghafouri-Fard S. Functional interplay between long non-coding RNAs and Breast CSCs. Cancer Cell Int 2022; 22:233. [PMID: 35864503 PMCID: PMC9306174 DOI: 10.1186/s12935-022-02653-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 07/12/2022] [Indexed: 12/14/2022] Open
Abstract
Breast cancer (BC) represents aggressive cancer affecting most women’s lives globally. Metastasis and recurrence are the two most common factors in a breast cancer patient's poor prognosis. Cancer stem cells (CSCs) are tumor cells that are able to self-renew and differentiate, which is a significant factor in metastasis and recurrence of cancer. Long non-coding RNAs (lncRNAs) describe a group of RNAs that are longer than 200 nucleotides and do not have the ability to code for proteins. Some of these lncRNAs can be mainly produced in various tissues and tumor forms. In the development and spread of malignancies, lncRNAs have a significant role in influencing multiple signaling pathways positively or negatively, making them promise useful diagnostic and prognostic markers in treating the disease and guiding clinical therapy. However, it is not well known how the interaction of lncRNAs with CSCs will affect cancer development and progression. Here, in this review, we attempt to summarize recent findings that focus on lncRNAs affect cancer stem cell self-renewal and differentiation in breast cancer development and progression, as well as the strategies and challenges for overcoming lncRNA's therapeutic resistance.
Collapse
Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil , Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Ramiar Kamal Kheder
- Department of Medical Analysis, Faculty of Science, Tishk International University, Erbil, Iraq.,Medical Laboratory Science, College of Science, University of Raparin, Rania, KGR, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Heshu Sulaiman Rahman
- Department of Physiology, College of Medicine, University of Sulaimani, Sulaimaniyah, Republic of Iraq.,Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Republic of Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
22
|
LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond. J Exp Clin Cancer Res 2022; 41:100. [PMID: 35292092 PMCID: PMC8922926 DOI: 10.1186/s13046-022-02319-z] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023] Open
Abstract
DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.
Collapse
|
|
23
|
Wang JP, Li C, Ding WC, Peng G, Xiao GL, Chen R, Cheng Q. Research Progress on the Inflammatory Effects of Long Non-coding RNA in Traumatic Brain Injury. Front Mol Neurosci 2022; 15:835012. [PMID: 35359568 PMCID: PMC8961287 DOI: 10.3389/fnmol.2022.835012] [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: 12/14/2021] [Accepted: 02/08/2022] [Indexed: 11/29/2022] Open
Abstract
Globally, traumatic brain injury (TBI) is an acute clinical event and an important cause of death and long-term disability. However, the underlying mechanism of the pathophysiological has not been fully elucidated and the lack of effective treatment a huge burden to individuals, families, and society. Several studies have shown that long non-coding RNAs (lncRNAs) might play a crucial role in TBI; they are abundant in the central nervous system (CNS) and participate in a variety of pathophysiological processes, including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis, and neurogenesis. Some lncRNAs modulate multiple therapeutic targets after TBI, including inflammation, thus, these lncRNAs have tremendous therapeutic potential for TBI, as they are promising biomarkers for TBI diagnosis, treatment, and prognosis prediction. This review discusses the differential expression of different lncRNAs in brain tissue during TBI, which is likely related to the physiological and pathological processes involved in TBI. These findings may provide new targets for further scientific research on the molecular mechanisms of TBI and potential therapeutic interventions.
Collapse
Affiliation(s)
- Jian-peng Wang
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Chong Li
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Wen-cong Ding
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Gang Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ge-lei Xiao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Rui Chen
- Department of Neurosurgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China
- *Correspondence: Rui Chen,
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Quan Cheng,
| |
Collapse
|
|
24
|
Fan B, Zhang Q, Wang N, Wang G. LncRNAs, the Molecules Involved in Communications With Colorectal Cancer Stem Cells. Front Oncol 2022; 12:811374. [PMID: 35155247 PMCID: PMC8829571 DOI: 10.3389/fonc.2022.811374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer stem cells (CRCSCs) can actively self-renew, as well as having multidirectional differentiation and tumor regeneration abilities. Because the high functional activities of CRCSCs are associated with low cure rates in patients with colorectal cancer, efforts have sought to determine the function and regulatory mechanisms of CRCSCs. To date, however, the potential regulatory mechanisms of CRCSCs remain incompletely understood. Many non-coding genes are involved in tumor invasion and spread through their regulation of CRCSCs, with long non-coding RNAs (lncRNAs) being important non-coding RNAs. LncRNAs may be involved in the colorectal cancer development and drug resistance through their regulation of CRCSCs. This review systematically evaluates the latest research on the ability of lncRNAs to regulate CRCSC signaling pathways and the involvement of these lncRNAs in colorectal cancer promotion and suppression. The regulatory network of lncRNAs in the CRCSC signaling pathway has been determined. Further analysis of the potential clinical applications of lncRNAs as novel clinical diagnostic and prognostic biomarkers and therapeutic targets for colorectal cancer may provide new ideas and protocols for the prevention and treatment of colorectal cancer.
