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Biswas S, Kanodia R, Seervi S, Kaur R, Shukla S, Singh S, Banerjee J, Banerjee S. Portrayal of the complex molecular landscape of multidrug resistance in gastric cancer: Unveiling the potential targets. Exp Cell Res 2025; 449:114580. [PMID: 40306607 DOI: 10.1016/j.yexcr.2025.114580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/27/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Gastric cancer (GC) is an aggressive malignancy among all Gastrointestinal cancer (GIC) types. Worldwide, among all cancer types, gastric cancer incidence and related mortality remain in fifth position. Multidrug resistance (MDR) in GC presents a major challenge to chemotherapy, and it significantly affects patient survival. A better understanding of the dynamic interaction of cellular factors contributing to MDR phenotype, e.g., the presence and expression of variants of MDR-related genes, including various drug-detoxifying and drug-efflux transporters, and expression of regulatory ncRNAs affecting the expression of MDR-related genes, is required to comprehend the molecular mechanisms for MDR development in GCs. This review article provides a holistic discussion of the cellular factors involved in the MDR development in GC cells, i.e., their roles and cross-talk between specific molecules that give rise to drug-sensitive and drug-resistant phenotypes. Moreover, the pharmacological perspective of drug resistance and the underlying biological processes that allow the escape of GC cells from the cytotoxic effects of drugs have also been discussed. Additionally, this review article provides an in-depth discussion on most potential candidates that can serve as MDR biomarkers in GIC cancer and the growing research interest in non-coding RNAs (ncRNAs) in GC. Notably, the miRNAs, circRNAs, and lncRNAs are not only emerging as crucial prognostic biomarkers of MDR in gastric cancers but also as potential targets for personalized medicine to combat the MDR challenge in GC patients.
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Affiliation(s)
- Siddhant Biswas
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Riya Kanodia
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Suman Seervi
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Rajinder Kaur
- Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Sakshi Shukla
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Samer Singh
- Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.
| | - Juni Banerjee
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India.
| | - Shuvomoy Banerjee
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India.
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2
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Jia H, Wei J, Zheng W, Li Z. The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance. J Transl Med 2025; 23:583. [PMID: 40414839 DOI: 10.1186/s12967-025-06595-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 05/08/2025] [Indexed: 05/27/2025] Open
Abstract
Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.
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Affiliation(s)
- Haiqing Jia
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Jing Wei
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Wei Zheng
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
| | - Zhuo Li
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
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3
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Ding X, Chen X, Liu Y, He J, Zhou Y, Li J. Elucidating the inhibitory role of miR-140-5p in SARS-CoV-2 infection. Int Immunopharmacol 2025; 152:114395. [PMID: 40090081 DOI: 10.1016/j.intimp.2025.114395] [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: 03/08/2024] [Revised: 12/10/2024] [Accepted: 02/27/2025] [Indexed: 03/18/2025]
Abstract
The ongoing COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has necessitated an urgent need for understanding the molecular mechanisms underlying viral infection and host response. MicroRNAs (miRNAs) have emerged as key regulators in viral pathogenesis, mediating complex interactions between the virus and the host's cellular machinery. In this study, we identify miR-140-5p as a significant factor in the regulation of SARS-CoV-2 entry into host cells. Through comprehensive RNA sequencing analysis of peripheral blood mononuclear cells from COVID-19 patients, we observed significant alterations in the expression of miR-140-5p and its target genes during infection. Further bioinformatics analysis revealed that miR-140-5p targets are predominantly associated with endocytosis-related signaling pathways, suggesting a mechanism by which miR-140-5p may influence SARS-CoV-2 entry. Experimental validation using miR-140-5p mimics demonstrated a significant reduction in viral entry across multiple SARS-CoV-2 variants, confirming the inhibitory role of miR-140-5p on viral replication. These findings suggest that miR-140-5p could potentially be explored as a target for inhibiting viral entry, providing new insights into the role of host miRNAs in SARS-CoV-2 infection and the development of antiviral strategies.
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Affiliation(s)
- Xiaoyan Ding
- College of Basic Medicine, Army Medical University, Chongqing 400038, China; Department of Pediatrics, Ludwig-Maximilians University of Munich, Munich 80337, Germany
| | - Xiaozhong Chen
- College of Basic Medicine, Army Medical University, Chongqing 400038, China
| | - Yuheng Liu
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing Medical University, Chongqing 400016, China
| | - Jiuxiang He
- College of Basic Medicine, Army Medical University, Chongqing 400038, China
| | - Yuxin Zhou
- College of Basic Medicine, Army Medical University, Chongqing 400038, China
| | - Jintao Li
- College of Basic Medicine, Army Medical University, Chongqing 400038, China.
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4
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Jia L, Meng Q, Xu X. Autophagy-related miRNAs, exosomal miRNAs, and circRNAs in tumor progression and drug-and radiation resistance in colorectal cancer. Pathol Res Pract 2024; 263:155597. [PMID: 39426141 DOI: 10.1016/j.prp.2024.155597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 07/16/2024] [Accepted: 09/20/2024] [Indexed: 10/21/2024]
Abstract
Targeted therapies are often more tolerable than traditional cytotoxic ones. Nurses play a critical role in providing patients and caregivers with information about the disease, available therapies, and the kind, severity, and identification of any potential adverse events. By doing this, it may be possible to ensure that any adverse effects are managed quickly, maximizing the therapeutic benefit. In colorectal cancer (CRC), autophagy-related activities are significantly influenced by miRNAs and exosomal miRNAs. CRC development and treatment resistance have been associated with the cellular process of autophagy. miRNAs, which are short non-coding RNA molecules, have the ability to control the expression of genes by binding to the 3' untranslated region (UTR) of target mRNAs and either preventing or suppressing translation. It has been discovered that several miRNAs are significant regulators of CRC autophagy. By preventing autophagy, these miRNAs enhance the survival and growth of cancer cells. Exosomes are small membrane vesicles that are released by cells and include miRNAs among other bioactive compounds. Exosomes have the ability to modify recipient cells' biological processes by delivering their cargo, which includes miRNAs. It has been demonstrated that exosomal miRNAs control autophagy in CRC in both autocrine and paracrine ways. We will discuss the potential roles of miRNAs, exosomal miRNAs, and circRNAs in CRC autophagy processes and how nursing care can reduce unfavorable outcomes.
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Affiliation(s)
- Liting Jia
- Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 102413, China
| | - Qingyun Meng
- Gastroenterology Department, Qingdao Municipal Hospital, Qingdao 266000, China
| | - Xiaofeng Xu
- Thoracic Surgery, Qingdao Municipal Hospital, Qingdao 266000, China.
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5
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Singh J, Narayan G, Dixit VK. The long intergenic non-coding RNA LINC01140 modulates gastric cancer phenotypes and cancer cell lines aggressiveness. Dig Liver Dis 2024; 56:1776-1783. [PMID: 38556409 DOI: 10.1016/j.dld.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Long-intergenic non-protein coding gene 01140 (LINC01140) a long non-coding RNA is highly expressed in various cancers. However, its biological functions in gastric cancer progression is still unknown. METHOD To elucidate LINC01140 function, 70 GC tumor samples and 30 normal gastric tissues were collected. LINC01140 expression level were determined by qRT-PCR analysis and correlated with different clinico-pathological parameters. Then we tried to see the impact of LINC01140 on gastric cell line aggressiveness by knocking down the target gene and performing cell viability assay, migration assay and invasive capacity of the cell lines along with immunoblotting to check several protein levels. RESULT LINC01140 RNA is found to be positively correlated with FGF9 and significantly up regulated in GC tissues. LINC01140 knockdown inhibited the viability, migratory capacity and invasive capacity of AGS cells. LINC01140 targets miR-140-5p, while miR-140-5p targeted FGF9 to form lncRNA-miRNA-mRNA axis. The affect of miR-140-5p inhibition on gastric cancer cell aggressiveness were opposite to those of LINC01140 or FGF9 knockdown. Additionally, inhibition partially reversed the effects of LINC01140 knockdown on FGF9 protein levels, gastric cancer cell phenotypes. CONCLUSION LINC01140, miR-140-5p and FGF9 form a lncRNA-miRNA-mRNA axis that modulates the gastric cancer phenotypes and in turn affects gastric cancer cell aggressiveness.
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Affiliation(s)
- Juhi Singh
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India
| | - Vinod Kumar Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India.
