1
|
Mete M, Ojha A, Dhar P, Das D. Deciphering Ferroptosis: From Molecular Pathways to Machine Learning-Guided Therapeutic Innovation. Mol Biotechnol 2025; 67:1290-1309. [PMID: 38613722 DOI: 10.1007/s12033-024-01139-0] [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: 12/10/2023] [Accepted: 03/11/2024] [Indexed: 04/15/2024]
Abstract
Ferroptosis is a unique form of cell death reliant on iron and lipid peroxidation. It disrupts redox balance, causing cell death by damaging the plasma membrane, with inducers acting through enzymatic pathways or transport systems. In cancer treatment, suppressing ferroptosis or circumventing it holds significant promise. Beyond cancer, ferroptosis affects aging, organs, metabolism, and nervous system. Understanding ferroptosis mechanisms holds promise for uncovering novel therapeutic strategies across a spectrum of diseases. However, detection and regulation of this regulated cell death are still mired with challenges. The dearth of cell, tissue, or organ-specific biomarkers muted the pharmacological use of ferroptosis. This review covers recent studies on ferroptosis, detailing its properties, key genes, metabolic pathways, and regulatory networks, emphasizing the interaction between cellular signaling and ferroptotic cell death. It also summarizes recent findings on ferroptosis inducers, inhibitors, and regulators, highlighting their potential therapeutic applications across diseases. The review addresses challenges in utilizing ferroptosis therapeutically and explores the use of machine learning to uncover complex patterns in ferroptosis-related data, aiding in the discovery of biomarkers, predictive models, and therapeutic targets. Finally, it discusses emerging research areas and the importance of continued investigation to harness the full therapeutic potential of targeting ferroptosis.
Collapse
Affiliation(s)
- Megha Mete
- Department of Bioengineering, National Institute of Technology Agartala, Agartala, Tripura, 799046, India
| | - Amiya Ojha
- Department of Bioengineering, National Institute of Technology Agartala, Agartala, Tripura, 799046, India
| | - Priyanka Dhar
- CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India
| | - Deeplina Das
- Department of Bioengineering, National Institute of Technology Agartala, Agartala, Tripura, 799046, India.
| |
Collapse
|
2
|
Lee KL, Liu JJ, Huang WJ, Hung CS, Liang YC. CircRNA hsa_circ_0004781 promoted cell proliferation by acting as a sponge for miR-9-5p and miR-338-3p and upregulating KLF5 and ADAM17 expression in pancreatic ductal adenocarcinoma. Cancer Cell Int 2025; 25:56. [PMID: 39972489 PMCID: PMC11841339 DOI: 10.1186/s12935-025-03687-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid tumor, and novel strategies must be developed for treating it. Previous studies predominantly utilized circular RNA (circRNA) expression plasmids incorporating Alu elements to facilitate the indirect expression of circRNA. METHODS Public databases and bioinformatics tools were used to identify hsa_circ_0004781 that is highly expressed in PDAC and its potential microRNA (miRNA) targets and corresponding mRNA targets. Real hsa_circ_0004781, which is identical to the native form of hsa_circ_0004781 without any exogenous sequences, was prepared through in vitro transcription by using a ribozyme and ion-pair reversed-phase high-performance liquid chromatography (IP-RP HPLC). The biological functions of hsa_circ_0004781 were evaluated using loss-of-function and gain-of-function approaches with circRNA expression plasmids and real hsa_circ_0004781. RESULTS Knockdown of hsa_circ_0004781 inhibited the proliferation and migration of PDAC cells, whereas its overexpression produced opposite effects. Hsa_circ_0004781 was identified as a sponge for miR-9-5p and miR-338-3p, and its expression was negatively correlated with that of these miRNAs. Among the targets of miR-9-5p and miR-338-3p, Kruppel-like factor 5 (KLF5) and a disintegrin and metalloproteinase domain 17 (ADAM17) were negatively correlated with survival in patients with PDAC and were inversely regulated by these miRNAs. Furthermore, real hsa_circ_0004781 exhibited the same effects as those of the circRNA expression plasmids. CONCLUSIONS This study is the first to use real circRNAs to validate results obtained using circRNA expression plasmids. The results suggest that hsa_circ_0004781 functions as an oncogene, promoting the proliferation of PDAC cells through the miR-9-5p/KLF5 and miR-338-3p/ADAM17 axes. Therefore, hsa_circ_0004781 might be a therapeutic target for PDAC.
Collapse
Affiliation(s)
- Kun-Lin Lee
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, New Taipei City, Taiwan
| | - Jun-Jen Liu
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, New Taipei City, Taiwan
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 301 Yuantong Rd., New Taipei City, 23564, Taiwan
| | - Wei-Jan Huang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ching-Sheng Hung
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 301 Yuantong Rd., New Taipei City, 23564, Taiwan
- Department of Laboratory Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chih Liang
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, New Taipei City, Taiwan.
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 301 Yuantong Rd., New Taipei City, 23564, Taiwan.
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
| |
Collapse
|
3
|
Xiang Y, Zhou R, Yang Y, Bai H, Liang F, Wang H, Wang X. A Novel circ_0075829/miR-326/GOT1 ceRNA Crosstalk Regulates the Malignant Phenotypes and Drug Sensitivity of Gemcitabine-Resistant Pancreatic Cancer Cells. J Biochem Mol Toxicol 2025; 39:e70089. [PMID: 39692397 DOI: 10.1002/jbt.70089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/29/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024]
Abstract
Although gemcitabine (GEM) is the cornerstone of the treatment of pancreatic cancer (PC), GEM resistance frequently arises. Circular RNA (circRNA) circ_0075829 is highly expressed in PC. However, whether circ_0075829 contributes to GEM resistance of PC is largely unknown. To generate GEM-resistant PC cells (BxPC-3/GR and SW1990/GR), we exposed GEM-sensitive PC cells to GEM. Circ_0075829, microRNA (miR)-326, and glutamic-oxaloacetic transaminase 1 (GOT1) were quantified by a qRT-PCR or western blot method. Cell survival and viability were gauged by MTS assay. Cell proliferation, apoptosis, invasion, and migration were assessed by EdU, flow cytometry, transwell, and wound-healing assays, respectively. Dual-luciferase reporter assays were used to verify the relationship between miR-326 and circ_0075829 or GOT1. Mouse xenografts were performed to evaluate the role of circ_0075829 in vivo. Our data showed that circ_0075829 was upregulated in GEM-resistant PC tissues and cells. Knockdown of circ_0075829 impeded the proliferation, invasion, migration, and glutamine metabolism, and promoted cell apoptosis and GEM sensitivity of GEM-resistant PC cells. Moreover, circ_0075829 silencing suppressed the tumorigenicity of SW1990/GR cells and sensitized them to the cytotoxic effect of GME in vivo. Mechanistically, circ_0075829 bound miR-326 and exerted regulatory effects by affecting miR-326 expression. GOT1 was a direct miR-326 target and a key downstream effector of miR-326. Furthermore, circ_0075829 modulated GOT1 expression via miR-326. Our findings establish a novel regulatory network, the circ_0075829/miR-326/GOT1 competing endogenous RNA (ceRNA) crosstalk, in the regulation of GEM resistance in PC.
Collapse
MESH Headings
- Gemcitabine
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Humans
- Drug Resistance, Neoplasm/genetics
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/metabolism
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Cell Line, Tumor
- Animals
- Mice
- Aspartate Aminotransferase, Cytoplasmic/genetics
- Aspartate Aminotransferase, Cytoplasmic/metabolism
- Mice, Nude
- Mice, Inbred BALB C
- Male
- Gene Expression Regulation, Neoplastic/drug effects
- Antimetabolites, Antineoplastic/pharmacology
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- RNA, Neoplasm/biosynthesis
- Female
- Xenograft Model Antitumor Assays
- RNA, Competitive Endogenous
Collapse
Affiliation(s)
- Yongjia Xiang
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Rubing Zhou
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Yang
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Hao Bai
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Fan Liang
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Hongmei Wang
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| | - Xia Wang
- Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, China
| |
Collapse
|
4
|
Peng H, Dou H, He S, Xie YA, Zhang Q, Zheng J. The role of GOT1 in cancer metabolism. Front Oncol 2024; 14:1519046. [PMID: 39777342 PMCID: PMC11703747 DOI: 10.3389/fonc.2024.1519046] [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: 10/29/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
GOT1, a cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in various metabolic pathways essential for cellular homeostasis and dysregulated metabolism. Recent studies have highlighted the significant plasticity and roles of GOT1 in metabolic reprogramming through participating in both classical and non-classical glutamine metabolism, glycolytic metabolism, and other metabolic pathways. This review summarizes emerging insights on the metabolic roles of GOT1 in cancer cells and emphasizes the response of cancer cells to altered metabolism when the expression of GOT1 is altered. We review how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT1 is inhibited and delineate the molecular mechanisms of GOT1's interaction with specific oncogenes and regulators at multiple levels, including transcriptional and epigenetic regulation, which govern cellular growth and metabolism. These insights may provide new directions for cancer metabolism research and novel targets for cancer treatment.