Collapse
Affiliation(s)
- Boyang Fan
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Zhang
- Department of Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Ning Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
25
|
Lu S, Ding X, Wang Y, Hu X, Sun T, Wei M, Wang X, Wu H. The Relationship Between the Network of Non-coding RNAs-Molecular Targets and N6-Methyladenosine Modification in Colorectal Cancer. Front Cell Dev Biol 2021; 9:772542. [PMID: 34938735 PMCID: PMC8685436 DOI: 10.3389/fcell.2021.772542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/11/2021] [Indexed: 12/11/2022] Open
Abstract
Recent accumulating researches implicate that non-coding RNAs (ncRNAs) including microRNA (miRNA), circular RNA (circRNA), and long non-coding RNA (lncRNAs) play crucial roles in colorectal cancer (CRC) initiation and development. Notably, N6-methyladenosine (m6A) methylation, the critical posttranscriptional modulators, exerts various functions in ncRNA metabolism such as stability and degradation. However, the interaction regulation network among ncRNAs and the interplay with m6A-related regulators has not been well documented, particularly in CRC. Here, we summarize the interaction networks and sub-networks of ncRNAs in CRC based on a data-driven approach from the publications (IF > 6) in the last quinquennium (2016–2021). Further, we extend the regulatory pattern between the core m6A regulators and m6A-related ncRNAs in the context of CRC metastasis and progression. Thus, our review will highlight the clinical potential of ncRNAs and m6A modifiers as promising biomarkers and therapeutic targets for improving the diagnostic precision and treatment of CRC.
Collapse
Affiliation(s)
- Senxu Lu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Xiangyu Ding
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Yuanhe Wang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang, China
| | - Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Tong Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China.,Shenyang Kangwei Medical Laboratory Analysis Co. Ltd., Liaoning, China
| | - Xiaobin Wang
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China
| |
Collapse
|
|
26
|
Zheng B, Wang J, Fan K, Sun W, Wan W, Gao Z, Ni X, Zhang D, Ni X, Suo T, Liu H, Liu H, Shen S. lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC. Mol Ther Oncolytics 2021; 23:124-137. [PMID: 34703881 PMCID: PMC8507201 DOI: 10.1016/j.omto.2021.08.016] [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] [Received: 03/09/2021] [Accepted: 08/31/2021] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been identified as critical contributors in tumor progression for many types of cancer. However, their functions in gallbladder cancer (GBC) have not been systematically clarified. In this study, the clinical significance, biological function, and underlying mechanism of lncRNA RP11-147L13.8 in GBC were investigated. The quantitative real-time PCR result indicated that lncRNA RP11-147L13.8 was found to be recurrently downregulated in GBC tumor samples. Kaplan-Meier analysis revealed that decreased lncRNA RP11-147L13.8 expression level was associated with poor survival of GBC patients (p = 0.025). Then, both in vitro and in vivo experiments elucidated that the overexpression of lncRNA RP11-147L13.8 suppressed the migration and invasion abilities of GBC cells and promoted the sensitivity to gemcitabine of GBC cells. Furthermore, we found that lncRNA RP11-147L13.8 physically interacted with c-Jun protein and decreased the phosphorylation on serine-73 (c-Jun-Ser73), which might cause the enhancement of the migration, invasion, and sensitivity to gemcitabine of GBC tumor cells. In conclusion, our study identified lncRNA RP11-147L13.8 as a promising prognostic indicator for patients with GBC, providing insights into the molecular pathogenesis of GBC. lncRNA RP11-147L13.8 is a potential therapeutic combination for gemcitabine in GBC treatment.
Collapse
Affiliation(s)
- Bohao Zheng
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Jiwen Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Kun Fan
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
- Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Wentao Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Wenze Wan
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Zhihui Gao
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaojian Ni
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Dexiang Zhang
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
- Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Xiaoling Ni
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Tao Suo
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Han Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
| | - Houbao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
- Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Sheng Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China
- Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China
- Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
27
|
Zheng B, Wang J, Fan K, Sun W, Wan W, Gao Z, Ni X, Zhang D, Ni X, Suo T, Liu H, Liu H, Shen S. lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC. Mol Ther Oncolytics 2021; 23:124-137. [PMID: 34703881 PMCID: PMC8640164 DOI: 10.1016/j.omto.2021.11.015] [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: 03/09/2021] [Accepted: 08/31/2021] [Indexed: 11/20/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have been identified as critical contributors in tumor progression for many types of cancer. However, their functions in gallbladder cancer (GBC) have not been systematically clarified. In this study, the clinical significance, biological function, and underlying mechanism of lncRNA RP11-147L13.8 in GBC were investigated. The quantitative real-time PCR result indicated that lncRNA RP11-147L13.8 was found to be recurrently downregulated in GBC tumor samples. Kaplan-Meier analysis revealed that decreased lncRNA RP11-147L13.8 expression level was associated with poor survival of GBC patients (p = 0.025). Then, both in vitro and in vivo experiments elucidated that the overexpression of lncRNA RP11-147L13.8 suppressed the migration and invasion abilities of GBC cells and promoted the sensitivity to gemcitabine of GBC cells. Furthermore, we found that lncRNA RP11-147L13.8 physically interacted with c-Jun protein and decreased the phosphorylation on serine-73 (c-Jun-Ser73), which might cause the enhancement of the migration, invasion, and sensitivity to gemcitabine of GBC tumor cells. In conclusion, our study identified lncRNA RP11-147L13.8 as a promising prognostic indicator for patients with GBC, providing insights into the molecular pathogenesis of GBC. lncRNA RP11-147L13.8 is a potential therapeutic combination for gemcitabine in GBC treatment.
Collapse
|
|
28
|
Naz F, Shi M, Sajid S, Yang Z, Yu C. Cancer stem cells: a major culprit of intra-tumor heterogeneity. Am J Cancer Res 2021; 11:5782-5811. [PMID: 35018226 PMCID: PMC8727794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 08/25/2021] [Indexed: 06/14/2023] Open
Abstract
Cancer is recognized as a preeminent factor of the world's mortality. Although various modalities have been designed to cure this life-threatening ailment, a significant impediment in the effective output of cancer treatment is heterogeneity. Cancer is characterized as a heterogeneous health disorder that comprises a distinct group of transformed cells to assist anomalous proliferation of affected cells. Cancer stem cells (CSCs) are a leading cause of cancer heterogeneity that is continually transformed by cellular extrinsic and intrinsic factors. They intensify neoplastic cells aggressiveness by strengthening their dissemination, relapse and therapy resistance. Considering this viewpoint, in this review article we have discussed some intrinsic (transcription factors, cell signaling pathways, genetic alterations, epigenetic modifications, non-coding RNAs (ncRNAs) and epitranscriptomics) and extrinsic factors (tumor microenvironment (TME)) that contribute to CSC heterogeneity and plasticity, which may help scientists to meddle these processes and eventually improve cancer research and management. Besides, the potential role of CSCs heterogeneity in establishing metastasis and therapy resistance has been articulated which signifies the importance of developing novel anticancer therapies to target CSCs along with targeting bulk tumor mass to achieve an effective output.