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6
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Liu M, Jiang H, Momeni MR. Epigenetic regulation of autophagy by non-coding RNAs and exosomal non-coding RNAs in colorectal cancer: A narrative review. Int J Biol Macromol 2024; 273:132732. [PMID: 38823748 DOI: 10.1016/j.ijbiomac.2024.132732] [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: 03/18/2024] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 06/03/2024]
Abstract
One of the major diseases affecting people globally is colorectal cancer (CRC), which is primarily caused by a lack of effective medical treatment and a limited understanding of its underlying mechanisms. Cellular autophagy functions to break down and eliminate superfluous proteins and substances, thereby facilitating the continual replacement of cellular elements and generating vital energy for cell processes. Non-coding RNAs and exosomal ncRNAs have a crucial impact on regulating gene expression and essential cellular functions such as autophagy, metastasis, and treatment resistance. The latest research has indicated that specific ncRNAs and exosomal ncRNA to influence the process of autophagy in CRC cells, which could have significant consequences for the advancement and treatment of this disease. It has been determined that a variety of ncRNAs have a vital function in regulating the genes essential for the formation and maturation of autophagosomes. Furthermore, it has been confirmed that ncRNAs have a considerable influence on the signaling pathways associated with autophagy, such as those involving AMPK, AKT, and mTOR. Additionally, numerous ncRNAs have the potential to affect specific genes involved in autophagy. This study delves into the control mechanisms of ncRNAs and exosomal ncRNAs and examines how they simultaneously influence autophagy in CRC.
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Affiliation(s)
- Minghua Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China
| | - Hongfang Jiang
- Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning, China.
| | - Mohammad Reza Momeni
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
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7
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Saeinasab M, Atlasi Y, M Matin M. Functional role of lncRNAs in gastrointestinal malignancies: the peculiar case of small nucleolar RNA host gene family. FEBS J 2024; 291:1353-1385. [PMID: 36282516 DOI: 10.1111/febs.16668] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/18/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Long noncoding RNAs (lncRNAs) play crucial roles in normal physiology and are often de-regulated in disease states such as cancer. Recently, a class of lncRNAs referred to as the small nucleolar RNA host gene (SNHG) family have emerged as important players in tumourigenesis. Here, we discuss new findings describing the role of SNHGs in gastrointestinal tumours and summarize the three main functions by which these lncRNAs promote carcinogenesis, namely: competing with endogenous RNAs, modulating protein function, and regulating epigenetic marking. Furthermore, we discuss how SNHGs participate in different hallmarks of cancer, and how this class of lncRNAs may serve as potential biomarkers in cancer diagnosis and therapy.
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Affiliation(s)
- Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Iran
| | - Yaser Atlasi
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Iran
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Iran
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8
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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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9
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Saadh MJ, Allela OQB, Sattay ZJ, Al Zuhairi RAH, Ahmad H, Eldesoky GE, Adil M, Ali MS. Deciphering the functional landscape and therapeutic implications of noncoding RNAs in the TGF-β signaling pathway in colorectal cancer: A comprehensive review. Pathol Res Pract 2024; 255:155158. [PMID: 38320438 DOI: 10.1016/j.prp.2024.155158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024]
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | - Zahraa Jasim Sattay
- Department of Medical Laboratory Technology l, University of imam Jaafar Al-Sadiq, Iraq
| | | | - Hijaz Ahmad
- Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, Rome 00186, Italy; Center for Applied Mathematics and Bioinformatics, Gulf University for Science and Technology, Kuwait; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon
| | - Gaber E Eldesoky
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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10
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Mobinikhaledi M, Faridzadeh A, Farkhondeh T, Pourhanifeh MH, Samarghandian S. The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy. Curr Mol Med 2024; 24:1269-1281. [PMID: 39300715 DOI: 10.2174/0115665240263059231002093454] [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: 05/18/2023] [Revised: 08/12/2023] [Accepted: 08/24/2023] [Indexed: 09/22/2024]
Abstract
Gynecological cancers are the leading cause of malignancy-related death and disability in the world. These cancers are diagnosed at end stages, and unfortunately, the standard therapeutic strategies available for the treatment of affected women [including chemotherapy, radiotherapy and surgery] are not safe and effective enough. Moreover, the unwanted side-effects lowering the patients' life quality is another problem for these therapies. Therefore, researchers should search for better alternative/complementary treatments. The involvement of autophagy in the pathogenesis of various cancers has been demonstrated. Recently, a novel crosstalk between microRNAs, small non-coding RNAs with important regulatory functions, and autophagy machinery has been highlighted. In this review, we indicate the importance of this interaction for targeted therapy in the treatment of cancers including gynecological cancers, with a focus on underlying mechanisms.
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Affiliation(s)
- Mahya Mobinikhaledi
- Department of Pediatrics, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tahereh Farkhondeh
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran
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11
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Tian Y, Liang L, Chen J, Liu J, Su Y, Shi M, Li W, Zhang J, Feng Y, He L, Liu H, Yang X. Knockdown LIMP2 inhibits colorectal cancer cells migration, invasion, and metastasis. Exp Cell Res 2023; 431:113757. [PMID: 37640260 DOI: 10.1016/j.yexcr.2023.113757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Colorectal cancer (CRC) is a common malignancy worldwide nowadays and liver metastasis is the primary cause of death in patients with CRC. Although lysosomal integral membrane protein 2 (LIMP2) has been reported to play important roles in gastric cancer and prostate cancer, its role in CRC remains unclear. The aim of this study was to investigate the function of LIMP2 in CRC invasion and migration, along with the potential underlying molecular mechanisms. We found that LIMP2 levels were higher in CRC tissues compared to adjacent normal tissues. Kaplan-Meier survival analysis showed that high expression of LIMP2 was associated with worse prognosis in CRC patients. Knockdown of LIMP2 significantly inhibited invasion, migration, and wound healing abilities of CRC cells in vitro, and inhibited CRC liver metastasis in vivo. Additionally, LIMP2 knockdown inhibited autophagy in CRC. Therefore, LIMP2 plays an important role in CRC progression. High expression of LIMP2 was associated with worse prognosis in CRC patients. Knockdown LIMP2 can effectively inhibit CRC cell migration and invasion in vitro and prevent liver metastasis in vivo. These findings suggest that LIMP2 may serve as an independent prognostic factor and potential therapeutic target for CRC.
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Affiliation(s)
- Yu Tian
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Liumei Liang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Junxiong Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Jiaqi Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Yixi Su
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Mengchen Shi
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Weiqian Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Jingdan Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Yanchun Feng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Lingyuan He
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China
| | - Huanliang Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
| | - Xiangling Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
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12
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Xiong B, Huang Q, Zheng H, Lin S, Xu J. Recent advances microRNAs and metabolic reprogramming in colorectal cancer research. Front Oncol 2023; 13:1165862. [PMID: 37576895 PMCID: PMC10415904 DOI: 10.3389/fonc.2023.1165862] [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: 02/16/2023] [Accepted: 06/07/2023] [Indexed: 08/15/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer with the highest incidence and mortality. Alteration of gene expression is the main pathophysiological mechanism of CRC, which results in disturbed signaling pathways and cellular metabolic processes. MicroRNAs are involved in almost all pathophysiological processes and are correlative with colorectal cancer metabolism, proliferation, and chemotherapy resistance. Metabolic reprogramming, an important feature of cancer, is strongly correlative with the development and prognosis of cancers, including colorectal cancer. MicroRNAs can target enzymes involved in metabolic processes, thus playing a regulatory role in tumor metabolism. The disorder of the signaling pathway is another characteristic of tumor, which induces the occurrence and proliferation of tumors, and is closely correlative with the prognosis and chemotherapy resistance of tumor patients. MicroRNAs can target the components of the signaling pathways to regulate their transduction. Understanding the function of microRNAs in the occurrence and proliferation of CRC provides novel insights into the optimal treatment strategies, prognosis, and development of diagnosis in CRC. This article reviews the relationship between CRC and microRNA expression and hopes to provide new options for the diagnosis and treatment of CRC.
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Affiliation(s)
- Bin Xiong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiaoyi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Huida Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jianhua Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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13
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Xu K, Guo H, Xia A, Wang Z, Wang S, Wang Q. Non-coding RNAs in radiotherapy resistance: Roles and therapeutic implications in gastrointestinal cancer. Biomed Pharmacother 2023; 161:114485. [PMID: 36917887 DOI: 10.1016/j.biopha.2023.114485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/19/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
Radiotherapy has become an indispensable and conventional means for patients with advanced solid tumors including gastrointestinal cancer. However, innate or acquired radiotherapy resistance remains a significant challenge and greatly limits the therapeutic effect, which results in cancer relapse and poor prognosis. Therefore, it is an urgent need to identify novel biomarkers and therapeutic targets for clarify the biological characteristics and mechanism of radiotherapy resistance. Recently, lots of studies have revealed that non-coding RNAs (ncRNAs) are the potential indicators and regulators of radiotherapy resistance via the mediation of various targets/pathways in different cancers. These findings may serve as a potential therapeutic strategy to overcome radiotherapy resistance. In this review, we will shed light on the recent findings regarding the functions and regulatory mechanisms of ncRNAs following radiotherapy, and comprehensively discuss their potential as biomarkers and therapeutic targets in radiotherapy resistance of gastrointestinal cancer.