Collapse
Affiliation(s)
- Huan Peng
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Huihong Dou
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Sheng He
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects Research and Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yu-an Xie
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Qinle Zhang
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jianqiu Zheng
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| |
Collapse
|
5
|
Machuca A, Peñalver GA, Garcia RAF, Martinez-Lopez A, Castillo-Lluva S, Garcia-Calvo E, Luque-Garcia JL. Advancing rhodium nanoparticle-based photodynamic cancer therapy: quantitative proteomics and in vivo assessment reveal mechanisms targeting tumor metabolism, progression and drug resistance. J Mater Chem B 2024; 12:12073-12086. [PMID: 39453320 DOI: 10.1039/d4tb01631a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
Rhodium nanoparticles have been recently discovered as good photosensitizers with great potential in cancer photodynamic therapy by effectively inducing cytotoxicity in cancer cells under near-infrared laser. This study evaluates the molecular mechanisms underlying such antitumoral effect through quantitative proteomics. The results revealed that rhodium nanoparticle-based photodynamic therapy disrupts tumor metabolism by downregulating key proteins involved in ATP synthesis and mitochondrial function, leading to compromised energy production. The treatment also induces oxidative stress and apoptosis while targeting the invasion capacity of cancer cells. Additionally, key proteins involved in drug resistance are also affected, demonstrating the efficacy of the treatment in a multi-drug resistant cell line. In vivo evaluation using a chicken embryo model also confirmed the effectiveness of the proposed therapy in reducing tumor growth without affecting embryo viability.
Collapse
Affiliation(s)
- Andres Machuca
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Gabriel A Peñalver
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | | | - Angelica Martinez-Lopez
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Sonia Castillo-Lluva
- Department Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain
| | - Estefania Garcia-Calvo
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Jose L Luque-Garcia
- Department Analytical Chemistry, Faculty of Chemical Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
| |
Collapse
|
6
|
Liu Y, Zeng M, Li Z, Lin C, Bao J, Ding W, Wang S, Fan Q, Sun Q, Luo H, Huang J, Chen S, Tang H. Linc01588 deletion inhibits the malignant biological characteristics of hydroquinone-induced leukemic cells via miR-9-5p/SIRT1. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 276:116295. [PMID: 38581908 DOI: 10.1016/j.ecoenv.2024.116295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/16/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Leukemia caused by environmental chemical pollutants has attracted great attention, the malignant leukemic transformation model of TK6 cells induced by hydroquinone (HQ) has been previously found in our team. However, the type of leukemia corresponding to this malignant transformed cell line model needs further study and interpretation. Furthermore, the molecular mechanism of malignant proliferation of leukemic cells induced by HQ remains unclear. This study is the first to reveal the expression of aberrant genes in leukemic cells of HQ-induced malignant transformation, which may correspond to chronic lymphocytic leukemia (CLL). The expression of Linc01588, a long non-coding RNA (lncRNA), was significantly up-regulated in CLL patients and leukemic cell line model which previously described. After gain-of-function assays and loss-of-function assays, feeble cell viability, severe apoptotic phenotype and the increased secretion of TNF-α were easily observed in malignant leukemic TK6 cells with Linc01588 deletion after HQ intervention. The tumors derived from malignant TK6 cells with Linc01588 deletion inoculated subcutaneously in nude mice were smaller than controls. In CLL and its cell line model, the expression of Linc01588 and miR-9-5p, miR-9-5p and SIRT1 were negative correlation respectively in CLL and cell line model, while the expression of Linc01588 and SIRT1 were positive correlation. The dual-luciferase reporter assay showed that Linc01588 & miR-9-5p, miR-9-5p & SIRT1 could bind directly, respectively. Furthermore, knockdown of miR-9-5p successfully rescued the severe apoptotic phenotype and the increased secretion of TNF-α caused by the Linc01588 deletion, the deletion of Linc01588 in human CLL cell line MEC-2 could also inhibit malignant biological characteristics, and the phenotype caused by the deletion of Linc01588 could also be rescued after overexpression of SIRT1. Moreover, the regulation of SIRT1 expression in HQ19 cells by Linc01588 and miR-9-5 P may be related to the Akt/NF-κB pathway. In brief, Linc01588 deletion inhibits the malignant biological characteristics of HQ-induced leukemic cells via miR-9-5p/SIRT1, and it is a novel and hopeful clue for the clinical targeted therapy of CLL.
Collapse
Affiliation(s)
- Yanquan Liu
- Department of Hematology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan 523808, China; School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Minjuan Zeng
- School of Basic Medicine, Guangdong Medical University, Dongguan Key Laboratory for Development and Application of Experimental Animal Resources in Biomedical Industry, Dongguan 523808, China
| | - Zhengzhen Li
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Caixiong Lin
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Jie Bao
- Department of Clinical Laboratory, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524002, China
| | - Weihua Ding
- Central People's Hospital of Zhanjiang, Zhanjiang 524033, China
| | - Shimei Wang
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Qin Fan
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Qian Sun
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Hao Luo
- School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China
| | - Jinqi Huang
- Department of Hematology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510180, China
| | | | - Huanwen Tang
- Department of Hematology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan 523808, China; School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, Dongguan 523808, China.
| |
Collapse
|
7
|
Yalav O, Sonmezler O, Erdogan KE, Rencuzogullari A, Doran F, Bisgin A, Boga I. Pre-operative Neo-adjuvant Chemotherapy Related miRNAs as Key Regulators and Therapeutic Targets in Colorectal Cancer. Curr Aging Sci 2024; 17:49-57. [PMID: 37723961 DOI: 10.2174/1874609816666230816152744] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 07/10/2023] [Accepted: 07/24/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND In colorectal cancer, the investigation of cancer pathogenesis and the determination of the relevant gene and gene pathways is particularly important to provide a basis for treatment-oriented studies. miRNAs which affect gene regulation in the molecular pathogenesis of cancer, have an active role in carcinogenesis. In the literature, miRNA expression levels have been associated with metastasis and prognosis in different cancers. OBJECTIVE In our study, expression profiling of miRNAs involved in oncogenic and apoptotic pathways in patients with locally advanced colorectal cancer receiving neoadjuvant therapy was performed. METHODS miRNAs were isolated from three different FFPE tissue samples taken at different times of the same patient (tumor tissue taken at the time of diagnosis, normal tissue samples, and after neoadjuvant therapy). The expression analysis of 84 miRNAs determined by PCR array (Fluidigm, USA) and mediated meta-analysis was performed comparatively to each study and non-cancerous control group. Evaluations were performed with ΔΔCT calculations. RESULTS As a result of the miRNA PCR array study, in addition to differences were observed in miRNA expression between control and study groups. The potential biomarkers which were hsamiR- 215-5p, hsa-miR-9-59, hsa-miR-193a-5p, hsa-miR-206, hsa-miR-1, hsa-miR-96-5p have been detected for possible treatment resistance, prognosis and predispositions to cancers. CONCLUSION In patients with colorectal cancer, miRNA expression in the tumoral regions before and after neoadjuvant therapy has represented a variable pattern. It has been shown that miRNA studies can be used to predict the clinical course and response to treatment with differences in expression levels. It has been concluded that specific miRNAs may be candidate biomarkers for colorectal cancer. .
Collapse
Affiliation(s)
- Orcun Yalav
- Department of General Surgery, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Ozge Sonmezler
- AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Cukurova University, Adana, Turkey
- Biotechnology Department, Cukurova University Institute of Natural and Applied Sciences, Adana, Turkey
| | - Kivilcim Eren Erdogan
- Department of Pathology, Faculty of Medicine, Cukurova University Institute of Natural and Applied Sciences, Adana, Turkey
| | - Ahmet Rencuzogullari
- Department of General Surgery, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Figen Doran
- Department of Pathology, Faculty of Medicine, Cukurova University Institute of Natural and Applied Sciences, Adana, Turkey
| | - Atil Bisgin
- Department of Medical Genetics, Faculty of Medicine, Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center) & Cukurova University, Adana, Turkey
| | - Ibrahim Boga
- AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Cukurova University, Adana, Turkey
- Department of Medical Genetics, Faculty of Medicine, Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center) & Cukurova University, Adana, Turkey
| |
Collapse
|
8
|
Gu X, Wei F, Tong J, Liu Y, Chen S, Zheng L, Xing Y. MiR-9 promotes G-MDSC recruitment and tumor proliferation by targeting SOCS3 in breast cancer. FASEB J 2024; 38:e23388. [PMID: 38145323 DOI: 10.1096/fj.202301764rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/17/2023] [Accepted: 12/11/2023] [Indexed: 12/26/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells that differentiate from myeloid cells, proliferate in cancer and inflammatory reactions, and mainly exert immunosuppressive functions. Nonetheless, the precise mechanisms that dictate both the accumulation and function of MDSCs remain only partially elucidated. In the course of our investigation, we observed a positive correlation between the content of MDSCs especially G-MDSCs and miR-9 level in the tumor tissues derived from miR-9 knockout MMTV-PyMT mice and 4T1 tumor-bearing mice with miR-9 overexpression. Combined with RNA-seq analysis, we identified SOCS2 and SOCS3 as direct targets of miR-9. Additionally, our research unveiled the pivotal role of the CCL5/CCR5 axis in orchestrating the chemotactic recruitment of G-MDSCs within the tumor microenvironment, a process that is enhanced by miR-9. These findings provide fresh insights into the molecular mechanisms governing the accumulation of MDSCs within the framework of breast cancer development.