Collapse
Affiliation(s)
- Faiza Naz
- College of Life Science and Technology, Beijing University of Chemical TechnologyBeijing 100029, China
| | - Mengran Shi
- College of Life Science and Technology, Beijing University of Chemical TechnologyBeijing 100029, China
| | - Salvia Sajid
- Department of Biotechnology, Jinnah University for WomenKarachi 74600, Pakistan
| | - Zhao Yang
- College of Life Science and Technology, Beijing University of Chemical TechnologyBeijing 100029, China
- College of Life Science, Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin of Xinjiang Production and Construction Corps, Tarim UniversityAlar 843300, Xinjiang, China
| | - Changyuan Yu
- College of Life Science and Technology, Beijing University of Chemical TechnologyBeijing 100029, China
| |
Collapse
|
|
29
|
Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
Collapse
Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| |
Collapse
|
|
30
|
Lenz G, Onzi GR, Lenz LS, Buss JH, Santos JAF, Begnini KR. The Origins of Phenotypic Heterogeneity in Cancer. Cancer Res 2021; 82:3-11. [PMID: 34785576 DOI: 10.1158/0008-5472.can-21-1940] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/14/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022]
Abstract
Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell -omics analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be key to better understand cancer cell fitness in tumor biology and therapeutics.
Collapse
|
|
31
|
Sharma A, Mir R, Galande S. Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer. Front Genet 2021; 12:681053. [PMID: 34552611 PMCID: PMC8450413 DOI: 10.3389/fgene.2021.681053] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies.
Collapse
Affiliation(s)
- Ankita Sharma
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India
| | - Rafeeq Mir
- Centre for Interdisciplinary Research and Innovations, University of Kashmir, Srinagar, India
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India.,Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India
| |
Collapse
|
|
32
|
Inhibition of HDAC1 alleviates monocrotaline-induced pulmonary arterial remodeling through up-regulation of miR-34a. Respir Res 2021; 22:239. [PMID: 34465322 PMCID: PMC8408973 DOI: 10.1186/s12931-021-01832-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 08/24/2021] [Indexed: 11/20/2022] Open
Abstract
Background It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. Methods PAH rat models were induced by intraperitoneal injection of MCT. HDAC1 was suppressed by intraperitoneal injection of the class I HDAC inhibitor MS-275, and miR-34a was over-expressed via tail vein injection of miR-34a agomiR. Results HDAC1 protein was significantly increased in MCT-induced PAH rats; this was accompanied with down-regulation of miR-34a and subsequent up-regulation of matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2/TIMP-2. Administration of PAH rats with MS-275 or miR-34a agomiR dramatically abolished MCT-induced reduction of miR-34a and subsequent up-regulation of MMP-9/TIMP-1 and MMP-2/TIMP-2, finally reduced extracellular matrix (ECM) accumulation, pulmonary arterial remodeling, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) in PAH rats. Conclusions HDAC1 contributes to the development of MCT-induced rat PAH by suppressing miR-34a level and subsequently up-regulating the ratio of MMP-9/TIMP-1 and MMP-2/TIMP-2. Inhibition of HDAC1 alleviates pulmonary arterial remodeling and PAH through up-regulation of miR-34a level and subsequent reduction of MMP-9/TIMP-1 and MMP-2/TIMP-2, suggesting that inhibition of HDAC1 might have potential value in the management of PAH.
Collapse
|
|
33
|
Li S, Wei X, He J, Cao Q, Du D, Zhan X, Zeng Y, Yuan S, Sun L. The comprehensive landscape of miR-34a in cancer research. Cancer Metastasis Rev 2021; 40:925-948. [PMID: 33959850 DOI: 10.1007/s10555-021-09973-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/29/2021] [Indexed: 12/12/2022]
Abstract
MicroRNA-34 (miR-34) plays central roles in human diseases, especially cancers. Inactivation of miR-34 is detected in cancer cell lines and tumor tissues versus normal controls, implying its potential tumor-suppressive effect. Clinically, miR-34 has been identified as promising prognostic indicators for various cancers. In fact, members of the miR-34 family, especially miR-34a, have been convincingly proved to affect almost the whole cancer progression process. Here, a total of 512 (miR-34a, 10/21), 85 (miR-34b, 10/16), and 114 (miR-34c, 10/14) putative targets of miR-34a/b/c are predicted by at least ten miRNA databases, respectively. These targets are further analyzed in gene ontology (GO), KEGG pathway, and the Reactome pathway dataset. The results suggest their involvement in the regulation of signal transduction, macromolecule metabolism, and protein modification. Also, the targets are implicated in critical signaling pathways, such as MAPK, Notch, Wnt, PI3K/AKT, p53, and Ras, as well as apoptosis, cell cycle, and EMT-related pathways. Moreover, the upstream regulators of miR-34a, mainly including transcription factors (TFs), lncRNAs, and DNA methylation, will be summarized. Meanwhile, the potential TF upstream of miR-34a/b/c will be predicted by PROMO, JASPAR, Animal TFDB 3.0, and GeneCard databases. Notably, miR-34a is an attractive target for certain cancers. In fact, miR-34a-based systemic delivery combined with chemotherapy or radiotherapy can more effectively control tumor progression. Collectively, this review will provide a panorama for miR-34a in cancer research.