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Affiliation(s)
- Kaiyue Xu
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China; Department of Radiation Oncology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing University Medical School, Suzhou 215000, China
| | - Huimin Guo
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China
| | - Anliang Xia
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China
| | - Zhangding Wang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China.
| | - Shouyu Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210000, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing 210093, China.
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, China; Medical Transformation Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei 230000, China.
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14
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Taheri F, Ebrahimi SO, Heidari R, Pour SN, Reiisi S. Mechanism and function of miR-140 in human cancers: A review and in silico study. Pathol Res Pract 2023; 241:154265. [PMID: 36509008 DOI: 10.1016/j.prp.2022.154265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022]
Abstract
MicroRNA-140 (miR-140) acts as a tumor suppressor and plays a vital role in cell biological functions such as cell proliferation, apoptosis, and DNA repair. The expression of this miRNA has been shown to be considerably decreased in cancer tissues and cell lines compared with normal adjacent tissues. Consequently, aberrant expression of some miR-140 target genes can lead to the initiation and progression of various human cancers, such as breast cancer, gastrointestinal cancers, lung cancer, and prostate cancer. The dysregulation of the miR-140 network also affects cell proliferation, invasion, metastasis, and apoptosis of cancer cells by affecting various signaling pathways. Besides, up-regulation of miR-140 could enhance the efficacy of chemotherapeutic agents in different cancer. We aimed to cover most aspects of miR-140 function in cancer development and address its importance in different stages of cancer progression.
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Affiliation(s)
- Forough Taheri
- Department of Genetics, Sharekord Branch, Islamic Azad University, Sharekord, Iran
| | - Seyed Omar Ebrahimi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Razieh Heidari
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Somaye Nezamabadi Pour
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Somayeh Reiisi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran.
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15
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Application of Bioinformatics Tools for the Prediction of Helper MicroRNAs for Improvement of Oncolytic Virus Efficacy. Cell Microbiol 2022. [DOI: 10.1155/2022/5756131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Purpose. Oncolytic Reoviruses, as a self-limiting virus, can be used in cancer treatment, because they have the ability to replicate in tumor cells selectively and destroy them. Studies show that some immune response proteins may interfere with the virus life cycle. So, the main aim of this bioinformatic study is to check which microRNA is able to target some reovirus inhibitory proteins. Experimental Design. By use of online bioinformatics software, the microRNAs that could target inhibitory genes were selected. Then, other features like content ++ score and cell type were checked and finally the eligible microRNAs were determined. Results. After choosing 15 inhibitory proteins, analysis was performed and finally 37 microRNAs which could target inhibitory proteins in colorectal cell lines were selected. In the end, by investigation of web-based tools, just two microRNAs were finalized. Conclusions and Clinical Relevance. This bioinformatic study shows that microRNA-140 and microRNA-92a have the potential to target some inhibitory proteins which interfere with oncolytic Reovirus replication and it may help in the optimal use of this virus as a cancer treatment. Because selective reproduction of Reovirus in tumor cells, as a nonchemical therapy, can be a good way to overcome this disease with broad advantages.
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16
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MicroRNA-140-5p inhibits cellular proliferation, migration and invasion by downregulating AKT/STAT3/NF-κB pathway in breast carcinoma cells. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2022; 72:587-597. [PMID: 36651361 DOI: 10.2478/acph-2022-0039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 02/01/2023]
Abstract
MicroRNA-140-5p (miR-140-5p) plays a pivotal role in human cancers. However, its role and molecular mechanisms in breast carcinoma are not fully explored. Using miR-140-5p transfected breast cancer cell line MDA-MB-231, several in vitro experiments were performed and described in this paper. They consist of the cell proliferation assay, wound healing assay, transwell assay, colony formation assays and qRTPCR. Expression levels of target proteins were determined using Western blotting. In addition, experiments on animal models were performed to study the possible role of miR-140-5p in tumorigenesis of breast carcinoma cells. The induction of experimental breast tumor in mice model was achieved through the incorporation of MDA-MB-231 tumor cells subcutaneously into the middle left side of the mice. The results showed that miR-140-5p up-regulation significantly suppresses proliferation, cellular invasion and migration of breast carcinoma cells. Furthermore, miR-140-5p up-regulation stops breast cancer cells at G0/G1 phase. The results of the animal model indicated that up-regulation of miR-140-5p suppresses its tumorigenic ability. Moreover, we also found that miR-140-5p up-regulation reduces the phosphorylation level of STAT3, p65, and AKT. In addition, miR-140-5p overexpression significantly decreases CDK2 expression while increasing E-cadherin expression level. These data revealed that miR-140-5p suppressed tumor progression of breast carcinoma cells through inhibition of the AKT/STAT3/NF-κB pathway. Taken the present study results together, we can conclude that miR-140-5p may act as a novel target in microRNA-targeting anticancer strategy for the treatment of breast cancer.
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17
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Yuen JG, Fesler A, Hwang GR, Chen LB, Ju J. Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics. Mol Ther 2022; 30:3450-3461. [PMID: 35933584 PMCID: PMC9637772 DOI: 10.1016/j.ymthe.2022.07.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 06/20/2022] [Accepted: 07/21/2022] [Indexed: 11/24/2022] Open
Abstract
MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.
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Affiliation(s)
- John G Yuen
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | | | - Ga-Ram Hwang
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Lan-Bo Chen
- Curamir Therapeutics Inc., Woburn, MA 01801, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Curamir Therapeutics Inc., Woburn, MA 01801, USA.
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18
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Xu L, Zhang J, Sun J, Hou K, Yang C, Guo Y, Liu X, Kalvakolanu DV, Zhang L, Guo B. Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers. Biochem Pharmacol 2022; 202:115110. [PMID: 35640714 DOI: 10.1016/j.bcp.2022.115110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/05/2023]
Abstract
The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.
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Affiliation(s)
- Libo Xu
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jinghua Zhang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Jicheng Sun
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Kunlin Hou
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Chenxin Yang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Ying Guo
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Xiaorui Liu
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China
| | - Dhan V Kalvakolanu
- Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School Medicine, Baltimore, MD, USA
| | - Ling Zhang
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China; Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China.
| | - Baofeng Guo
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China.
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19
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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20
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Qian Y, Li Q, Chen L, Sun J, Cao K, Mei Z, Lu X. Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate M1 Microglial Activation in Brain Injury of Mice With Subarachnoid Hemorrhage via microRNA-140-5p Delivery. Int J Neuropsychopharmacol 2022; 25:328-338. [PMID: 35015859 PMCID: PMC9017768 DOI: 10.1093/ijnp/pyab096] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/01/2021] [Accepted: 01/06/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND It is documented that mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs) to modulate subarachnoid hemorrhage (SAH) development. miR-140-5p expression has been detected in MSC-derived EVs, while the mechanism of MSC-derived EVs containing miR-140-5p in SAH remains unknown. We aim to fill this void by establishing SAH mouse models and extracting MSCs and MSC-EVs. METHODS After ALK5 was silenced in SAH mice, neurological function was evaluated, neuron apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling with NeuN staining, and expression of serum inflammatory factors (interleukin-6, interleukin-1β, and tumor necrosis factor-α) was determined by enzyme-linked immunosorbent assay. The effect of ALK5 on NOX2 expression was assessed by western-blot analysis. Targeting the relationship between miR-140-5p and ALK5 was evaluated by dual luciferase assay. Following extraction of MSCs and MSC-EVs, EVs and miR-140-5p were labeled by PKH67 and Cy3, respectively, to identify the transferring of miR-140-5p by MSC-EVs. SAH mice were treated with EVs from miR-140-5p mimic/inhibitor-transfected MSCs to detect effects of MSC-EV-miR-140-5p on brain injury and microglial polarization. RESULTS ALK5 silencing increased the neurological score and reduced neuron apoptosis and neuroinflammation in SAH mice. ALK5 silencing inhibited M1 microglia activation by inactivating NOX2. ALK5 was a target gene of miR-140-5p. MSC-derived EVs contained miR-140-5p and transferred miR-140-5p into microglia. MSC-EV-delivered miR-140-3p reduced ALK5 expression to contribute to repression of brain injury and M1 microglia activation in SAH mice. CONCLUSIONS MSC-derived EVs transferred miR-140-5p into microglia to downregulate ALK5 and NOX2, thus inhibiting M1 microglia activation in SAH mice.