Collapse
Affiliation(s)
- Xinyue Gu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Fang Wei
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jinzhe Tong
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yichen Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Simiao Chen
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Lufeng Zheng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| |
Collapse
|
9
|
Liu J, Qi Y, Hou S, Zhang S, Wang Z. Linc01116 Silencing Inhibits the Proliferation and Invasion, Promotes Apoptosis of Chordoma Cells via Regulating the Expression of Mir-9-5p/PKG1. Curr Mol Med 2024; 24:1056-1071. [PMID: 37489776 DOI: 10.2174/1566524023666230719121758] [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: 11/18/2022] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND Long intergenic non-protein coding RNA 1116 (LINC01116) plays a carcinogenic role in a variety of cancers. The study aims to investigate the roles of LINC01116 and hsa-miR-9-5p (miR-9-5p) and fathom their interaction in chordoma. METHODS The predicted binding sites between miR-9-5p with LINC01116 and phosphoglycerate kinase 1 (PGK1) by starBase were confirmed through dual-luciferase reporter assay. The behaviors of chordoma cells undergoing transfection with siLINC01116 or miR-9-5p inhibitor were determined by Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and flow cytometry assays. The glucose consumption, lactate production, and adenosine triphosphate (ATP) production of chordoma cells were examined with specific kits. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to determine relevant gene expressions in chordoma cells. RESULTS Silencing of LINC01116 facilitated the apoptosis and expressions of Bcl-2- associated X (Bax), cleaved caspase-3 (C caspase-3) and miR-9-5p while repressing the cell cycle, viability, proliferation, invasion, glucose consumption, lactate production, ATP production, and expressions of PGK1 and Bcl-2. Meanwhile, LINC01116 sponged miR-9-5p, which could target PGK1. Moreover, the miR-9-5p inhibitor acted contrarily and reversed the role of siLINC01116 in chordoma cells. Besides, LINC01116 downregulation facilitated apoptosis and attenuated the proliferation and invasion of chordoma cells as well as PGK1 expression by upregulating miR-9-5p expression. CONCLUSION LINC01116/miR-9-5p plays a regulatory role in the progression of chordoma cells and is a potential biomarker for chordoma.
Collapse
Affiliation(s)
- Junqi Liu
- Department of Otorhinolaryngology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China
| | - Yan Qi
- Department of Otorhinolaryngology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China
| | - Siyuan Hou
- Department of Otorhinolaryngology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China
| | - Siyuan Zhang
- Department of Otorhinolaryngology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China
| | - Zhenlin Wang
- Department of Otorhinolaryngology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China
| |
Collapse
|
10
|
Kciuk M, Yahya EB, Mohamed MMI, Abdulsamad MA, Allaq AA, Gielecińska A, Kontek R. Insights into the Role of LncRNAs and miRNAs in Glioma Progression and Their Potential as Novel Therapeutic Targets. Cancers (Basel) 2023; 15:3298. [PMID: 37444408 DOI: 10.3390/cancers15133298] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Accumulating evidence supports that both long non-coding and micro RNAs (lncRNAs and miRNAs) are implicated in glioma tumorigenesis and progression. Poor outcome of gliomas has been linked to late-stage diagnosis and mostly ineffectiveness of conventional treatment due to low knowledge about the early stage of gliomas, which are not possible to observe with conventional diagnostic approaches. The past few years witnessed a revolutionary advance in biotechnology and neuroscience with the understanding of tumor-related molecules, including non-coding RNAs that are involved in the angiogenesis and progression of glioma cells and thus are used as prognostic biomarkers as well as novel therapeutic targets. The emerging research on lncRNAs and miRNAs highlights their crucial role in glioma progression, offering new insights into the disease. These non-coding RNAs hold significant potential as novel therapeutic targets, paving the way for innovative treatment approaches against glioma. This review encompasses a comprehensive discussion about the role of lncRNAs and miRNAs in gene regulation that is responsible for the promotion or the inhibition of glioma progression and collects the existing links between these key cancer-related molecules.
Collapse
Affiliation(s)
- Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
- Doctoral School of Exact and Natural Sciences, University of Lodz, 90-237 Lodz, Poland
| | - Esam Bashir Yahya
- Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, Penang 11800, Malaysia
| | | | - Muhanad A Abdulsamad
- Department of Molecular Biology, Faculty of Science, Sabratha University, Sabratha 00218, Libya
| | - Abdulmutalib A Allaq
- Faculty of Applied Science, Universiti Teknologi MARA, Shah Alam 40450, Malaysia
| | - Adrianna Gielecińska
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
- Doctoral School of Exact and Natural Sciences, University of Lodz, 90-237 Lodz, Poland
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland
| |
Collapse
|
11
|
Liu C, Li C, Liu Y. The role of metabolic reprogramming in pancreatic cancer chemoresistance. Front Pharmacol 2023; 13:1108776. [PMID: 36699061 PMCID: PMC9868425 DOI: 10.3389/fphar.2022.1108776] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023] Open
Abstract
Pancreatic cancer is characterized by hidden onset, high malignancy, and early metastasis. Although a few cases meet the surgical indications, chemotherapy remains the primary treatment, and the resulting chemoresistance has become an urgent clinical problem that needs to be solved. In recent years, the importance of metabolic reprogramming as one of the hallmarks of cancers in tumorigenesis has been validated. Metabolic reprogramming involves glucose, lipid, and amino acid metabolism and interacts with oncogenes to affect the expression of key enzymes and signaling pathways, modifying the tumor microenvironment and contributing to the occurrence of drug tolerance. Meanwhile, the mitochondria are hubs of the three major nutrients and energy metabolisms, which are also involved in the development of drug resistance. In this review, we summarized the characteristic changes in metabolism during the progression of pancreatic cancer and their impact on chemoresistance, outlined the role of the mitochondria, and summarized current studies on metabolic inhibitors.
Collapse
|
12
|
DNA methylation-induced ablation of miR-133a accelerates cancer aggressiveness in glioma through upregulating peroxisome proliferator-activated receptor γ. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2023; 28:19-28. [PMID: 36067936 DOI: 10.1016/j.slasd.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 01/31/2023]
Abstract
Emerging evidences suggest that miRNAs can be used as theranostic biomarkers for multiple cancers, including glioma. Thus, identification of novel miRNAs for glioma treatment and prognosis becomes necessary and urgent. Here, by analyzing miRNA expression profiles in the glioma and para-cancer tissues by miRNA microarray and verified by RT-PCR, we found that miR-133a was significantly downregulated in the cancerous tissues, and patients with low-expressed miR-133a levels predicted an unfavorable prognosis. The following functional experiments confirmed that overexpression of miR-133a restrained cell proliferation and colony formation abilities, and induced cell cycle arrest to restrain cancer progression in glioma cells. Then, the underlying mechanisms were uncovered, and the peroxisome proliferator-activated receptor γ (PPARγ, PPARG) was verified as the downstream target of miR-133a. Mechanistically, miR-133a negatively regulated PPARG expressions by binding to its 3' untranslated regions (3'UTR). The following rescuing experiments evidenced that miR-133a overexpression-induced anti-cancer effects in glioma cells were abrogated by upregulating PPARγ. Interestingly, we noticed that the promoter region of miR-133a was hypermethylated, and removal of DNA methylation by 5-Azacytidine (AZA) significantly increased the expression levels of miR-133a in glioma cells. Taken together, we concluded that DNA-methylation-induced miR-133a silence contributed to cancer progression in glioma through upregulating PPARγ, and firstly identified the DNA-methylation-regulated miR-133a/PPARG axis as the novel indicators for glioma treatment and prognosis.
Collapse
|
13
|
Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression. Cells 2022; 11:cells11233893. [PMID: 36497150 PMCID: PMC9735520 DOI: 10.3390/cells11233893] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/20/2022] [Accepted: 11/10/2022] [Indexed: 12/03/2022] Open
Abstract
Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.
Collapse
|
14
|
Tripathi SK, Pal A, Ghosh S, Goel A, Aggarwal R, Banerjee S, Das S. LncRNA NEAT1 regulates HCV-induced Hepatocellular carcinoma by modulating the miR-9-BGH3 axis. J Gen Virol 2022; 103. [PMID: 36748628 DOI: 10.1099/jgv.0.001809] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9-5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9-5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9-5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.
Collapse
Affiliation(s)
| | - Apala Pal
- Indian Institute of Science, Bangalore, India
| | - Suchandrima Ghosh
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Amit Goel
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rakesh Aggarwal
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Soma Banerjee
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Saumitra Das
- Indian Institute of Science, Bangalore, India
- National Institute of Biomedical Genomics, Kalyani, India
| |
Collapse
|
15
|
Alshahrani SH, Ibrahim YS, Jalil AT, Altoum AA, Achmad H, Zabibah RS, Gabr GA, Ramírez-Coronel AA, Alameri AA, Qasim QA, Karampoor S, Mirzaei R. Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism. Front Oncol 2022; 12:1042196. [PMID: 36483029 PMCID: PMC9723351 DOI: 10.3389/fonc.2022.1042196] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/24/2022] [Indexed: 01/15/2023] Open
Abstract
MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8+ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.