Collapse
Affiliation(s)
- Sijing Li
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaohui Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jinyong He
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
- China Cell-Gene Therapy Translational Medicine Research Center, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
- School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Quanquan Cao
- MARBEC, Université Montpellier, UM-CNRS-IRD-IFREMER, cc 092, Place E. Bataillon, 34095, Montpellier Cedex 05, France
| | - Danyu Du
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaoman Zhan
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuqi Zeng
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Shengtao Yuan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li Sun
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China.
| |
Collapse
|
|
34
|
Zhang J, Ding T, Zhang H. Insight Into Chromatin-Enriched RNA: A Key Chromatin Regulator in Tumors. Front Cell Dev Biol 2021; 9:649605. [PMID: 33937246 PMCID: PMC8079759 DOI: 10.3389/fcell.2021.649605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/18/2021] [Indexed: 12/20/2022] Open
Abstract
Chromatin-enriched RNAs (cheRNAs) constitute a special class of long noncoding RNAs (lncRNAs) that are enriched around chromatin and function to activate neighboring or distal gene transcription. Recent studies have shown that cheRNAs affect chromatin structure and gene expression by recruiting chromatin modifiers or acting as bridges between distal enhancers and promoters. The abnormal transcription of cheRNAs plays an important role in the occurrence of many diseases, particularly tumors. The critical effect of cancer stem cells (CSCs) on the formation and development of tumors is well known, but the function of cheRNAs in tumorigenesis, especially in CSC proliferation and stemness maintenance, is not yet fully understood. This review focuses on the mechanisms of cheRNAs in epigenetic regulation and chromatin conformation and discusses the way cheRNAs function in CSCs to deepen the understanding of tumorigenesis and provide novel insight to advance tumor-targeting therapy.
Collapse
Affiliation(s)
- Jixing Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
- Frontier Science Research Center for Stem Cells, Tongji University, Shanghai, China
| | - Tianyi Ding
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
- Frontier Science Research Center for Stem Cells, Tongji University, Shanghai, China
| | - He Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
- Frontier Science Research Center for Stem Cells, Tongji University, Shanghai, China
| |
Collapse
|
|
35
|
Jahangiri L, Ishola T, Pucci P, Trigg RM, Pereira J, Williams JA, Cavanagh ML, Gkoutos GV, Tsaprouni L, Turner SD. The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13061239. [PMID: 33799834 PMCID: PMC7998932 DOI: 10.3390/cancers13061239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) represent a distinct cancer subpopulation that can influence the tumour microenvironment, in addition to cancer progression and relapse. A multitude of factors including CSC properties, long noncoding RNAs (lncRNAs), and autophagy play pivotal roles in maintaining CSCs. We discuss the methods of detection of CSCs and how our knowledge of regulatory and cellular processes, and their interaction with the microenvironment, may lead to more effective targeting of these cells. Autophagy and lncRNAs can regulate several cellular functions, thereby promoting stemness factors and CSC properties, hence understanding this triangle and its associated signalling networks can lead to enhanced therapy response, while paving the way for the development of novel therapeutic approaches. Abstract Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.
Collapse
Affiliation(s)
- Leila Jahangiri
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Correspondence: (L.J.); (G.V.G.)
| | - Tala Ishola
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Perla Pucci
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
| | - Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Department of Functional Genomics, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Joao Pereira
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - John A. Williams
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
| | - Megan L. Cavanagh
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Georgios V. Gkoutos
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
- Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire OX110RD, UK
- MRC Health Data Research Midlands, University of Birmingham, Birmingham B15 2TT, UK
- NIHR Experimental Cancer Medicine Centre, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham B15 2TT, UK
- NIHR Biomedical Research Centre, Birmingham B15 2TT, UK
- Correspondence: (L.J.); (G.V.G.)
| | - Loukia Tsaprouni
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Central European Institute of Technology (CEITEC), Masaryk University, 625 00 Brno, Czech Republic
| |
Collapse
|
|
36
|
Li WJ, Wang Y, Liu R, Kasinski AL, Shen H, Slack FJ, Tang DG. MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic. Front Cell Dev Biol 2021; 9:640587. [PMID: 33763422 PMCID: PMC7982597 DOI: 10.3389/fcell.2021.640587] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/03/2021] [Indexed: 12/17/2022] Open
Abstract
Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Intrinsic cancer cell heterogeneity and induced cancer cell plasticity, constantly and dynamically, generate a pool of CSC subpopulations with varying levels of epigenomic stability and stemness. Despite the dynamic and transient nature of CSCs, they play fundamental roles in mediating therapy resistance and tumor relapse. It is now clear that the stemness of CSCs is coordinately regulated by genetic factors and epigenetic mechanisms. Here, in this perspective, we first provide a brief updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse.
Collapse
Affiliation(s)
- Wen Jess Li
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Experimental Therapeutics Graduate Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Yunfei Wang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Department of Gynecology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Ruifang Liu
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Andrea L Kasinski
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Haifa Shen
- Department of Nanomedicine, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, United States
| | - Frank J Slack
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Experimental Therapeutics Graduate Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| |
Collapse
|
|
37
|
Zhang L, Niu H, Yang P, Ma J, Yuan BY, Zeng ZC, Xiang ZL. Serum lnc34a is a potential prediction biomarker for bone metastasis in hepatocellular carcinoma patients. BMC Cancer 2021; 21:161. [PMID: 33588789 PMCID: PMC7885499 DOI: 10.1186/s12885-021-07808-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
Background Early screening and intervention therapies are crucial to improve the prognosis of hepatocellular carcinoma (HCC) patients with bone metastasis. We aimed to identify serum lncRNA as a prediction biomarker in HCC bone metastasis. Methods The expression levels of lnc34a in serum samples from 157 HCC patients were detected by quantitative real-time polymerase chain reaction (PCR). Univariate analysis and multivariate analysis were performed to determine statistically significant variables. Results Expression levels of lnc34a in serum from HCC patients with bone metastasis were significantly higher than those without bone metastasis. The high expressions of lnc34a, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage were associated with bone metastasis by analysis. Moreover, lnc34a expression was specifically associated with bone metastasis rather than lung or lymph node metastasis in HCC. Conclusions High serum lnc34a expression was a independent risk factor for developing bone metastasis in HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07808-6.