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Affiliation(s)
- Yu Qian
- Department of Neurosurgery, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, P.R. China
- Department of Neurosurgery, Nanjing Medical University Affiliated Zhenjiang First People’s Hospital, Zhenjiang, P.R. China
| | - Qiaoyu Li
- Department of Neurosurgery, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, P.R. China
- Department of Neurosurgery, Nanjing Medical University Affiliated Zhenjiang First People’s Hospital, Zhenjiang, P.R. China
| | - Lulu Chen
- Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, P.R. China
| | - Jinyu Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
| | - Kan Cao
- Department of Neurosurgery, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, P.R. China
- Department of Neurosurgery, Nanjing Medical University Affiliated Zhenjiang First People’s Hospital, Zhenjiang, P.R. China
| | - Zhaojun Mei
- Department of Neurosurgery, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, P.R. China
- Department of Neurosurgery, Nanjing Medical University Affiliated Zhenjiang First People’s Hospital, Zhenjiang, P.R. China
| | - Xinyu Lu
- Department of Neurosurgery, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, P.R. China
- Department of Neurosurgery, Nanjing Medical University Affiliated Zhenjiang First People’s Hospital, Zhenjiang, P.R. China
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21
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [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: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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lncRNA KCNQ1OT1 Promotes EMT, Angiogenesis, and Stemness of Pituitary Adenoma by Upregulation of RAB11A. JOURNAL OF ONCOLOGY 2022; 2022:4474476. [PMID: 35432529 PMCID: PMC9010184 DOI: 10.1155/2022/4474476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/20/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022]
Abstract
This study is aimed at investigating the effect and mechanism of long noncoding RNA (lncRNA) KCNQ1OT1 on pituitary adenoma (PA). The KCNQ1OT1 expression in invasive and noninvasive PA tissues was detected by real-time fluorescence quantitative polymerase chain reaction (qPCR). The effects of KCNQ1OT1 on the proliferation of PA cells, namely, GH3 and HP75, were detected by CCK-8 experiment. The Transwell assay detected the effect of KCNQ1OT1 on the invasion of GH3 and HP75 cells. The effect of KCNQ1OT1 on the clonal formation ability was detected by clonal formation experiment. The double luciferase reporter assay and the miRNA pull down assay verified the binding of KCNQ1OT1 to miR-140-5p. Meanwhile, the regulatory effect of miR-140-5p on RAB11A was verified. qPCR results showed that KCNQ1OT1 was significantly increased in invasive PA compared with noninvasive PA tissues. Knockdown KCNQ1OT1 inhibited PA cell stemness, angiogenesis, and EMT. In addition, knockdown KCNQ1OT1 inhibited the proliferation, invasion, and clonal formation of PA. miR-140-5p is the target gene of KCNQ1OT1. miR-140-5p targets RAB11A directly. RAB11A can mediate the biological effects of KCNQ1OT1. Meanwhile, lncRNA KCNQ1OT1 can promote the EMT and cellular stemness of PA. Its mechanism of action is realized by inhibiting miR-140-5p. This result can provide a molecular basis for the further study of PA.
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Wang X, Geng B, Wang H, Wang S, Zhao D, He J, Lu F, An J, Wang C, Xia Y. Fluid shear stress-induced down-regulation of microRNA-140-5p promotes osteoblast proliferation by targeting VEGFA via the ERK5 pathway. Connect Tissue Res 2022; 63:156-168. [PMID: 33588662 DOI: 10.1080/03008207.2021.1891228] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Fluid shear stress (FSS) plays a critical role in osteoblast proliferation. However, the role of miRNA in osteoblast proliferation induced by FSS and the possible molecular mechanisms remain to be defined. The aim of the present study was to investigate whether miR-140-5p regulates osteoblast proliferation under FSS and its molecular mechanism. MATERIALS AND METHODS miR-140-5p expression was measured by qRT-PCR. Western blot was used to measure the expressions of P-ERK1/2, ERK1/2, P-ERK5 and ERK5. The levels of VEGFA, PCNA, CDK4 and Cyclin D1 were identified through qRT-PCR and western blot, respectively. Cell proliferation was detected by CCK-8 assay and EdU labeling assay. Dual-luciferase reporter assay was used to validate the target of miR-140-5p. RESULTS miR-140-5p was significantly down-regulated when MC3T3-E1 cells were exposed to FSS. We then confirmed that up-regulation of miR-140-5p inhibited and down-regulation of miR-140-5p promoted osteoblast proliferation. In addition, FSS promotes osteoblast proliferation via down-regulating miR-140-5p. Luciferase reporter assay demonstrated that VEGFA is a direct target of miR-140-5p. Furthermore, transfection of mimic-140-5p inhibited the up-regulation of VEGFA protein level induced by FSS, suggesting that FSS regulates VEGFA protein expression via miR-140-5p. Further investigations demonstrated that VEGFA could promote osteoblast proliferation. Lastly, we demonstrated that miR-140-5p regulates osteoblast proliferation and ERK5 activation through VEGFA. CONCLUSIONS Our study demonstrates that FSS-induced the down-regulation of miR-140-5p promotes osteoblast proliferation through activing VEGFA/ERK5 signaling pathway. These findings may provide a novel mechanism of FSS-induced osteoblast proliferation and offer a new avenue to further investigate osteogenesis induced by mechanical loading.
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Affiliation(s)
- Xingwen Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Bin Geng
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Hong Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Shenghong Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Dacheng Zhao
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Jinwen He
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Fan Lu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Jiangdong An
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Cuifang Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
| | - Yayi Xia
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, China.,Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, China
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Sadri Nahand J, Salmaninejad A, Mollazadeh S, Tamehri Zadeh SS, Rezaee M, Sheida AH, Sadoughi F, Dana PM, Rafiyan M, Zamani M, Taghavi SP, Dashti F, Mirazimi SMA, Bannazadeh Baghi H, Moghoofei M, Karimzadeh M, Vosough M, Mirzaei H. Virus, Exosome, and MicroRNA: New Insights into Autophagy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:97-162. [DOI: 10.1007/5584_2022_715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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25
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Abd El-Aziz YS, Leck LYW, Jansson PJ, Sahni S. Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:6152. [PMID: 34944772 PMCID: PMC8699656 DOI: 10.3390/cancers13246152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.
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Affiliation(s)
- Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
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26
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Wang XX, Wu LH, Ai L, Pan W, Ren JY, Zhang Q, Zhang HM. Construction of an HCC recurrence model based on the investigation of immune-related lncRNAs and related mechanisms. MOLECULAR THERAPY - NUCLEIC ACIDS 2021; 26:1387-1400. [PMID: 34900397 PMCID: PMC8626812 DOI: 10.1016/j.omtn.2021.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/10/2021] [Accepted: 11/03/2021] [Indexed: 01/27/2023]
Abstract
Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in immune regulation. Growing evidence suggests that immune-related genes and lncRNAs can serve as markers to predict the prognosis of patients with cancers, including hepatocellular carcinoma (HCC). This study aimed to contract an immune-related lncRNA (IR-lncRNA) signature for prospective assessment to predict early recurrence of HCC. A total of 319 HCC samples under radical resection were randomly divided into a training cohort (161 samples) and a testing cohort (158 samples). In the training dataset, univariate, lasso, and multivariate Cox regression analyses identified a 9-IR-lncRNA signature closely related to disease-free survival. Kaplan-Meier analysis, principal component analysis, gene set enrichment analysis, and nomogram were used to evaluate the risk model. The results were further confirmed in the testing cohort. Furthermore, we constructed a competitive endogenous RNA regulatory network. The results of the present study indicated that this 9-IR-lncRNA signature has important clinical implications for improving predictive outcomes and guiding individualized treatment in HCC patients. These IR-lncRNAs and regulated genes may be potential biomarkers associated with the prognosis of HCC.
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Affiliation(s)
- Xiang-Xu Wang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Li-Hong Wu
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Liping Ai
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Wei Pan
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jing-Yi Ren
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Qiong Zhang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Hong-Mei Zhang
- Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
- Corresponding author: Hong-Mei Zhang, Department of Clinical Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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Nikkhah H, Vafaei M, Farashahi-Yazd E, Sheikhha MH, Jafari-Nudoshan J. The significant increase of miR-140-5P in papillary thyroid cancer samples. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Moazzendizaji S, Sevbitov A, Ezzatifar F, Jalili HR, Aalii M, Hemmatzadeh M, Aslani S, Gholizadeh Navashenaq J, Safari R, Hosseinzadeh R, Rahmany MR, Mohammadi H. microRNAs: Small molecules with a large impact on colorectal cancer. Biotechnol Appl Biochem 2021; 69:1893-1908. [PMID: 34550619 DOI: 10.1002/bab.2255] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/03/2021] [Indexed: 12/23/2022]
Abstract
Colorectal cancer (CRC) accounts for one of the main cancer-related mortality and morbidity worldwide. The molecular mechanisms of CRC development have been broadly investigated and, over the last decade, it has become evident that aberrant transcription of microRNAs (miRNAs), a class of small, noncoding RNA molecules, has a significant role in the inception and promotion of CRC. In the involved tissues of CRC, the transcription profile of miRNAs is modulated, and their expression templates are related with prognosis, diagnosis, and treatment outcomes. Here, in the current review, we attempted to discuss the latest information regarding the aberrantly expressed miRNAs in CRC and the advantages of utilizing miRNAs as biomarkers for early diagnosis and prognosis of CRC as well as potential therapeutic application. The effect of miRNAs involved in various signaling pathways, primarily p53, EGFR, Wnt, and TGF-β pathways, was clarified.