Collapse
Affiliation(s)
- Shadia Hamoud Alshahrani
- Medical Surgical Nursing Department, King Khalid University, Almahala, Khamis Mushate, Saudi Arabia
| | - Yousif Saleh Ibrahim
- Department of Medical Laboratory Techniques, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, Iraq
| | - Abdelgadir Alamin Altoum
- Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Harun Achmad
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - Rahman S. Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Gamal A. Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
- Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Andrés Alexis Ramírez-Coronel
- Health and Behavior Research Group (HBR), Catholic University of Cuenca, Cuenca, Ecuador
- Laboratory of Psychometry and Ethology, Catholic University of Cuenca, Cuenca, Ecuador
- Epidemiology and Biostatistics Research Group, Universidad CES, Medellin, Colombia
| | | | | | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
16
|
Fang S, Wang L, Luo C, Yi H, Wang X, Ning B. Curcumol inhibits the growth of xenograft-tumors in mice and the biological activities of pancreatic cancer cells by regulating the miR-21-5p/SMAD7 axis. Cell Cycle 2022; 21:1249-1266. [PMID: 35253605 PMCID: PMC9132406 DOI: 10.1080/15384101.2022.2046983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/12/2022] [Accepted: 02/22/2022] [Indexed: 11/03/2022] Open
Abstract
Anti-cancer effects of curcumol on various cancers have been reported previously. This study focused on investigating the role of curcumol in pancreatic cancer from the molecular perspective. The survival of pancreatic cancer patients with high or low expression of miR-21-5pand the target gene of miR-21-5pwere analyzed by bioinformatics. MiR-21-5p expression in cancer tissues was analyzed by RT-qPCR. Anxenograft-tumor BALB/c nude mice model was established and pancreatic cancer cells were cultured. Later, the mice and cells were further treated with curcumol. The tumor size and weightas well as mice body weight were recorded. The viability, proliferation, migration, and invasion of the cells were evaluated by MTT, colony formation, and transwell assays, respectively. The expressions of molecules in the xenograft-tumor tissues or cells were detected by immunohistochemical assay, Western blot, or RT-qPCR. MiR-21-5p was high-expressed in pancreatic cancer tissues and patients with high expression of miR-21-5p had poor survival. Curcumol inhibited the xenograft-tumor size, tumor weight, and PCNA and miR-21-5p expressions while promoting Cleaved caspase-3 expression in xenograft-tumor tissues. Curcumol inhibited the viability, proliferation, migration, invasion, and miR-21-5p expression, but increased SMAD7 expression in cancer cells. MiR-21-5p overexpression reversed the effect of curcumol on cancer cells, and decreased the E-cadherin expression while elevating the expressions of PCNA, N-cadherin, Vimentin, p-SMAD2, and p-SMAD3 in curcumol-treated cells. The overexpression of SMAD7, a target gene of miR-21-5p, reversed the effect of miR-21-5p on curcumol-treated cells. Curcumol inhibited growth of xenograft-tumors and the biological activities of pancreatic cancer cells by regulating the miR-21-5p/SMAD7 axis.
Collapse
Affiliation(s)
- Songlin Fang
- Gastroenterology Department, The Fifth Hospital of Xiamen, Xiamen, China
| | - Lezeng Wang
- General Surgery Department, Gaotang County People’s Hospital, Liaocheng, China
| | - Chunmei Luo
- Pharmacy Department, Chongqing Traditional Chinese Medicine Hospital , Chongqing, China
| | - Hang Yi
- Gastroenterology Department, The Second Affiliated Hospital of Chongqing Medical University , Chongqing, China
| | - Xiangrui Wang
- Gastroenterology Department, The Second Affiliated Hospital of Chongqing Medical University , Chongqing, China
| | - Bo Ning
- Gastroenterology Department, The Second Affiliated Hospital of Chongqing Medical University , Chongqing, China
| |
Collapse
|
17
|
Feng Y, Sun X, Yang T, Han J, Zhou D, Ren H, Sheng Y, Wang Y. Comprehensive Analysis of Subtypes and Identification of Key lncRNAs Based on Glutamine Metabolism-Related Long Noncoding RNAs. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2807354. [PMID: 35529265 PMCID: PMC9076293 DOI: 10.1155/2022/2807354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/21/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
Abstract
Background Long noncoding RNAs (lncRNAs) are becoming a critical class of metabolic regulate molecule in cancer. Glutamine is a regulator that contributes to each of the core metabolic tasks in proliferating tumor cells. Thus, we aimed to evaluate the association of lncRNAs with glutamine metabolism in lung adenocarcinoma (LUAD). Methods Using single-sample gene set enrichment analysis (ssGSEA), LUAD specimens were assigned scores based on glutamine metabolism-related genes, and the shared common glutamine metabolism-related lncRNAs in three different LUAD data cohorts were identified. ConsensusClusterPlus was used to perform unsupervised clustering analysis in patients with LUAD. Key glutamine metabolism-related lncRNAs were identified by first-order partial correlation analysis. Results A total of 11 shared glutamine metabolism-associated lncRNAs were identified in three LUAD data cohorts, and LUAD patients were classified into three glutamine metabolism subtypes based on the expressions of the related genes. C1 exhibited shorter overall survival (OS), poor genomic instability, and inadequate infiltration of immune cell types in the tumor microenvironment (TME) and was representative of the immunodeficiency phenotype. C2 represented the immunosuppressive phenotype while C3 represented the immune activation phenotype, exhibiting the highest sensitivity to immunotherapy. Nine of the 11 lncRNAs were localized to the nucleus. Finally, three key lncRNAs, significantly enriched in multiple metabolic pathways, were screened and found to be remarkably related to the OS of LUAD. Conclusion We identified three glutamine metabolism subtypes of LUAD, which reflected different OS, genomic, and TME features, and identified three key glutamine metabolism-associated lncRNAs may contribute to further study of lncRNAs in cancer metabolism.
Collapse
Affiliation(s)
- Yuwei Feng
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, Shandong Province, China
| | - Xiaowei Sun
- Department of Medical Imaging, Qingdao Women and Children's Hospital, 6 Tongfu Road, Shibei District, Qingdao, Shandong, China
| | - Tiangu Yang
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, Shandong Province, China
| | - Jingqi Han
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, 369 Shanghai Road, Pingdu, Qingdao, Shandong, China
| | - Dapeng Zhou
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, 369 Shanghai Road, Pingdu, Qingdao, Shandong, China
| | - Haitao Ren
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, 369 Shanghai Road, Pingdu, Qingdao, Shandong, China
| | - Yulong Sheng
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, 369 Shanghai Road, Pingdu, Qingdao, Shandong, China
| | - Yanhua Wang
- Department of Interventional Medicine, Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, Shandong Province, China
| |
Collapse
|
18
|
Liao J, Zhang Z, Yuan Q, Luo L, Hu X. The Mouse Anxa6/miR-9-5p/Anxa2 Axis Modulates TGF-β1-induced Mouse Hepatic Stellate Cell (mHSC) Activation and CCl 4-caused Liver Fibrosis. Toxicol Lett 2022; 362:38-49. [PMID: 35483553 DOI: 10.1016/j.toxlet.2022.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/23/2022] [Accepted: 04/20/2022] [Indexed: 01/18/2023]
Abstract
Chronic liver disease such as hepatic fibrosis is a major cause of morbidity and mortality and has been related to high individual risk of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) activation is a central event of hepatic fibrosis progression. In this study, the up-regulation of lncRNA ANXA2P2 (mouse Anxa6) was found in liver fibrosis. Within CCl4-caused liver fibrosis murine model, Anxa6 knockdown partially ameliorated CCl4-induced hepatic fibrosis and blocked the PI3K/Akt signaling activation. In TGF-β1-stimulated HSCs, Anxa6 knockdown partially inhibited TGF-β1-induced HSC activation and blocked the PI3K/Akt signaling activation. Mouse Anxa6 downstream mmu-miR-9-5p directly targeted Anxa2; Anxa6 negatively regulated mmu-miR-9-5p, and mmu-miR-9-5p negatively regulated mouse Anxa2. In TGF-β1-stimulated HSCs, miR-9-5p inhibitor promoted TGF-β1-induced HSC activation and PI3K/Akt signaling activation, whereas Anxa2 knockdown exerted opposite effects; Anxa2 knockdown significantly attenuated miR-9-5p inhibitor effects upon TGF-β1-stimulated HSCs. In conclusion, lncRNA ANXA2P2 (mouse Anxa6) expression is up-regulated in hepatic fibrosis and exerts pro-fibrotic effects on CCl4-caused liver fibrosis model mice and TGF-β1-stimulated HSCs. The mouse Anxa6/miR-9-5p/Anxa2 axis and the PI3K/Akt pathway might participate in the functions of lncRNA ANXA2P2 (mouse Anxa6) on hepatic fibrosis.
Collapse
Affiliation(s)
- Jinmao Liao
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Zheng Zhang
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Qi Yuan
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Lidan Luo
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Xiaoxuan Hu
- Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
| |
Collapse
|
19
|
Non-coding RNAs in ferroptotic cancer cell death pathway: meet the new masters. Hum Cell 2022; 35:972-994. [PMID: 35415781 DOI: 10.1007/s13577-022-00699-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/01/2022] [Indexed: 02/08/2023]
Abstract
Despite the recent advances in cancer therapy, cancer chemoresistance looms large along with radioresistance, a major challenge in dire need of thorough and minute investigation. Not long ago, cancer cells were reported to have proven refractory to the ferroptotic cell death, a newly discovered form of regulated cell death (RCD), conspicuous enough to draw attention from scholars in terms of targeting ferroptosis as a prospective therapeutic strategy. However, our knowledge concerning the underlying molecular mechanisms through which cancer cells gain immunity against ferroptosis is still in its infancy. Of late, the implication of non-coding RNAs (ncRNAs), including circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) in ferroptosis has been disclosed. Nevertheless, precisely explaining the molecular mechanisms behind the contribution of ncRNAs to cancer radio/chemotherapy resistance remains a challenge, requiring further clarification. In this review, we have presented the latest available information on the ways and means of regulating ferroptosis by ncRNAs. Moreover, we have provided important insights about targeting ncRNAs implicated in ferroptosis with the hope of opening up new horizons for overcoming cancer treatment modalities. Though a long path awaits until we make this ambitious dream come true, recent progress in gene therapy, including gene-editing technology will aid us to be optimistic that ncRNAs-based ferroptosis targeting would soon be on stream as a novel therapeutic strategy for treating cancer.