Collapse
Affiliation(s)
- Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Hao Niu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Ping Yang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Jie Ma
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Bao-Ying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.
| | - Zuo-Lin Xiang
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China. .,Shanghai East Hospital Ji'an Hospital, 80 Ji'an South Road, Ji'an City, 343000, Jiangxi Province, China.
| |
Collapse
|
|
38
|
Hitomi M, Chumakova AP, Silver DJ, Knudsen AM, Pontius WD, Murphy S, Anand N, Kristensen BW, Lathia JD. Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells. JCI Insight 2021; 6:130510. [PMID: 33351787 PMCID: PMC7934841 DOI: 10.1172/jci.insight.130510] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD generated a daughter cell with enhanced therapeutic resistance and increased coenrichment of EGFR and neurotrophin receptor (p75NTR) from a glioblastoma CSC. Stimulation of both receptors antagonized differentiation induction and promoted self-renewal capacity. p75NTR knockdown enhanced the therapeutic efficacy of EGFR inhibition, indicating that coinheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with coenriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.
Collapse
Affiliation(s)
- Masahiro Hitomi
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Anastasia P Chumakova
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Daniel J Silver
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Arnon M Knudsen
- Department of Pathology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - W Dean Pontius
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Stephanie Murphy
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Neha Anand
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Bjarne W Kristensen
- Department of Pathology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Justin D Lathia
- Cancer Impact Area, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.,Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland, Ohio, USA
| |
Collapse
|
|
39
|
Angius A, Scanu AM, Arru C, Muroni MR, Rallo V, Deiana G, Ninniri MC, Carru C, Porcu A, Pira G, Uva P, Cossu-Rocca P, De Miglio MR. Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome. Int J Mol Sci 2021; 22:1603. [PMID: 33562604 PMCID: PMC7915330 DOI: 10.3390/ijms22041603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.
Collapse
Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Antonio Mario Scanu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Giulia Deiana
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Maria Chiara Ninniri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Alberto Porcu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- IRCCS G. Gaslini, 16147 Genoa, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| |
Collapse
|
|
40
|
MicroRNA-34a: the bad guy in age-related vascular diseases. Cell Mol Life Sci 2021; 78:7355-7378. [PMID: 34698884 PMCID: PMC8629897 DOI: 10.1007/s00018-021-03979-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/08/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
The age-related vasculature alteration is the prominent risk factor for vascular diseases (VD), namely, atherosclerosis, abdominal aortic aneurysm, vascular calcification (VC) and pulmonary arterial hypertension (PAH). The chronic sterile low-grade inflammation state, alias inflammaging, characterizes elderly people and participates in VD development. MicroRNA34-a (miR-34a) is emerging as an important mediator of inflammaging and VD. miR-34a increases with aging in vessels and induces senescence and the acquisition of the senescence-associated secretory phenotype (SASP) in vascular smooth muscle (VSMCs) and endothelial (ECs) cells. Similarly, other VD risk factors, including dyslipidemia, hyperglycemia and hypertension, modify miR-34a expression to promote vascular senescence and inflammation. miR-34a upregulation causes endothelial dysfunction by affecting ECs nitric oxide bioavailability, adhesion molecules expression and inflammatory cells recruitment. miR-34a-induced senescence facilitates VSMCs osteoblastic switch and VC development in hyperphosphatemia conditions. Conversely, atherogenic and hypoxic stimuli downregulate miR-34a levels and promote VSMCs proliferation and migration during atherosclerosis and PAH. MiR34a genetic ablation or miR-34a inhibition by anti-miR-34a molecules in different experimental models of VD reduce vascular inflammation, senescence and apoptosis through sirtuin 1 Notch1, and B-cell lymphoma 2 modulation. Notably, pleiotropic drugs, like statins, liraglutide and metformin, affect miR-34a expression. Finally, human studies report that miR-34a levels associate to atherosclerosis and diabetes and correlate with inflammatory factors during aging. Herein, we comprehensively review the current knowledge about miR-34a-dependent molecular and cellular mechanisms activated by VD risk factors and highlight the diagnostic and therapeutic potential of modulating its expression in order to reduce inflammaging and VD burn and extend healthy lifespan.
Collapse
|
|
41
|
Chen S, Shen X. Long noncoding RNAs: functions and mechanisms in colon cancer. Mol Cancer 2020; 19:167. [PMID: 33246471 PMCID: PMC7697375 DOI: 10.1186/s12943-020-01287-2] [Citation(s) in RCA: 197] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/20/2020] [Indexed: 12/28/2022] Open
Abstract
Evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in the carcinogenesis and progression of a wide variety of human malignancies including colon cancer. In this review, we describe the functions and mechanisms of lncRNAs involved in colon oncogenesis, such as HOTAIR, PVT1, H19, MALAT1, SNHG1, SNHG7, SNHG15, TUG1, XIST, ROR and ZEB1-AS1. We summarize the roles of lncRNAs in regulating cell proliferation, cell apoptotic death, the cell cycle, cell migrative and invasive ability, epithelial-mesenchymal transition (EMT), cancer stem cells and drug resistance in colon cancer. In addition, we briefly highlight the functions of circRNAs in colon tumorigenesis and progression, including circPPP1R12A, circPIP5K1A, circCTIC1, circ_0001313, circRNA_104916 and circRNA-ACAP2. This review provides the rationale for anticancer therapy via modulation of lncRNAs and circular RNAs (circRNAs) in colon carcinoma.