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Affiliation(s)
- Sahand Moazzendizaji
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Andrey Sevbitov
- Head of Department of Propaedeutics of Dental Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Fatemeh Ezzatifar
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamid Reza Jalili
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Morteza Aalii
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Roghaiyeh Safari
- Molecular and Cellular Epigenetics (GIGA), University of Liege, Sart-Tilman Liège, Belgium.,13. Molecular and Cellular Biology (TERRA), Gembloux Agro-Bio Tech, University of Liege, Gembloux, Belgium
| | - Ramin Hosseinzadeh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Rahmany
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
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Zheng M, Liu J, Meng C, Tang K, Liao J. Prognostic and clinicopathological importance of microRNA-140 expression in cancer patients: a meta-analysis. World J Surg Oncol 2021; 19:266. [PMID: 34479600 PMCID: PMC8417971 DOI: 10.1186/s12957-021-02380-6] [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: 06/04/2021] [Accepted: 08/26/2021] [Indexed: 12/21/2022] Open
Abstract
Background MicroRNA-140 (miR-140) is one of the most widely investigated miRNAs in cell carcinogenesis and cancer development. Despite present proposals of employing miR-140 as a candidate biomarker for cancer prognosis, its effectiveness in predicting patient survival and clinicopathological outcome is still under debate. Methods A systematic search for English literature using online databases was performed with pre-established criteria. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were collected to delineate the correlation between miR-140 levels and cancer patient prognosis. Results For this meta-analysis, we selected 12 papers for analysis, involving 1386 participants. Based on our analysis, high levels of miR-140 were strongly correlated with enhanced patient overall survival (OS) (HR = 0.728, 95% CI = 0.601-0.882, P = 0.001). In addition, we also observed that elevated miR-140 levels significantly led to better OS in patients with cancers in different parts of the body like digestive system (HR = 0.675, 95% CI = 0.538-0.848, P = 0.001), digestive tract (HR = 0.709, 95% CI = 0.565-0.889, P = 0.003), and head and neck (HR = 0.603, 95% CI = 0.456-0.797, P < 0.001). Additionally, we verified that the low miR-140 levels was related to advanced TNM stage (OR = 0.420, 95% CI = 0.299-0.590, P < 0.001), worse histologic grade (OR = 0.410, 95% CI = 0.261-0.643, P < 0.001), and positive lymph node metastasis status (OR = 0.341, 95% CI = 0.144-0.807, P = 0.014). Conclusions Taken together, our results suggest that elevated miR-140 levels can be employed as a favorable biomarker for cancer patient prognosis. This information can greatly benefit in the formation of an individualized therapeutic plan for the treatment of cancer patients.
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Affiliation(s)
- Mengxia Zheng
- Department of General Surgery, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 12 Lingyin Road, Zhejiang, 310013, Hangzhou, China
| | - Jingting Liu
- Department of Health Management, Sir Run Run Shaw International Medical Centre, 9 Jingtan Road, Zhejiang, 310000, Hangzhou, China
| | - Chunyan Meng
- Department of General Surgery, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 12 Lingyin Road, Zhejiang, 310013, Hangzhou, China
| | - Kaifeng Tang
- Department of General Surgery, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 12 Lingyin Road, Zhejiang, 310013, Hangzhou, China
| | - Jianhua Liao
- Department of General Surgery, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 12 Lingyin Road, Zhejiang, 310013, Hangzhou, China.
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30
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Ahmed F, Adnan M, Malik A, Tariq S, Kamal F, Ijaz B. Perception of breast cancer risk factors: Dysregulation of TGF-β/miRNA axis in Pakistani females. PLoS One 2021; 16:e0255243. [PMID: 34297787 PMCID: PMC8301651 DOI: 10.1371/journal.pone.0255243] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/12/2021] [Indexed: 01/10/2023] Open
Abstract
Breast cancer poses a serious health risk for women throughout the world. Among the Asian population, Pakistani women have the highest risk of developing breast cancer. One out of nine women is diagnosed with breast cancer in Pakistan. The etiology and the risk factor leading to breast cancer are largely unknown. In the current study the risk factors that are most pertinent to the Pakistani population, the etiology, molecular mechanisms of tumor progression, and therapeutic targets of breast cancer are studied. A correlative, cross-sectional, descriptive, and questionnaire-based study was designed to predict the risk factors in breast cancer patients. Invasive Ductal Carcinoma (90%) and grade-II tumor (73.2%) formation are more common in our patient’s data set. Clinical parameters such as mean age of 47.5 years (SD ± 11.17), disturbed menstrual cycle (> 2), cousin marriages (repeated), and lactation period (< 0.5 Y) along with stress, dietary and environmental factors have an essential role in the development of breast cancer. In addition to this in silico analysis was performed to screen the miRNA regulating the TGF-beta pathway using TargetScanHuman, and correlation was depicted through Mindjet Manager. The information thus obtained was observed in breast cancer clinical samples both in peripheral blood mononuclear cells, and biopsy through quantitative real-time PCR. There was a significant dysregulation (**P>0.001) of the TGF-β1 signaling pathway and the miRNAs (miR-29a, miR-140, and miR-148a) in patients’ biopsy in grade and stage specifically, correlated with expression in blood samples. miRNAs (miR-29a and miR-140, miR-148a) can be an effective diagnostic and prognostic marker as they regulate SMAD4 and SMAD2 expression respectively in breast cancer blood and biopsy samples. Therefore, proactive therapeutic strategies can be devised considering negatively regulated cascade genes and amalgamated miRNAs to control breast cancer better.
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Affiliation(s)
- Fayyaz Ahmed
- Laboratory of Applied and Functional Genomics, National Center of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore, Pakistan
| | - Muhammad Adnan
- Laboratory of Applied and Functional Genomics, National Center of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore, Pakistan
| | - Ayesha Malik
- Laboratory of Applied and Functional Genomics, National Center of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore, Pakistan
| | - Somayya Tariq
- Laboratory of Applied and Functional Genomics, National Center of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore, Pakistan
| | - Farukh Kamal
- Department of Pathology, Fatima Jinnah Medical University, Lahore, Pakistan
| | - Bushra Ijaz
- Laboratory of Applied and Functional Genomics, National Center of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore, Pakistan
- * E-mail:
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Chen L, He M, Zhang M, Sun Q, Zeng S, Zhao H, Yang H, Liu M, Ren S, Meng X, Xu H. The Role of non-coding RNAs in colorectal cancer, with a focus on its autophagy. Pharmacol Ther 2021; 226:107868. [PMID: 33901505 DOI: 10.1016/j.pharmthera.2021.107868] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the potency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metastasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical biomarkers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, involving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs- and autophagy-based therapeutic strategies for CRC in clinical setting.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Man He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Meng Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Sha Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Jiang M, Liu X, Zhang C, Zhu L, Wu HD, Dong L, Wang T, Lin T, He Y. Bioinformatics identification of the candidate microRNAs and construction of a competing endogenous RNA regulatory network in lacrimal gland adenoid cystic carcinoma high-grade transformation. Oncol Lett 2021; 21:360. [PMID: 33747217 PMCID: PMC7967933 DOI: 10.3892/ol.2021.12621] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/09/2020] [Indexed: 12/30/2022] Open
Abstract
Adenoid cystic carcinoma of the lacrimal gland (LACC) is a major orbital malignancy. The recurrence rate and mortality rate are higher in LACC high-grade transformation (LACC-HGT) compared with in LACC. The present study aimed to identify the candidate microRNAs (miRNAs/miRs) and construct a competing endogenous RNA (ceRNA) regulatory network for LACC-HGT. A miRNA microarray on paraffin-embedded tissues was performed to identify the differentially expressed miRNAs (DEMs) of LACC-HGT. The overlap with the salivary adenoid cystic carcinoma miRNA/RNA sequencing dataset in the Gene Expression Omnibus was used to identify candidate miRNAs. In order to construct a ceRNA regulatory network of LACC-HGT, a microarray of mRNA and circRNA in primary cell lines was performed. The circRNAs and genes with high expression in LACC-HGT were predicted as targeting miRNAs, and the circRNA-miRNA-mRNA regulatory network was constructed. miR-140-3p was identified as part of the ceRNA network and as a candidate miRNA, therefore this was further analyzed using reverse transcription-quantitative (RT-q)PCR. Overall, the Agilent Human microarray analysis identified a total of 16 DEMs from the LACC-HGT paraffin-embedded tissues. A total of 653 DECs and 9,566 DEGs of LACC-HGT primary cell lines were screened via the microarray of mRNA and circRNA. The ceRNA regulatory network was constructed using the cross-binding of circRNA-miRNA, miRNA-mRNA and the downregulated miRNAs in LACC-HGT to clearly demonstrate the circRNA-miRNA-mRNA interaction relationship. RT-qPCR results confirmed that miR-140-3p was downregulated in LACC-HGT tissues and primary cell lines compared with LACC. Target genes CD200 and parathyroid hormone-related protein were significantly upregulated in LACC-HGT primary cell lines. miR-140-3p and its target genes may play an important role in LACC-HGT pathogenesis. In conclusion, the current bioinformatics study constructed a ceRNA network based on a microarray, which may help identify novel miRNA therapeutic targets for LACC-HGT.