Collapse
|
20
|
miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression. Cell Mol Life Sci 2022; 79:216. [PMID: 35348905 PMCID: PMC8964646 DOI: 10.1007/s00018-022-04228-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs about 22 nucleotides in length that regulate the expression of target genes post-transcriptionally, and are highly involved in cancer progression. They are able to impact a variety of cell processes such as proliferation, apoptosis and differentiation and can consequently control tumor initiation, tumor progression and metastasis formation. miRNAs can regulate, at the same time, metabolic gene expression which, in turn, influences relevant traits of malignancy such as cell adhesion, migration and invasion. Since the interaction between metabolism and adhesion or cell movement has not, to date, been well understood, in this review, we will specifically focus on miRNA alterations that can interfere with some metabolic processes leading to the modulation of cancer cell movement. In addition, we will analyze the signaling pathways connecting metabolism and adhesion/migration, alterations that often affect cancer cell dissemination and metastasis formation.
Collapse
|
21
|
Song Z, Yang Y, Wu Y, Zheng M, Sun D, Li H, Chen L. Glutamic oxaloacetic transaminase 1 as a potential target in human cancer. Eur J Pharmacol 2022; 917:174754. [PMID: 35007521 DOI: 10.1016/j.ejphar.2022.174754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 12/31/2022]
Abstract
Glutamic Oxaloacetic Transaminase 1 (GOT1) is one distinct isoenzyme of glutamic oxaloacetic transaminase in eukaryotic cells, which is located in the cytoplasm. To date, several studies have shown that GOT1 plays a critical role in regulating cell proliferation by participating in amino acid metabolism, especially in glutamine metabolism. In addition, GOT1 is overexpressed in many cancer, so GOT1 has been identified as a potentially therapeutic target. Herein, this review summarizes the structure and function of GOT1 and the important roles of GOT1 in some tumor progress, as well as the characterization of GOT1 inhibitors. It may provide new insight into the discovery of small compounds as potential anti-GOT1 drugs for treatment of cancer.
Collapse
Affiliation(s)
- Zhuorui Song
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yueying Yang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yanli Wu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| |
Collapse
|
22
|
Evaluation of Serum MicroRNAs (miR-9-5p, miR-17-5p, and miR-148a-3p) as Potential Biomarkers of Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9961412. [PMID: 35111850 PMCID: PMC8803421 DOI: 10.1155/2022/9961412] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 12/21/2021] [Indexed: 12/11/2022]
Abstract
Background MicroRNAs (miRNAs) play important roles in the initiation and progression of cancers. The purpose of the present study was to evaluate the use of serum miRNA biomarkers in the early diagnosis of breast cancer. Methods The expression levels of miR-9-5p, miR-17-5p, and miR-148a-3p were analyzed by quantitative reverse transcription-polymerase chain reaction in 49 patients with newly diagnosed breast cancer and 49 healthy controls. The associations between miR-9-5p, miR-17-5p, and miR-148a-3p levels and clinicopathological parameters were also analyzed. Regression analysis and sensitivity and specificity analyses were used to determine the diagnostic efficacy of the miRNAs. Results Serum levels of miR-9-5p and miR-148a-3p were significantly higher in breast cancer patients than in healthy controls (both P < 0.05), but miR-17-5p levels were not different between the two groups (P = 0.996). Serum miR-9-5p levels were markedly higher in patients with human epidermal growth factor receptor 2- (HER2-) positive breast cancer than in those with HER2-negative breast cancer (P = 0.049). Serum levels of miR-9-5p and miR-148a-3p were positively correlated with the presence of breast cancer, and both miRNAs had high sensitivity and specificity for the diagnosis of breast cancer. Conclusions These findings provide evidence that serum miR-9-5p and miR-148a-3p levels may be used as noninvasive biological markers for the clinical diagnosis of breast cancer.
Collapse
|
23
|
Garnier D, Ratcliffe E, Briand J, Cartron PF, Oliver L, Vallette FM. The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p. Biomedicines 2022; 10:biomedicines10010112. [PMID: 35052791 PMCID: PMC8773192 DOI: 10.3390/biomedicines10010112] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/28/2021] [Accepted: 12/31/2021] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, and despite initial response to chemo- and radio-therapy, the persistence of glioblastoma stem cells (GSCs) unfortunately always results in tumor recurrence. It is now largely admitted that tumor cells recruit normal cells, including mesenchymal stem cells (MSCs), and components of their environment, to participate in tumor progression, building up what is called the tumor microenvironment (TME). While growth factors and cytokines constitute essential messengers to pass on signals between tumor and TME, recent uncovering of extracellular vesicles (EVs), composed of microvesicles (MVs) and exosomes, opened new perspectives to define the modalities of this communication. In the GBM context particularly, we investigated what could be the nature of the EV exchange between GSCs and MSCs. We show that GSCs MVs can activate MSCs into cancer-associated fibroblasts (CAFs)-like cells, that subsequently increase their secretion of exosomes. Moreover, a significant decrease in anti-tumoral miR-100-5p, miR-9-5p and let-7d-5p was observed in these exosomes. This clearly suggests a miRNA-mediated GBM tumor promotion by MSCs exosomes, after their activation by GBM MVs.
Collapse
Affiliation(s)
- Delphine Garnier
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, 75006 Paris, France
- Correspondence:
| | - Edward Ratcliffe
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Joséphine Briand
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Pierre-François Cartron
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Lisa Oliver
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - François M. Vallette
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| |
Collapse
|
24
|
Using bioinformatics approaches to identify survival-related oncomiRs as potential targets of miRNA-based treatments for lung adenocarcinoma. Comput Struct Biotechnol J 2022; 20:4626-4635. [PMID: 36090818 PMCID: PMC9449502 DOI: 10.1016/j.csbj.2022.08.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022] Open
Abstract
Lung cancer is a major cause of cancer-associated deaths worldwide, and lung adenocarcinoma (LUAD) is the most common lung cancer subtype. Micro RNAs (miRNAs) regulate the pattern of gene expression in multiple cancer types and have been explored as potential drug development targets. To develop an oncomiR-based panel, we identified miRNA candidates that show differential expression patterns and are relevant to the worse 5-year overall survival outcomes in LUAD patient samples. We further evaluated various combinations of miRNA candidates for association with 5-year overall survival and identified a four-miRNA panel: miR-9-5p, miR-1246, miR-31-3p, and miR-3136-5p. The combination of these four miRNAs outperformed any single miRNA for predicting 5-year overall survival (hazard ratio [HR]: 3.47, log-rank p-value = 0.000271). Experiments were performed on lung cancer cell lines and animal models to validate the effects of these miRNAs. The results showed that singly transfected antagomiRs largely inhibited cell growth, migration, and invasion, and the combination of all four antagomiRs considerably reduced cell numbers, which is twice as effective as any single miRNA-targeted transfected. The in vivo studies revealed that antagomiR-mediated knockdown of all four miRNAs significantly reduced tumor growth and metastatic ability of lung cancer cells compared to the negative control group. The success of these in vivo and in vitro experiments suggested that these four identified oncomiRs may have therapeutic potential.
Collapse
|
25
|
Uzuner E, Ulu GT, Gürler SB, Baran Y. The Role of MiRNA in Cancer: Pathogenesis, Diagnosis, and Treatment. Methods Mol Biol 2022; 2257:375-422. [PMID: 34432288 DOI: 10.1007/978-1-0716-1170-8_18] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is also determined by the alterations of oncogenes and tumor suppressor genes. These gene expressions can be regulated by microRNAs (miRNA). At this point, researchers focus on addressing two main questions: "How are oncogenes and/or tumor suppressor genes regulated by miRNAs?" and "Which other mechanisms in cancer cells are regulated by miRNAs?" In this work we focus on gathering the publications answering these questions. The expression of miRNAs is affected by amplification, deletion or mutation. These processes are controlled by oncogenes and tumor suppressor genes, which regulate different mechanisms of cancer initiation and progression including cell proliferation, cell growth, apoptosis, DNA repair, invasion, angiogenesis, metastasis, drug resistance, metabolic regulation, and immune response regulation in cancer cells. In addition, profiling of miRNA is an important step in developing a new therapeutic approach for cancer.
Collapse
Affiliation(s)
- Erez Uzuner
- Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey
| | - Gizem Tugçe Ulu
- Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey
| | - Sevim Beyza Gürler
- Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey
| | - Yusuf Baran
- Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey.
| |
Collapse
|
26
|
Rajagopal MU, Bansal S, Kaur P, Jain SK, Altadil T, Hinzman CP, Li Y, Moulton J, Singh B, Bansal S, Chauthe SK, Singh R, Banerjee PP, Mapstone M, Fiandaca MS, Federoff HJ, Unger K, Smith JP, Cheema AK. TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC. Cancers (Basel) 2021; 13:cancers13246204. [PMID: 34944824 PMCID: PMC8699757 DOI: 10.3390/cancers13246204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/26/2021] [Accepted: 12/06/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Pancreatic cancer is an aggressive disease with most patients diagnosed at late stages resulting in poor outcomes. While it is known that pancreatic tumor cells undergo epithelial to mesenchymal transition, the metabolic alterations accompanying that transition are not characterized. This study leveraged a metabolomics approach to understand the small molecule and biochemical perturbations that can be targeted for designing strategies for improving outcomes in pancreatic cancer. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.