Collapse
Affiliation(s)
- Sian Chen
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, No 109 Xueyuan West Road, Wenzhou, Zhejiang, 325027, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, No 109 Xueyuan West Road, Wenzhou, Zhejiang, 325027, China.
| |
Collapse
|
|
42
|
Wen XQ, Qian XL, Sun HK, Zheng LL, Zhu WQ, Li TY, Hu JP. MicroRNAs: Multifaceted Regulators of Colorectal Cancer Metastasis and Clinical Applications. Onco Targets Ther 2020; 13:10851-10866. [PMID: 33149603 PMCID: PMC7602903 DOI: 10.2147/ott.s265580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third-commonest malignant cancer, and its metastasis is the major reason for cancer-related death. The process of metastasis is highly coordinated and involves a complex cascade of multiple steps. In recent years, miRNAs, as highly conserved, endogenous, noncoding, single-stranded RNA, has been confirmed to be involved in the development of various cancers. Considering that miRNA is also involved in a series of biological behaviors, regulating CRC occurrence and development, we review and summarize the role of miRNAs and related signaling pathways in several CRC-metastasis stages, including invasion and migration, mobility, metabolism, epithelial-mesenchymal transition, tumor-microenvironment communication, angiogenesis, anoikis, premetastatic-niche formation, and cancer stemness. In addition, we review the application of miRNAs as diagnostic CRC markers and in clinical treatment resistance. This review can contribute to understanding of the mechanism of miRNAs in CRC progression and provide a theoretical basis for clinical CRC treatment.
Collapse
Affiliation(s)
- Xiang-Qiong Wen
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Xian-Ling Qian
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China
- Department of Medical Imaging, Shanghai Medical College,Fudan University, Shanghai, 200032, People's Republic of China
| | - Huan-Kui Sun
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Lin-Lin Zheng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Wei-Quan Zhu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Tai-Yuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Jia-Ping Hu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| |
Collapse
|
|
43
|
Gu H, Xia Y, Guo L, Wang Z, Wu S, Xu Y, Zhang Y, Huang J, Lei Y, Hu W. Long non-coding RNA MILNR1 retards colorectal cancer growth by inhibiting c-Myc. Cancer Commun (Lond) 2020; 40:456-460. [PMID: 32697425 PMCID: PMC7494064 DOI: 10.1002/cac2.12079] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/30/2020] [Accepted: 07/03/2020] [Indexed: 01/20/2023] Open
Affiliation(s)
- Hao Gu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Yang Xia
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Lili Guo
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Zifei Wang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Shuang Wu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Yuan Xu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Yaqin Zhang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Jing Huang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Yu Lei
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| | - Wanglai Hu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, P. R. China
| |
Collapse
|
|
44
|
Javed Z, Khan K, Sadia H, Raza S, Salehi B, Sharifi-Rad J, Cho WC. LncRNA & Wnt signaling in colorectal cancer. Cancer Cell Int 2020; 20:326. [PMID: 32699525 PMCID: PMC7372757 DOI: 10.1186/s12935-020-01412-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
The outlook for new therapeutic approaches is pivotal to ameliorate the deterioration caused by the abrogated Wnt signaling. Long non-coding RNAs (lncRNAs) are tiny molecules that have begun emerging as vital molecular manager for the regulation of various cellular processes at transcription and translation levels in the colorectal cancer (CRC). Targeting Wnt pathway with lncRNA seems a promising approach to eradicate CRC. However, little is known of their active role in commencing both apoptosis and proliferation in CRC. This article reviews the importance of these molecules in the pathogenesis of CRC and also emphasizes on the development of new therapeutic strategies to cope with the Wnt mediated CRC.
Collapse
Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Sector-C, Phase VI, DHA, Lahore, Pakistan
| | - Khushbukhat Khan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, 44000 Pakistan
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Shahid Raza
- Department of Biotechnology, University of Central Punjab, Lahore, Pakistan
| | - Bahare Salehi
- Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran
- Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
| |
Collapse
|
|
45
|
The DNMT1/miR-34a/FOXM1 Axis Contributes to Stemness of Liver Cancer Cells. JOURNAL OF ONCOLOGY 2020; 2020:8978930. [PMID: 32308683 PMCID: PMC7142390 DOI: 10.1155/2020/8978930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/08/2020] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
Background Whether DNA methyltransferase 1 (DNMT1)/miR-34a/FoxM1 signaling promotes the stemness of liver cancer stem cells (LCSCs) remains unclear. This study aimed to assess whether methylation-based silencing of miR-34a by DNMT1 contributes to stemness features via FoxM1 upregulation in LCSCs. Methods The CD133+ subgroup of MHCC97H cells sorted by MACS was used as LCSCs. DNMT1, BMI1, SOX2, and OCT4 mRNA levels, and miR-34a amounts were determined by qRT-PCR. DNMT1, CD44, and FoxM1 proteins were analyzed by immunoblot. Sphere and colony formation abilities were detected by respective assays. CD133+ cell percentages were assessed by flow cytometry. In vivo oncogenicity was evaluated using a tumor xenograft model in mice. The effects of DNMT1/miR-34a signaling on the stemness of LCSCs were examined by knockdown or overexpression of DNMT1 and/or transfection of miR-34a mimic or inhibitor using lentivirus-delivery systems. FoxM1 association with miR-34a was detected by a reporter assay. Results We here showed that LCSCs exhibited elevated DNMT1 activity and expression, lower miR-34a expression with higher promoter methylation, and stronger stemness, compared with the parental liver cancer cells. DNMT1 knockdown repressed DNMT1, increased miR-34a amounts by promoter demethylation, and reduced stemness in LCSCs, whereas DNMT1 overexpression had the opposite effects in liver cancer cells. Transfection with miR-34a mimic repressed the stemness of LCSCs, while miR-34a inhibitor significantly downregulated miR-34a and enhanced stemness, without affecting DNMT1 in liver cancer cells. MiR-34a mimic rescued the effects of DNMT1 overexpression on the stemness of LCSCs, without affecting DNMT1 expression. Finally, FOXM1 was identified as a direct target by miR-34a in LCSCs. Conclusions We revealed that aberrant activation of DNMT1 causes miR-34a promoter methylation and suppression, leading to FoxM1 upregulation by disinhibition and promotion of LCSC stemness. These findings suggest that blockage of DNMT1/miR-34a-mediated FOXM1 upregulation might suppress liver cancer by targeting LCSCs.