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Affiliation(s)
- Meixia Jiang
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Xun Liu
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Chuanli Zhang
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Limin Zhu
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Hai-Dong Wu
- Tianjin Key Laboratory of Early Draggability Evaluation of Innovative Drugs, Tianjin International Joint Academy of Biomedicine, Tianjin 300384, P.R. China
| | - Lijie Dong
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Tingting Wang
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Tingting Lin
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Yanjin He
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
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Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
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Effects of miRNA-140 on the Growth and Clinical Prognosis of SMMC-7721 Hepatocellular Carcinoma Cell Line. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6638915. [PMID: 33628799 PMCID: PMC7884124 DOI: 10.1155/2021/6638915] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/27/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
Background A growing number of studies have suggested that microRNAs exert an essential role in the development and occurrence of multiple tumours and act as crucial regulators in various biological processes. However, the expression and function of miRNA-140 in hepatocellular carcinoma (HCC) cells are not yet adequately identified and manifested. Methods The expression of miRNA-140 was determined in HCC tissues and adjacent nontumour tissues by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis and Cox regression analysis were performed to explore the correlation between miRNA-140 expression level and the survival rate of patients with HCC. Additionally, overexpression experiments were conducted to investigate the biological role of miRNA-140 in HCC cells. Bioinformatics was used to predict the related target genes and pathways of miRNA-140. Results QRT-PCR results signified that the expression level of miRNA-140 in HCC was lower than that of adjacent normal tissues (P < 0.0001). Compared with the control group, the SMMC-7721 HCC cells in the miRNA-140 mimic group had a decrease in proliferation, migration, and invasion (P < 0.05), whereas those in the miRNA-140 inhibitor group had an increase in proliferation, migration, and invasion (P < 0.05). Cell cycle arrest occurred in the G0/1 phase. Prognosis analysis showed that the expression level of miRNA-140 was not related to the prognosis of HCC. Furthermore, the Kaplan-Meier test revealed that patients with lower miRNA-140 expression levels in liver cancer tissue had significantly shorter disease-free survival (DFS, P = 0.004) and overall survival (OS) times (P = 0.010) after hepatectomy. Cox regression analysis further indicated that miRNA-140 was an independent risk factor that may affect the DFS (P = 0.004) and OS times (P = 0.014) of patients after hepatectomy. Our results suggested that miRNA-140 might be a crucial regulator involved in the HCC progression and is thus considered a potential prognostic biomarker and therapeutic target for HCC.
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Sharma T, Radosevich JA, Mandal CC. Dual Role of microRNAs in Autophagy of Colorectal Cancer. Endocr Metab Immune Disord Drug Targets 2021; 21:56-66. [DOI: 10.2174/1871530320666200519075908] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/14/2020] [Accepted: 02/19/2020] [Indexed: 12/24/2022]
Abstract
Autophagy is an evolutionarily conserved pathway that eliminates unwanted proteins out of
the cell and increases cell survival. However, dysfunctional autophagy is associated with cancer progression,
cellular adaptation, cancer metastasis and makes it an attractive therapeutic target. MicroRNAs
(miRNAs) are small single-stranded non-coding RNA molecules that usually bind to 3’UTR of
mRNAs. This interaction eventually inhibits protein synthesis by repressing translation and/or by degrading
mRNAs. miRNAs play a crucial role in the regulation of autophagy and also behave as both
tumor suppressors and promoters in colorectal cancer. This paper defines an overall molecular view of
how miRNAs regulate the dual role of autophagy in colorectal cancer. It also highlights how long noncoding
RNAs modulate miRNAs expression to regulate autophagy in colorectal cancer. Thus, targeting
autophagy by miRNAs seems to be a potential therapeutic strategy for colorectal cancer.
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Affiliation(s)
- Tanu Sharma
- Department of Biochemistry, Central University of Rajasthan, Ajmer, Rajasthan, 305817, India
| | - James A. Radosevich
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois, Chicago, 60612, Illinois, United States
| | - Chandi C. Mandal
- Department of Biochemistry, Central University of Rajasthan, Ajmer, Rajasthan, 305817, India
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Shan C, Chen X, Cai H, Hao X, Li J, Zhang Y, Gao J, Zhou Z, Li X, Liu C, Li P, Wang K. The Emerging Roles of Autophagy-Related MicroRNAs in Cancer. Int J Biol Sci 2021; 17:134-150. [PMID: 33390839 PMCID: PMC7757044 DOI: 10.7150/ijbs.50773] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a conserved catabolic process involving the degradation and recycling of damaged biomacromolecules or organelles through lysosomal-dependent pathways and plays a crucial role in maintaining cell homeostasis. Consequently, abnormal autophagy is associated with multiple diseases, such as infectious diseases, neurodegenerative diseases and cancer. Currently, autophagy is considered to be a dual regulator in cancer, functioning as a suppressor in the early stage while supporting the growth and metastasis of cancer cells in the later stage and may also produce therapeutic resistance. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by silencing targeted mRNA. MiRNAs have great regulatory potential for several fundamental biological processes, including autophagy. In recent years, an increasing number of studies have linked miRNA dysfunction to the growth, metabolism, migration, metastasis, and responses of cancer cells to therapy. Therefore, the study of autophagy-related miRNAs in cancer will provide insights into cancer biology and lead to the development of novel anti-cancer strategies. In the present review, we summarise the current knowledge of miRNA dysregulation during autophagy in cancer, focusing on the relationship between autophagy and miRNAs, and discuss their involvement in cancer biology and cancer treatment.
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Affiliation(s)
- Chan Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinzhe Chen
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Hongjing Cai
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiaodan Hao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jing Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yinfeng Zhang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jinning Gao
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Zhixia Zhou
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xinmin Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Cuiyun Liu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kun Wang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
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The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int J Mol Sci 2020; 22:ijms22010179. [PMID: 33375363 PMCID: PMC7795059 DOI: 10.3390/ijms22010179] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.
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Wu S, Xu R, Zhu X, He H, Zhang J, Zeng Q, Wang Y, Zhao X. The long noncoding RNA LINC01140/miR-140-5p/FGF9 axis modulates bladder cancer cell aggressiveness and macrophage M2 polarization. Aging (Albany NY) 2020; 12:25845-25864. [PMID: 33234721 PMCID: PMC7803526 DOI: 10.18632/aging.202147] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 09/09/2020] [Indexed: 12/15/2022]
Abstract
MIBC (muscle invasive bladder cancer) only accounts for only a minority of bladder cancers, however, the disease-specific and overall survival rates of patients with MIBC are low. Macrophage M2 polarization has been reported to be associated with poorer prognosis in bladder cancer. Through cancer bioinformatics and experimental analyses, FGF9 was found to be upregulated in MIBC tissues. FGF9 knockdown in T24 cells strongly suppressed the viability, migratory capacity, and invasive capacity of cells; culture with medium from FGF9 knockdown T24 cells (si-FGF9-CM) significantly inhibited macrophage M2 polarization, while promoting M1 polarization. The long noncoding RNA (lncRNA) LINC01140 was positively correlated with FGF9 and was significantly upregulated in MIBC tissues. LINC01140 knockdown inhibited the viability, migratory capacity and invasive capacity of T24 cells; culture in si-LINC01140-CM also inhibited macrophage M2 polarization, while promoting M1 polarization. LINC01140 targeted miR-140-5p, while miR-140-5p targeted FGF9 to form a lncRNA-miRNA-mRNA axis. The effects of miR-140-5p inhibition on bladder cancer aggressiveness and macrophage M2 polarization were opposite to those of LINC01140 or FGF9 knockdown; additionally, miR-140-5p inhibition partially reversed the effects of LINC01140 knockdown on FGF9 protein levels, bladder cancer phenotype, and macrophage M2 polarization. In conclusion, LINC01140, miR-140-5p, and FGF9 form a lncRNA-miRNA-mRNA axis that modulates the bladder cancer phenotype, affects macrophage M2 polarization through the tumor microenvironment, and in turn affects bladder cancer cell aggressiveness.