Collapse
Affiliation(s)
- Meena U. Rajagopal
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Shivani Bansal
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Prabhjit Kaur
- Department of Botany, Khalsa College, Amritsar 143002, India; (P.K.); (R.S.)
| | - Shreyans K. Jain
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India;
| | - Tatiana Altadil
- Biomedical Research Group in Gynaecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain;
| | - Charles P. Hinzman
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA; (C.P.H.); (P.P.B.)
| | - Yaoxiang Li
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Joanna Moulton
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Baldev Singh
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Sunil Bansal
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
| | - Siddheshwar Kisan Chauthe
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad 380054, India;
| | - Rajbir Singh
- Department of Botany, Khalsa College, Amritsar 143002, India; (P.K.); (R.S.)
| | - Partha P. Banerjee
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA; (C.P.H.); (P.P.B.)
| | - Mark Mapstone
- Department of Neurology, University of California, Irvine, CA 92697, USA; (M.M.); (M.S.F.); (H.J.F.)
| | - Massimo S. Fiandaca
- Department of Neurology, University of California, Irvine, CA 92697, USA; (M.M.); (M.S.F.); (H.J.F.)
- Department of Neurological Surgery, University of California, Irvine, CA 92697, USA
| | - Howard J. Federoff
- Department of Neurology, University of California, Irvine, CA 92697, USA; (M.M.); (M.S.F.); (H.J.F.)
| | - Keith Unger
- Radiation Medicine, Med-Star Georgetown University Hospital, Washington, DC 20057, USA;
| | - Jill P. Smith
- Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Amrita K. Cheema
- Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA; (M.U.R.); (S.B.); (Y.L.); (J.M.); (B.S.); (S.B.)
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA; (C.P.H.); (P.P.B.)
- Correspondence: ; Tel.: +1-202-687-2756; Fax: +1-202-687-8860
| |
Collapse
|
27
|
Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
Collapse
Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
| |
Collapse
|
28
|
Sheng W, Xu W, Ding J, Li L, You X, Wu Y, He Q. Curcumol inhibits the malignant progression of prostate cancer and regulates the PDK1/AKT/mTOR pathway by targeting miR‑9. Oncol Rep 2021; 46:246. [PMID: 34590156 PMCID: PMC8493056 DOI: 10.3892/or.2021.8197] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023] Open
Abstract
Curcumol has been reported to exert anti-tumor activity, but its intrinsic molecular mechanism in prostate cancer remains to be elucidated. The present study aimed to analyze the effect of curcumol on prostate cancer and identify its possible internal regulatory pathway using in vitro cell culture and in vivo tumor model experiments. The cytotoxicity of curcumol was detected using a Cell Counting Kit-8 assay and it was found that curcumol had no obvious toxicity or side effects on RWPE-1 cells. Wound healing, Transwell and flow cytometry assays demonstrated that curcumol could affect the activity of PC3 cells. The luciferase reporter assay also indicated that microRNA (miR)-9 could directly target pyruvate dehydrogenase kinase 1 (PDK1). After PC3 cells were transfected with miR-9 inhibitor or treated with curcumol, the expression levels of the PDK1/AKT/mTOR signaling pathway-related proteins [PDK1, phosphorylated (p)-AKT and p-mTOR] were increased or decreased, respectively. Next, the prostate cancer cell xenograft model was established. Tumor size and the expression levels of PDK1/AKT/mTOR signaling pathway-related factors were altered following treatment with curcumol. The in vitro and in vivo experiments collectively demonstrated that curcumol could inhibit the PDK1/AKT/mTOR signaling pathway by upregulating the expression level of miR-9. The present study found that curcumol regulates the PDK1/AKT/mTOR signaling pathway via miR-9 and affects the development of prostate cancer. These findings could provide a possible scientific insight for research into treatments for prostate cancer.
Collapse
Affiliation(s)
- Wen Sheng
- Andrology Laboratory, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Wenjing Xu
- Dermatology Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410021, P.R. China
| | - Jin Ding
- Andrology Clinic, Shenzhen Baoan Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong 518133, P.R. China
| | - Ling Li
- Medical Basic Teaching Experiment Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Xujun You
- Andrology Clinic, Shenzhen Baoan Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong 518133, P.R. China
| | - Yongrong Wu
- Andrology Laboratory, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Qinghu He
- Andrology Laboratory, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| |
Collapse
|
29
|
Li P, Wang H, Tang Y, Sun S, Ma Y, Xu Y, Chen G. Knockdown of LINC00657 inhibits the viability, migration and invasion of pancreatic cancer cells by regulating the miR-520h/CKS1B axis. Exp Ther Med 2021; 22:1142. [PMID: 34504588 DOI: 10.3892/etm.2021.10576] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
Long non-coding RNA LINC00657 has a critical role in multiple cancers. The aim of the present study was to investigate the regulatory effect of LINC00657 in pancreatic cancer (PC) and reveal its molecular mechanism of function. The expression levels of LINC00657 and microRNA (miR)-520h were detected by reverse transcription-quantitative PCR in PC tissues and cell lines. MTT, wound healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Dual-luciferase reporter assay was utilized to examine the relationship between LINC00657 and miR-520h and that between miR-520h and cyclin-dependent kinases regulatory subunit 1 (CKS1B). Western blotting was performed to detect CKS1B expression. The expression levels of LINC00657 and CKS1B were enhanced and miR-520h expression level was reduced in PC tissues and cell lines compared with adjacent normal tissues or HPDE6 cells. LINC00657 knockdown decreased the viability, migration and invasion of PC cells. Additionally, LINC00657 targeted miR-520h and negatively modulated miR-520h expression. Furthermore, miR-520h overexpression inhibited the viability, migration and invasion of PC cells. In addition, miR-520h targeted CKS1B and reversely regulated CKS1B expression. miR-520h inhibition and CKS1B overexpression alleviated the inhibition effect of LINC00657 knockdown on the viability, migration and invasion of PACA-2 PC cells. In conclusion, the results of the present study demonstrated that LINC00657 knockdown repressed the viability, migration and invasion of PC cells via targeting the miR-520h/CKS1B axis, which may offer a future target for PC therapy.
Collapse
Affiliation(s)
- Peng Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Hongsheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Ying Tang
- Department of Nursing, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Shuo Sun
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yue Ma
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yansong Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Guangyu Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| |
Collapse
|
30
|
Dobre M, Herlea V, Vlăduţ C, Ciocîrlan M, Balaban VD, Constantinescu G, Diculescu M, Milanesi E. Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma. Cells 2021; 10:1856. [PMID: 34440625 PMCID: PMC8391367 DOI: 10.3390/cells10081856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. METHOD We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). RESULTS We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. CONCLUSIONS We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.
Collapse
Affiliation(s)
- Maria Dobre
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (E.M.)
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Cătălina Vlăduţ
- Department of Gastroenterology, “Prof Dr Agrippa Ionescu” Clinical Emergency Hospital, 011356 Bucharest, Romania;
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
| | - Mihai Ciocîrlan
- Department of Gastroenterology, “Prof Dr Agrippa Ionescu” Clinical Emergency Hospital, 011356 Bucharest, Romania;
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
| | - Vasile Daniel Balaban
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
- Department of Gastroenterology, Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Gabriel Constantinescu
- Department of Gastroenterology, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania;
| | - Mircea Diculescu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (V.D.B.); (M.D.)
- Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Elena Milanesi
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; (M.D.); (E.M.)
| |
Collapse
|
31
|
Zhi Y, Gao L, Wang B, Ren W, Liang KX, Zhi K. Ferroptosis Holds Novel Promise in Treatment of Cancer Mediated by Non-coding RNAs. Front Cell Dev Biol 2021; 9:686906. [PMID: 34235152 PMCID: PMC8255676 DOI: 10.3389/fcell.2021.686906] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/21/2021] [Indexed: 12/17/2022] Open
Abstract
Ferroptosis is a newly identified form of regulated cell death that is associated with iron metabolism and oxidative stress. As a physiological mechanism, ferroptosis selectively removes cancer cells by regulating the expression of vital chemical molecules. Current findings on regulation of ferroptosis have largely focused on the function of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), in mediating ferroptotic cell death, while the sponging effect of circular RNAs (circRNAs) has not been widely studied. In this review, we discuss the molecular regulation of ferroptosis and highlight the value of circRNAs in controlling ferroptosis and carcinogenesis. Herein, we deliberate future role of this emerging form of regulated cell death in cancer therapeutics and predict the progression and prognosis of oncogenesis in future clinical therapy.
Collapse
Affiliation(s)
- Yuan Zhi
- Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Stomatology, Central South University, Changsha, China
| | - Ling Gao
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Baisheng Wang
- Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital and School of Stomatology, Central South University, Changsha, China
| | - Wenhao Ren
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kristina Xiao Liang
- Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
| | - Keqian Zhi
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
32
|
Gao J, Zong X, Chen N, Lan T, Yu W, Long H, Cui F, Tu Y. Research progress on three different types of noncoding RNAs related to ionizing radiation. RADIATION MEDICINE AND PROTECTION 2021. [DOI: 10.1016/j.radmp.2021.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
33
|
Shen Y, Xue C, You G, Liu C. miR-9 alleviated the inflammatory response and apoptosis in caerulein-induced acute pancreatitis by regulating FGF10 and the NF-κB signaling pathway. Exp Ther Med 2021; 22:795. [PMID: 34093751 PMCID: PMC8170642 DOI: 10.3892/etm.2021.10227] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs) have been implicated in the development of acute pancreatitis (AP). However, the role and potential mechanism of miR-9 in AP progression remains unclear. Caerulein-treated AR42J cells were used as a cellular model of AP. Results revealed caerulein triggered an inflammatory response by promoting the secretion of inflammatory cytokines [tumor necrosis factor-α, interleukin (IL) 1β and IL-6], as evidenced by ELISA. Furthermore, caerulein-induced apoptosis was reported by flow cytometry and western blot assays. Additionally, miR-9 expression was downregulated by caerulein treatment, as demonstrated by reverse transcription quantitative PCR. However, miR-9 overexpression reduced the inflammatory response and apoptosis in caerulein-treated AR42J cells. miR-9 knockdown resulted in opposite effects. Furthermore, fibroblast growth factor (FGF) 10 was validated to be targeted via miR-9 by luciferase, RNA immunoprecipitation and RNA pull-down assays. Results demonstrated increased FGF10 expression in caerulein-treated AR42J cells and that FGF10 overexpression exacerbated the caerulein-induced inflammatory response and apoptosis, while its knockdown had the opposite effect. Additionally, FGF10 reversed the effect of miR-9 on caerulein-induced injury in AR42J cells. Results demonstrated that miR-9 inhibited the expression of the nuclear factor κB (NF-κB) pathway-related proteins by downregulating FGF10. As a result, miR-9 decreased inflammatory response and apoptosis in caerulein-treated AR42J cells by targeting FGF10 and blocking NF-κB signaling, suggesting that miR-9 may serve as a novel target for AP treatment.