Collapse
|
|
46
|
Interaction of Long Noncoding RNAs and Notch Signaling: Implications for Tissue Homeostasis Loss. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1227:107-129. [PMID: 32072502 DOI: 10.1007/978-3-030-36422-9_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The Notch signaling is a crucial pathway involved in cellular development, progression, and differentiation. Deregulation of Notch signaling pathway commonly impacts tissue homeostasis, being highly associated with proliferative disorders. The long noncoding RNAs (lncRNAs), which are transcripts with more than 200 nucleotides that do not code for proteins, were already described as Notch signaling pathway-interacting molecules. Many of them act as important transcriptional and posttranscriptional regulators, affecting gene expression and targeting other regulatory molecules, such as miRNAs. Due to their strong impact on function and gene expression of Notch-related molecules, lncRNAs influence susceptibility to cancer and other diseases, and can be regarded as potential biomarkers and therapeutic targets. Along this chapter, we summarize the cross talk between the Notch signaling pathway and their most important modulating lncRNAs, as well as the pathological consequences of these interactions, in different tissues.
Collapse
|
|
47
|
Zhan W, Liao X, Wang Y, Li L, Li J, Chen Z, Tian T, He J. circCTIC1 promotes the self-renewal of colon TICs through BPTF-dependent c-Myc expression. Carcinogenesis 2020; 40:560-568. [PMID: 30403769 DOI: 10.1093/carcin/bgy144] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/10/2018] [Indexed: 12/27/2022] Open
Abstract
Colon tumor is a conman tumor in the world. There are various kinds of cells in colon tumor bulk, and only a small population can initiate tumor efficiently and termed as tumor-initiating cells (TICs). With self-renewal and differentiation capacities, colon TICs drive colon tumorigenesis, metastasis and relapse. However, the molecular mechanisms of colon TICs self-renewal are elusive. Here, we found that circular RNA (circCTIC1) was highly expressed in colon tumor and colon TICs. circCTIC1 knockdown impaired the self-renewal of colon TICs, and its overexpression played an opposite role. circCTIC1 promoted the expression of c-Myc and drove the self-renewal of colon TIC through c-Myc-dependent manner. circCTIC1 interacted with nuclear remodeling factor (NURF) complex, recruited NURF complex onto c-Myc promoter and finally drove the transcriptional initiation of c-Myc. Altogether, circCTIC1 drove the self-renewal of colon TICs through bromodomain PHD finger transcription factor (BPTF)-mediated c-Myc expression.
Collapse
Affiliation(s)
- Wei Zhan
- Department of Colorectal Surgery, Affiliated Hospital of Guizhou Medical University, Gui Zhou Province, Guiyang, China.,Guizhou Medical University, Gui Zhou Province, Guiyang, China
| | - Xin Liao
- Guizhou Medical University, Gui Zhou Province, Guiyang, China.,Department of Imaging, Affiliated Hospital of Guizhou Medical University, Gui Zhou Province, Guiyang, China
| | - Yuan Wang
- Oncology Department in the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Jiangsu Province, Huaian, China
| | - Lianghe Li
- Department of Imaging, Affiliated Hospital of Guizhou Medical University, Gui Zhou Province, Guiyang, China
| | - Jin Li
- Oncology Department in the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Jiangsu Province, Huaian, China
| | - Zhongsheng Chen
- Department of Imaging, Affiliated Hospital of Guizhou Medical University, Gui Zhou Province, Guiyang, China
| | - Tian Tian
- Department of Imaging, Affiliated Hospital of Guizhou Medical University, Gui Zhou Province, Guiyang, China
| | - Jingdong He
- Guizhou Medical University, Gui Zhou Province, Guiyang, China.,Oncology Department in the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Jiangsu Province, Huaian, China
| |
Collapse
|
|
48
|
Li X, Zhang Y, Pei W, Zhang M, Yang H, Zhong M, Kong X, Xu Y, Zhu X, Chen T, Ye J, Lv K. LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization. FASEB J 2020; 34:5077-5091. [PMID: 32052888 DOI: 10.1096/fj.201902379r] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/07/2020] [Accepted: 01/27/2020] [Indexed: 01/18/2023]
Abstract
Long non-coding RNAs (lncRNAs) play key roles in various biological processes. However, the roles of lncRNAs in macrophage polarization remain largely unexplored. In this study, thousands of lncRNAs were identified that are differentially expressed in distinct polarized bone marrow-derived macrophages. Among them, Dnmt3aos (DNA methyltransferase 3A, opposite strand), as a known lncRNA, locates on the antisense strand of Dnmt3a. Functional experiments further confirmed that Dnmt3aos were highly expressed in M(IL-4) macrophages and participated in the regulation of Dnmt3a expression, and played a key role in macrophage polarization. The DNA methylation profiles between the Dnmt3aos knockdown group and the control group in M(IL-4) macrophages were determined by MeDIP-seq technique for the first time, and the Dnmt3aos-Dnmt3a axis-mediated DNA methylation modification-regulated macrophage polarization- related gene IFN-γ was identified. Our study will help to enrich our knowledge of the mechanism of macrophage polarization.