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Affiliation(s)
- Shuiqing Wu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Ran Xu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Xuan Zhu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Haiqing He
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Jinhua Zhang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Qi Zeng
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Yinhuai Wang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
| | - Xiaokun Zhao
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People’s Republic of China
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Wu L, Li H, Chen S, Wu X, Chen X, Wang F. Catalpol inhibits the proliferation, migration and metastasis of HCC cells by regulating miR‑140‑5p expression. Mol Med Rep 2020; 23:29. [PMID: 33179108 PMCID: PMC7673346 DOI: 10.3892/mmr.2020.11667] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 07/15/2020] [Indexed: 01/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a frequent malignant tumor. Catalpol is a Chinese medicine extract with a number of pharmacologically active properties. The present study aimed to investigate the effects and mechanisms of catalpol in HCC. HCC cells were treated with catalpol in the presence or absence of microRNA (miR)-140-5p inhibitor, and assays to determine cell viability, proliferation, invasion and migration were performed. Reverse transcription-quantitative PCR and western blotting were performed to determine the mRNA and protein expression levels of miR-140-5p, vimentin, N-Cadherin and E-Cadherin. Moreover, cells were treated with catalpol in the absence or presence of transforming growth factor (TGF)-β1, and the cell morphology was observed under a microscope. The results demonstrated that catalpol inhibited cell proliferation, invasion and migration, and decreased the expression levels of vimentin and N-cadherin, but increased the expression levels of E-cadherin and miR-140-5p. Catalpol inhibited morphological changes in epithelial-mesenchymal transformation (EMT) of cells induced by TGF-β1. Following inhibition of miR-140-5p expression, the proliferation, invasion and migration of HCC cells were promoted, E-cadherin expression was decreased, and the levels of vimentin and N-cadherin were increased. The miR-140-5p inhibitor effectively reversed the inhibitory effect of catalpol on cell proliferation, invasion and migration. Thus, the results suggested that the antitumor potential of catalpol in HCC may be exerted by regulating the expression of miR-140-5p to inhibit proliferation, invasion, migration and EMT of HCC cells.
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Affiliation(s)
- Linsheng Wu
- Department of Geriatric Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Haoxia Li
- Department of Geriatric Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Shengyou Chen
- Department of Geriatric Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Xiaoqiang Wu
- Department of Geriatric Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Xiaomin Chen
- Department of Geriatric Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Fangping Wang
- Department of Hepatobiliary Surgery, The People's Hospital of Xinchang, Shaoxing, Zhejiang 312500, P.R. China
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Pourhanifeh MH, Vosough M, Mahjoubin-Tehran M, Hashemipour M, Nejati M, Abbasi-Kolli M, Sahebkar A, Mirzaei H. Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers. Pharmacol Res 2020; 161:105133. [DOI: 10.1016/j.phrs.2020.105133] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/23/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
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Zhang YH, Jin M, Li J, Kong X. Identifying circulating miRNA biomarkers for early diagnosis and monitoring of lung cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165847. [DOI: 10.1016/j.bbadis.2020.165847] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/28/2020] [Accepted: 05/19/2020] [Indexed: 02/09/2023]
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Long J, He Q, Yin Y, Lei X, Li Z, Zhu W. The effect of miRNA and autophagy on colorectal cancer. Cell Prolif 2020; 53:e12900. [PMID: 32914514 PMCID: PMC7574865 DOI: 10.1111/cpr.12900] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/29/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) has become a concern because of its high recurrence rate and metastasis rate, low early diagnosis rate and poor therapeutic effect. At present, various studies have shown that autophagy is closely connected with the occurrence and progression of CRC. Autophagy is a highly cytosolic catabolic process involved in lysosomes in biological evolution. Cells degrade proteins and damaged organelles by autophagy to achieve material circulation and maintain cell homeostasis. Moreover, microRNAs are key regulators of autophagy, and their mediated regulation of transcriptional and post-transcriptional levels plays an important role in autophagy in CRC cells. This review focuses on the recent research advances of how autophagy and related microRNAs are involved in affecting occurrence and progression of CRC and provides a new perspective for the study of CRC treatment strategies.
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Affiliation(s)
- Jiali Long
- Department of PathologyGuangdong Medical UniversityDongguanChina
- Department of Pathologythe Eighth Affiliated HospitalSun Yat‐Sen UniversityShenzhenChina
| | - Qinglian He
- Department of PathologyGuangdong Medical UniversityDongguanChina
| | - Yuting Yin
- Department of PathologyGuangdong Medical UniversityDongguanChina
| | - Xue Lei
- Department of PathologyGuangdong Medical UniversityDongguanChina
| | - Ziqi Li
- Department of PathologyGuangdong Medical UniversityDongguanChina
| | - Wei Zhu
- Department of PathologyGuangdong Medical UniversityDongguanChina
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Du G, Zhou J, Cheng L, Ma X, Gui Y, Tan B. High Expression of miR-206 Predicts Adverse Outcomes: A Potential Therapeutic Target for Esophageal Cancer. Comb Chem High Throughput Screen 2020; 22:599-611. [PMID: 31648633 DOI: 10.2174/1386207322666191018145825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/11/2019] [Accepted: 09/23/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND MicroRNA-206 (miR-206) inhibits cell proliferation, invasion and migration in a variety of tumors, but the prognostic value of its Esophageal Cancer (EC) remains unclear. OBJECTIVE To study the role of miR-206 in EC. METHODS The datasets of RNA-Seq, miRNA-Seq, methylation, copy number variation (CNV), and clinical follow-up information were download from The Cancer Genome Atlas (TCGA). After integration and standardization, the prognostic value and potential function of miR-206 were analyzed. The important roles of miR-206 expression in EC genetic and epigenetic mechanisms were analyzed by RNA-Seq, miRNA-Seq, and methylation data. The potential mechanism of CNV in different miR-206 expression groups was analyzed using GISTIC. RESULTS High expression of miR-206 was associated with poor outcome of EC (OS: p=0.005, AUC=0.69, N=178). Transforming growth factor β (TGF-β) signaling pathway, Wnt signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway were inhibited in high expression group. the aberrant methylation sites in the high and low expression groups were mainly distributed in the promoter region containing CpG islands, and there were different copy number patterns in the H and L samples, and the genes in the differential copy number were mainly enriched in cancer-related pathways, such as thyroid cancer, central carbon metabolism. CONCLUSION This study explored the unique genomic and epigenetic landscape associated with the expression of miR-206, provided evidence of mir-206 as a prognostic biomarker or a potential therapeutic target for EC patients.
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Affiliation(s)
- Guobo Du
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
| | - Jing Zhou
- Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
| | - Long Cheng
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
| | - Xiaojie Ma
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
| | - Yan Gui
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
| | - Bangxian Tan
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, China
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Luo R, Yan Z, Yang Q, Huang X, Gao X, Wang P, Wang W, Xie K, Gun S. Inhibition of ssc-microRNA-140-5p ameliorates the Clostridium perfringens beta2 toxin-induced inflammatory response in IPEC-J2 cells via the ERK1/2 and JNK pathways by targeting VEGFA. Mol Immunol 2020; 127:12-20. [PMID: 32905904 DOI: 10.1016/j.molimm.2020.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/24/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023]
Abstract
Piglet diarrhea and even death due to Clostridium perfringens (C. perfringens) type C infection have led to huge economic losses in the pig industry worldwide. C. perfringens beta2 (CPB2) toxin is the main virulence factor for this pathogen. MiR-140-5p can exacerbate toxin-induced toxicity of toxin to cells by promoting oxidative stress. However, the role of pig miR-140-5p (ssc-miR-140-5p) in piglet diarrhea caused by C. perfringens type C has not been studied. Here, we study investigated the function of ssc-miR-140-5p by generating an in vitro CPB2-induced injury model in intestinal porcine epithelial (IPEC-J2) cells. Our results revealed that transfection with an ssc-miR-140-5p inhibitor significantly increased the viability of CPB2-induced IPEC-J2 cells, decrease the release of lactate dehydrogenase (LDH) and reactive oxygen species (ROS), and inhibit inflammatory responses and apoptosis. In addition, vascular endothelial growth factor A (VEGFA) was identified as a direct target of ssc-miR-140-5p by luciferase reporter assay. Western blot analysis showed that inhibition of ssc-miR-140-5p could activate the ERK1/2 signaling pathway and inhibit the JNK signaling pathway. In summary, we showed that down-regulation of ssc-miR-140-5p ameliorated CPB2-induced inflammatory responses in IPEC-J2 cells via the ERK1/2 and JNK signaling pathways by targeting VEGFA.