Collapse
Affiliation(s)
- Yang Shen
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Chengjun Xue
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Guoli You
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Cui Liu
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| |
Collapse
|
34
|
Prusinkiewicz MA, Mymryk JS. Metabolic Control by DNA Tumor Virus-Encoded Proteins. Pathogens 2021; 10:560. [PMID: 34066504 PMCID: PMC8148605 DOI: 10.3390/pathogens10050560] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
Viruses co-opt a multitude of host cell metabolic processes in order to meet the energy and substrate requirements for successful viral replication. However, due to their limited coding capacity, viruses must enact most, if not all, of these metabolic changes by influencing the function of available host cell regulatory proteins. Typically, certain viral proteins, some of which can function as viral oncoproteins, interact with these cellular regulatory proteins directly in order to effect changes in downstream metabolic pathways. This review highlights recent research into how four different DNA tumor viruses, namely human adenovirus, human papillomavirus, Epstein-Barr virus and Kaposi's associated-sarcoma herpesvirus, can influence host cell metabolism through their interactions with either MYC, p53 or the pRb/E2F complex. Interestingly, some of these host cell regulators can be activated or inhibited by the same virus, depending on which viral oncoprotein is interacting with the regulatory protein. This review highlights how MYC, p53 and pRb/E2F regulate host cell metabolism, followed by an outline of how each of these DNA tumor viruses control their activities. Understanding how DNA tumor viruses regulate metabolism through viral oncoproteins could assist in the discovery or repurposing of metabolic inhibitors for antiviral therapy or treatment of virus-dependent cancers.
Collapse
Affiliation(s)
| | - Joe S. Mymryk
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada;
- Department of Otolaryngology, Head & Neck Surgery, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
| |
Collapse
|
35
|
Zhou X, Liu K, Cui J, Xiong J, Wu H, Peng T, Guo Y. Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. J Exp Clin Cancer Res 2021; 40:124. [PMID: 33832516 PMCID: PMC8034179 DOI: 10.1186/s13046-021-01894-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a malignant tumor and ranks the sixth in incidence among cancers. Circular RNA (circRNA) has been reported to regulate the progression of pancreatic cancer. However, the effects of circ-membrane bound O-acyltransferase domain containing 2 (circ-MBOAT2) on regulating pancreatic cancer process were unclear. METHODS The expression levels of circ-MBOAT2, microRNA-433-3p (miR-433-3p) and glutamic-oxaloacetic transaminase 1 (GOT1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). GOT1 protein expression was determined by western blot analysis. Cell proliferation was illustrated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and cell colony formation assay. Cell apoptosis was demonstrated by flow cytometry analysis. Cell invasion and migration were investigated by transwell invasion and wound-healing assays. Glutamine catabolism was explained by detecting glutamine consumption, alpha ketoglutarate (α-KG) production and glutamate production. In vivo assay was performed to illustrate the impacts of circ-MBOAT2 silencing on tumor formation in vivo. The binding relationship between miR-433-3p and circ-MBOAT2 or GOT1 was predicted by circinteractome or starbase online databases, and identified by dual-luciferase reporter assay. RESULTS Circ-MBOAT2 and GOT1 expression were significantly upregulated, while miR-433-3p expression was downregulated in pancreatic cancer tissues and cells compared with normal pancreatic tissues or cells. Circ-MBOAT2 silencing repressed cell proliferation, migration, invasion and glutamine catabolism, whereas promoted cell apoptosis in pancreatic cancer. Additionally, circ-MBOAT2 acted as a sponge of miR-433-3p, which was found to be associate with GOT1. MiR-433-3p inhibitors hindered circ-MBOAT2 silencing-mediated impacts on pancreatic cancer progression and glutamine catabolism. Furthermore, circ-MBOAT2 silencing repressed tumor formation in vivo. CONCLUSION Circ-MBOAT2 modulated tumor development and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. This finding suggests that circ-MBOAT2 may be a therapeutic target for pancreatic cancer.
Collapse
Affiliation(s)
- Xiaoxiao Zhou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Kun Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Jing Cui
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Jiongxin Xiong
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Tao Peng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China.
| | - Yao Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China.
| |
Collapse
|
36
|
Lin J, Liao S, Liu Z, Li E, Wu X, Zeng W. LncRNA FGD5-AS1 accelerates cell proliferation in pancreatic cancer by regulating miR-520a-3p/KIAA1522 axis. Cancer Biol Ther 2021; 22:257-266. [PMID: 33794727 DOI: 10.1080/15384047.2021.1883184] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In recent years, FGD5 antisense RNA 1 (FGD5-AS1) was confirmed to be the long non-coding RNAs (lncRNAs) that could accelerate the development of multiple cancers. Nevertheless, specific biological functions and latent mechanism of FGD5-AS1 were not yet clear in pancreatic cancer (PC). This research was aimed to search the functions of FGD5-AS1 on the PC progression. The expression of FGD5-AS1 in PC cells was tested by using RT-qPCR assay. Colony formation assay, EdU assay, flow cytometry assay and transwell assay as well as western blot were adopted to test the cell abilities of proliferation, apoptosis and migration, separately. Furthermore, RIP experiment and pull down assay were applied for validating the correlation FGD5-AS1, miR-520a-3p and KIAA1522. As a result, the abnormal high expression of FGD5-AS1 was observed in PC cells. And cell proliferative and migratory abilities could be restrained via FGD5-AS1 depletion. Moreover, FGD5-AS1 was proven to combine with miR-520a-3p directly. It was also confirmed that KIAA1522 could be targeted by miR-520a-3p. Rescue assay results indicated that overexpressed KIAA1522 could reverse the repressive function of silencing FGD5-AS1 on PC progression. Taken together, FGD5-AS1 accelerated cell proliferation and migration via sponging miR-520a-3p and upregulating KIAA1522.
Collapse
Affiliation(s)
- Jing Lin
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou, Shantou, Guangdong, China
| | - Shasha Liao
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
| | - Zewa Liu
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou, Shantou, Guangdong, China
| | - E Li
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
| | - Xiaohua Wu
- Department of Oncology, Shantou Longhu people's Hospital, Shantou, Guangdong, China
| | | |
Collapse
|
37
|
Chen W, Yu J, Xie R, Zhou T, Xiong C, Zhang S, Zhong M. Roles of the SNHG7/microRNA‑9‑5p/DPP4 ceRNA network in the growth and 131I resistance of thyroid carcinoma cells through PI3K/Akt activation. Oncol Rep 2021; 45:3. [PMID: 33649840 PMCID: PMC7877006 DOI: 10.3892/or.2021.7954] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 07/31/2020] [Indexed: 02/01/2023] Open
Abstract
Radioactive iodine (RAI, 131I) therapy is the main treatment for thyroid carcinoma (TC). Long noncoding RNA (lncRNA)/microRNA (miR) competing endogenous RNA (ceRNA) networks have aroused great interest for their roles in gene expression. The present study aimed to investigate the effect of lncRNA SNHG7 on the growth and 131I resistance of TC. Differentially expressed lncRNAs in TC and paracancerous tissues were analyzed. The binding of miR-9-5p with small nucleolar RNA host gene 7 (SNHG7) and dipeptidyl-peptidase 4 (DPP4) was identified. Gain- and loss-of-function analyses of SNHG7 and miR-9-5p were performed to determine their effects on the growth and 131I resistance of TC cells. The activity of the PI3K/Akt pathway was evaluated. Consequently, upregulated SNHG7 was revealed in TC tissues and correlated with 131I resistance. Silencing of SNHG7 or overexpressing miR-9-5p inhibited the growth and 131I resistance of TC cells. SNHG7 acted as a ceRNA of miR-9-5p to enhance DPP4 expression. Overexpressed SNHG7 increased DPP4 expression and activated the PI3K/Akt signaling pathway by sponging miR-9-5p. The in vitro results were reproduced in vivo. In summary, the present study provided evidence that the SNHG7/miR-9-5p/DPP4 ceRNA network could promote the growth and 131I resistance of TC cells via PI3K/Akt activation. The present study may offer novel options for TC treatment.