Collapse
Affiliation(s)
- Xueqin Li
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Yingying Zhang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Laboratory Medicine of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Weiya Pei
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Mengying Zhang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Hui Yang
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Min Zhong
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Xiang Kong
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Yang Xu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Xiaolong Zhu
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Tianbing Chen
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Jingjing Ye
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| | - Kun Lv
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.,Central Laboratory of Yijishan Hospital, Wannan Medical College, Wuhu, PR China
| |
Collapse
|
|
49
|
Tripathi S, Chakraborty P, Levine H, Jolly MK. A mechanism for epithelial-mesenchymal heterogeneity in a population of cancer cells. PLoS Comput Biol 2020; 16:e1007619. [PMID: 32040502 PMCID: PMC7034928 DOI: 10.1371/journal.pcbi.1007619] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 02/21/2020] [Accepted: 12/20/2019] [Indexed: 12/15/2022] Open
Abstract
Epithelial-mesenchymal heterogeneity implies that cells within the same tumor can exhibit different phenotypes-epithelial, mesenchymal, or one or more hybrid epithelial-mesenchymal phenotypes. This behavior has been reported across cancer types, both in vitro and in vivo, and implicated in multiple processes associated with metastatic aggressiveness including immune evasion, collective dissemination of tumor cells, and emergence of cancer cell subpopulations with stem cell-like properties. However, the ability of a population of cancer cells to generate, maintain, and propagate this heterogeneity has remained a mystifying feature. Here, we used a computational modeling approach to show that epithelial-mesenchymal heterogeneity can emerge from the noise in the partitioning of biomolecules (such as RNAs and proteins) among daughter cells during the division of a cancer cell. Our model captures the experimentally observed temporal changes in the fractions of different phenotypes in a population of murine prostate cancer cells, and describes the hysteresis in the population-level dynamics of epithelial-mesenchymal plasticity. The model is further able to predict how factors known to promote a hybrid epithelial-mesenchymal phenotype can alter the phenotypic composition of a population. Finally, we used the model to probe the implications of phenotypic heterogeneity and plasticity for different therapeutic regimens and found that co-targeting of epithelial and mesenchymal cells is likely to be the most effective strategy for restricting tumor growth. By connecting the dynamics of an intracellular circuit to the phenotypic composition of a population, our study serves as a first step towards understanding the generation and maintenance of non-genetic heterogeneity in a population of cancer cells, and towards the therapeutic targeting of phenotypic heterogeneity and plasticity in cancer cell populations.
Collapse
Affiliation(s)
- Shubham Tripathi
- PhD Program in Systems, Synthetic, and Physical Biology, Rice University, Houston, TX, United States of America
- Center for Theoretical Biological Physics, Rice University, Houston, TX, United States of America
- Department of Physics, Northeastern University, Boston, MA, United States of America
| | - Priyanka Chakraborty
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India
| | - Herbert Levine
- Center for Theoretical Biological Physics, Rice University, Houston, TX, United States of America
- Department of Physics, Northeastern University, Boston, MA, United States of America
- * E-mail: (H.L.); (M.K.J.)
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India
- * E-mail: (H.L.); (M.K.J.)
| |
Collapse
|
|
50
|
Li L, Zheng Y, Zhang W, Hou L, Gao Y. Scutellarin circumvents chemoresistance, promotes apoptosis, and represses tumor growth by HDAC/miR-34a-mediated down-modulation of Akt/mTOR and NF-κB-orchestrated signaling pathways in multiple myeloma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:212-219. [PMID: 32211101 PMCID: PMC7061792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/23/2020] [Indexed: 06/10/2023]
Abstract
Multiple myeloma (MM) is a neoplastic dyscrasia of monoclonal immunoglobulin-secreting plasma cells culminating in multi-organ dysfunction. In this study, we sought to investigate whether scutellarin (STN), a flavonoid, could reduce MM progression, mitigate chemoresistance of MM cells to bortezomib (BTB), and cause MM cell apoptosis in a xenograft mouse model of MM. Epigenetic signalling plays a main role in the modulation of various pathways involved in multiple myeloma progression. At the outset, mechanistic analyses of the MM pathways indicated that key epigenetic molecules including HDAC1/3 and miR-34a were up-modulated and down-modulated respectively, in the MM mice. Besides, the downstream signalling analysis of miR-34a depicted that the c-Met/AKT/mTOR pathway was activated in the MM mice. We also investigated the expression of NF-κB, one of the major chemoresistance inducers in cancer treatment, in the MM mice. As anticipated, the tumor-bearing mice expressed more NF-κB along with elevated anti-apoptotic Bcl-xL protein, as well as reduced pro-apoptotic Bim protein. On the other hand, STN+BTB co-treatment effectively combated the MM tumor progression, and STN circumvented the MM tumor resistance to BTB and provoked apoptotic cell death in MM. Based on our study data, we deduce that STN, in combination with BTB, appears to be a reliable tumoricidal strategy.
Collapse
Affiliation(s)
- Lan Li
- Department of Hematology, Shaanxi Provincial People's Hospital Xi'an 710068, Shaanxi, China
| | - Yan Zheng
- Department of Hematology, Shaanxi Provincial People's Hospital Xi'an 710068, Shaanxi, China
| | - Weihua Zhang
- Department of Hematology, Shaanxi Provincial People's Hospital Xi'an 710068, Shaanxi, China
| | - Limin Hou
- Department of Hematology, Shaanxi Provincial People's Hospital Xi'an 710068, Shaanxi, China
| | - Ying Gao
- Department of Hematology, Shaanxi Provincial People's Hospital Xi'an 710068, Shaanxi, China
| |
Collapse
|