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Affiliation(s)
- Ruirui Luo
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Zunqiang Yan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Wei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Kaihui Xie
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; Gansu Research Center for Swine Production Engineering and Technology, Lanzhou 730070, China.
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Vaghari-Tabari M, Majidinia M, Moein S, Qujeq D, Asemi Z, Alemi F, Mohamadzadeh R, Targhazeh N, Safa A, Yousefi B. MicroRNAs and colorectal cancer chemoresistance: New solution for old problem. Life Sci 2020; 259:118255. [PMID: 32818543 DOI: 10.1016/j.lfs.2020.118255] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/01/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs. METHODS Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment. RESULTS Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance. CONCLUSION The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Soheila Moein
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Mohamadzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nilofar Targhazeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Safa
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Das PK, Islam F, Lam AK. The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma. Cells 2020; 9:1392. [PMID: 32503256 PMCID: PMC7348976 DOI: 10.3390/cells9061392] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 12/22/2022] Open
Abstract
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs' therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh;
- Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia
| | - Alfred K. Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia
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Zhu G, Lin C, Cheng Z, Wang Q, Hoffman RM, Singh SR, Huang Y, Zheng W, Yang S, Ye J. TRAF6-Mediated Inflammatory Cytokines Secretion in LPS-induced Colorectal Cancer Cells Is Regulated by miR-140. Cancer Genomics Proteomics 2020; 17:23-33. [PMID: 31882548 DOI: 10.21873/cgp.20164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/03/2019] [Accepted: 10/15/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIM Colorectal cancer (CRC) cells secrete inflammatory cytokines that affect CRC progression. The aim of the present study was to determine if micro-RNA-140(miR-140) regulates inflammatory cytokine secretion induced by lipopolysaccharide (LPS) in colorectal cancer cells by targeting tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). MATERIALS AND METHODS Fifty fresh colon-cancer specimens and normal colorectal tissues were collected from patients with CRC and tested for the expression miR-140. Human CRC cell lines SW480 and HCT116 were treated with various concentrations and times with LPS. miR-140 and mRNA expression of potentially related genes were analyzed by qPCR. Protein expression was analyzed using western blot or ELISA. Overexpression plasmids with pcDNA3.1-TRAF6, pGL4.10-wtTRAF6 and pGL4.10-mutTRAF6 were constructed. miRNA target gene prediction and a dual luciferase assay were used to analyze miR-140-targeted TRAF6. RESULTS miR-140 expression was up-regulated in CRC tissues. In CRC cells, LPS could increase miR-140 expression in a time- and concentration-dependent manner. LPS increased inflammatory cytokine mRNA expression levels in SW480 and HCT116 human colon-cancer cells. miRNA-140 suppressed TRAF6 expression via targeting the 3'UTR. TRAF6 affected miR-140-mediated inflammatory cytokine expression of SW480 and HCT116 cells under LPS treatment. CONCLUSION miR-140 regulates inflammatory cytokine secretion of LPS-induced colorectal cancer cells by targeting TRAF6.
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Affiliation(s)
- Guangwei Zhu
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Chunlin Lin
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China
| | - Zhibin Cheng
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Qin Wang
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Robert M Hoffman
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Shree Ram Singh
- Basic Research Laboratory, National Cancer Institute, Frederick, MD, U.S.A.
| | - Yongjian Huang
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China
| | - Wei Zheng
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China
| | - Shugang Yang
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China
| | - Jianxin Ye
- Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, P.R. China .,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
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48
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El-Gowily AH, Abosheasha MA. Differential mechanisms of autophagy in cancer stem cells: Emphasizing gastrointestinal cancers. Cell Biochem Funct 2020; 39:162-173. [PMID: 32468609 DOI: 10.1002/cbf.3552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/17/2020] [Accepted: 05/03/2020] [Indexed: 12/15/2022]
Abstract
Gastrointestinal (GI) cancers are one of the most common forms of malignancies and still are the most important cause of cancer-related mortality worldwide. Autophagy is a conserved catabolic pathway involving lysosomal degradation and recycling of whole cellular components, which is essential for cellular homeostasis. For instance, it acts as a pivotal intracellular quality control and repair mechanism but also implicated in cell reformation during cell differentiation and development. Indeed, GI cancer stem cells (CSCs) are thought to be responsible for tumour initiation, traditional therapies resistance, metastasis and tumour recurrence. Molecular mechanisms of autophagy in normal vs CSCs gain great interest worldwide. Here, we shed light on the role of autophagy in normal stem cells differentiation for embryonic progression and its role in maintaining the activity and self-renewal capacity of CSCs which offer novel viewpoints on promising cancer therapeutic strategies based on the differential roles of autophagy in CSCs.
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Affiliation(s)
- Afnan H El-Gowily
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt.,Organ and Cell physiology Department, Juntendo University, Tokyo, Japan
| | - Mohammed A Abosheasha
- Cellular Genetics Laboratory, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan
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Fan L, Huang X, Chen J, Zhang K, Gu YH, Sun J, Cui SY. Long Noncoding RNA MALAT1 Contributes to Sorafenib Resistance by Targeting miR-140-5p/Aurora-A Signaling in Hepatocellular Carcinoma. Mol Cancer Ther 2020; 19:1197-1209. [PMID: 32220970 DOI: 10.1158/1535-7163.mct-19-0203] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 09/09/2019] [Accepted: 03/11/2020] [Indexed: 11/16/2022]
Abstract
Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial-mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.
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Affiliation(s)
- Lei Fan
- Department of General Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nangjing, P.R. China
| | - Xiang Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
| | - Jing Chen
- Department of Respiratory, Zhongda Hospital, Southeast University, Nanjing, P.R. China
| | - Kai Zhang
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yan-Hong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
| | - Jing Sun
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
| | - Shi-Yun Cui
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
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Guan SS, Wu CT, Liao TZ, Luo TY, Lin KL, Liu SH. Indium-111-labeled CD166-targeted peptide as a potential nuclear imaging agent for detecting colorectal cancer stem-like cells in a xenograft mouse model. EJNMMI Res 2020; 10:13. [PMID: 32096011 PMCID: PMC7040160 DOI: 10.1186/s13550-020-0597-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/17/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are involved in drug resistance, metastasis, and relapse of cancers, which can significantly affect tumor therapy. Hence, to develop specifically therapeutic target probe at CSCs for improvement of survival and quality of life of cancer patients is urgently needed. The CD166 protein has been suggested to be involved in colorectal cancer (CRC) tumorigenesis and to be considered a marker for colorectal CSCs (CRCSCs) detection. In this study, therefore, we attend to apply a nuclear imaging agent probe, Glycine18-Cystine-linked CD166-targeted peptides (CD166tp-G18C), to detect the changes of CD166 level in a CRC xenograft mouse model. RESULTS We isolated the CD166-positive cells from the HCT15 CRC cell line (CD166+HCT15) and evaluated their morphology and ability of clone formation, migration, protein expression, and drug resistance. The CD166-positive HCT15 cells display the CSCs characteristics. We discovered and designed a CD166-targeted peptide (CD166tp-G18C) as a targeted probe of CRC stem-like cell for cell binding assay. The CD166tp-G18C confirmed the CD166 protein targeting ability in CD166+HCT15 cells. The diethylenetriaminopentaacetic acid (DTPA)-conjugated CD166tp-G18C further was labeled with indium-111 (111In-DTPA-CD166tp-G18C) as nuclear imaging agent for imaging and bio-distribution analysis in vivo. Finally, we observed that the 111In-DTPA-CD166tp-G18C was significantly enhanced in tumor tissues of CD166+HCT15 xenograft mice as compared to the non-CD166tp-G18C control. CONCLUSIONS Our results indicated that the indium-111-labeled CD166tp-G18C may be served as a powerful tool for colorectal CSCs nuclear imaging in the CRC patients.
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Affiliation(s)
- Siao-Syun Guan
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Cheng-Tien Wu
- Department of Nutrition, China Medical University, Taichung, 40402, Taiwan.,Master Program of Food and Drug Safety, China Medical University, Taichung, 40402, Taiwan
| | - Tse-Zung Liao
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Tsai-Yueh Luo
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Kun-Liang Lin
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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