Collapse
Affiliation(s)
- Wanzhi Chen
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jichun Yu
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Rong Xie
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Tao Zhou
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chengfeng Xiong
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shuyong Zhang
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Meijun Zhong
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| |
Collapse
|
38
|
Ma N, Li X, Wei H, Zhang H, Zhang S. Circular RNA circNFATC3 acts as a miR-9-5p sponge to promote cervical cancer development by upregulating SDC2. Cell Oncol (Dordr) 2021; 44:93-107. [PMID: 32902825 DOI: 10.1007/s13402-020-00555-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 10/23/2022] Open
Abstract
PURPOSE Circular RNAs (circRNAs) constitute a class of regulatory RNAs that are thought to play important roles in tumor initiation and progression. Several studies have reported that circRNAs may be involved in various biological processes via networks of competing endogenous RNAs (ceRNAs). However, the regulatory roles and underlying mechanisms of circRNAs in cervical cancer (CC) still largely remain to be resolved. METHODS CircNFATC3 (hsa_circ_0005615) expression was assessed in CC cell lines (SiHa, H8) using circRNA microarray analysis, whereas qRT-PCR was used to detect circNFATC3 and miR-9-5p expression in primary human CC tissues and cell lines. The tumor promoting role of circNFATC3 was verified in CC cells using a series of functional assays, and interactions between circNFATC3, miR-9-5p and syndecan-2 (SDC2) were investigated using dual-luciferase reporter assays. SDC2 protein expression was detected using Western blotting and immunohistochemistry. The tumor promoting role of circNFATC3 was confirmed in vivo using a CC xenograft model. RESULTS We found that circNFATC3 expression was upregulated in primary CC tissues and positively correlated with CC tumor size and stromal invasion. In addition, we found that exogenous circNFATC3 overexpression enhanced the proliferation, migration and invasion of HeLa cells, while its knockdown reduced the malignancy of SiHa cells. We also found that circNFATC3 may act directly as a miR-9-5p sponge to regulate SDC2 expression and its downstream signaling pathways, thereby enhancing CC development. CONCLUSION Our data indicate that circNFATC3 sponges miR-9-5p to regulate SDC2 expression and, thereby, to promote CC tumor development.
Collapse
Affiliation(s)
- Ningye Ma
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, China
| | - Xinhui Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, China
| | - Heng Wei
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, China
| | - Huijie Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, China
| | - Shulan Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, China.
| |
Collapse
|
39
|
Yu Y, Lai S, Peng X. Long non-coding RNA MCM3AP-AS1 facilitates colorectal cancer progression by regulating the microRNA-599/ARPP19 axis. Oncol Lett 2021; 21:225. [PMID: 33613714 PMCID: PMC7856695 DOI: 10.3892/ol.2021.12486] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most aggressive malignancies worldwide. Increasing evidence has indicated that microRNA (miR)-599 is involved in the occurrence and development of different types of tumors, such as breast cancer and glioma. However, the role of miR-599 in CRC remains unclear. Thus, the present study aimed to identify the regulatory mechanism of miR-599 in CRC progression. Reverse transcription-quantitative PCR was used to analyze the expression levels of MCM3AP-AS1, miR-599 and ARPP19, and Cell Counting Kit-8 and Transwell assays were used to determine the cell proliferation and migration of CRC cells. In addition, a Dual-luciferase reporter assay was used to analyze the direct interaction between miR-599 and MCM3AP-AS1 or ARPP19. Reverse transcription-quantitative PCR analysis demonstrated that miR-599 expression decreased in patients with CRC and in CRC cell lines, while miR-599 overexpression inhibited cell proliferation and migration abilities in vitro. MCM3AP-AS1 was identified as a molecular sponge of miR-599, and further investigation indicated that MCM3AP-AS1 silencing inhibited cell proliferation and migration of the CRC cell lines. In addition, ARPP19 was identified as a target gene of miR-599, and MCM3AP-AS1-knockdown decreased ARPP19 mRNA expression and increased miR-599 expression. Furthermore, silencing ARPP19 inhibited the proliferation and migration of the CRC cell lines. The results also demonstrated that MCM3AP-AS1 promoted CRC cell progression by regulating the miR-599/ARPP19 axis. Taken together, the results of the present study suggest that MCM3AP-AS1 may be a novel therapeutic target for patients with CRC.
Collapse
Affiliation(s)
- You Yu
- Department of General Surgery, The Bishan Hospital of Chongqing, Chongqing 402760, P.R. China
| | - Suhe Lai
- Department of General Surgery, The Bishan Hospital of Chongqing, Chongqing 402760, P.R. China
| | - Xiaochao Peng
- Department of General Surgery, The Bishan Hospital of Chongqing, Chongqing 402760, P.R. China
| |
Collapse
|
40
|
Zhang T, Li M, Lu H, Peng T. Up-Regulation of circEIF6 Contributes to Pancreatic Cancer Development Through Targeting miR-557/ SLC7A11/PI3K/AKT Signaling. Cancer Manag Res 2021; 13:247-258. [PMID: 33469368 PMCID: PMC7811442 DOI: 10.2147/cmar.s280307] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Accruing evidences have pointed out that abnormal expression of circular RNAs (circRNAs) was closely related to the development of many malignancies. The present study intended to disclose the role of circRNA eukaryotic translation initiation factor 6 (circEIF6; hsa_circ_0060055) in pancreatic cancer progression. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circEIF6, EIF6 messenger RNA (mRNA), microRNA-557 (miR-557) and solute carrier family 7 member 11 (SLC7A11) mRNA. Cell proliferation ability, migration and invasion abilities and apoptosis were evaluated by Cell Counting Kit 8 (CCK8) assay, transwell migration and invasion assays and flow cytometry. Western blot assay was performed for the expression determination of all proteins. The predicted interaction between miR-557 and circEIF6 or SLC7A11 was confirmed by dual-luciferase reporter assay. Xenograft tumor model was used for exploring the biological function of circEIF6 in vivo. RESULTS CircEIF6 abundance was aberrantly up-regulated in pancreatic tumor tissues and cell lines. Cell proliferation, migration and invasion were significantly restrained while cell apoptosis was induced with the silencing of circEIF6 in pancreatic cancer cells. CircEIF6 silencing also hampered the activation of phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway. CircEIF6 bound to miR-557, and circEIF6 silencing elevated the expression of miR-557 in pancreatic cancer cells. MiR-557 knockdown partly overturned circEIF6 silencing-induced effects in pancreatic cancer cells. SLC7A11 was a target of miR-557, and miR-557 overexpression suppressed malignant potential of pancreatic cancer cells partly through reducing the expression of SLC7A11. CircEIF6 knockdown blocked xenograft tumor growth in vivo. CONCLUSION CircEIF6 aggravated pancreatic cancer development through promoting cell proliferation, migration and invasion and suppressing cell apoptosis through targeting miR-557/SLC7A11/PI3K/AKT signaling.
Collapse
Affiliation(s)
- Tiequan Zhang
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
- Correspondence: Tiequan Zhang Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, No. 8 Hangkong Road, Shashi District, Jingzhou, Hubei434000, People’s Republic of ChinaTel +86-716-8115036 Email
| | - Mi Li
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
| | - Haofeng Lu
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First People’s Hospital of Jingzhou, Jingzhou434000, People’s Republic of China
| |
Collapse
|
41
|
Zhu X, Han J, Lan H, Lin Q, Wang Y, Sun X. A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC). BMC Cancer 2020; 20:1190. [PMID: 33276753 PMCID: PMC7716498 DOI: 10.1186/s12885-020-07680-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/23/2020] [Indexed: 12/22/2022] Open
Abstract
Background Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated. Methods Cell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3′ untranslated region (3’UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues. Results Here we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo. Conclusions Analysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07680-w.
Collapse
Affiliation(s)
- Xiang Zhu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Jing Han
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Huiyin Lan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Qingren Lin
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Yuezhen Wang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Xiaojiang Sun
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| |
Collapse
|
42
|
Ying M, Feng H, Zhang X, Liu R, Ning H. MiR-9-5p Inhibits the Proliferation, Migration and Invasion of Choroidal Melanoma by Targeting BRAF. Technol Cancer Res Treat 2020; 19:1533033820956987. [PMID: 33138697 PMCID: PMC7645805 DOI: 10.1177/1533033820956987] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objective: According to different reports, miR-9-5p either facilitates or suppresses the
occurrence of tumors. BRAF is a serine/threonine kinase involved in the MAPK
pathway and is a proto-oncogene promoting the progression of many tumors,
especially melanoma. The present study aimed to reveal the mechanism of
action of miR-9-5p and BRAF in choroidal melanoma (CM). Methods: RT-qPCR was used to detect the expression of miR-9-5p in CM cells after
transfection with miR-9-5p mimics and inhibitor. EdU assay and Transwell
assay, respectively, showed the proliferation, migration and invasion of CM
cells after transfection with miR-9-5p mimics and inhibitor. A
bioinformatics website was used for target prediction and the dual
luciferase reporter assay was used to verify the interaction between
miR-9-5p and BRAF. RT-qPCR and Western blot were performed to examine the
expression of BRAF mRNA and protein, respectively. The BRAF protein was
knocked down by siRNAs and then examined by Western blot. The effects of
BRAF in CM cells were investigated by EdU assay and Transwell assay.
Overexpressing BRAF and transfecting miR-9-5p mimics into choroidal melanoma
cells confirmed the interaction between miR-9-5p and BRAF. Results: miR-9-5p could bind to the BRAF mRNA 3’UTR and inhibit the transcription and
translation of BRAF, thereby suppressing the proliferation, migration and
invasion of CM cell lines. Moreover, silencing BRAF inhibited the
progression of CM cells. Conclusions: In conclusion, this study is the first to investigate the association among
BRAF, miR-9-5p and the progression of CM cells. In addition, the interaction
between BRAF and miR-9-5p was explored for the first time in CM. Thus, our
study suggests that miR-9-5p, BRAF and their interaction may act as
potential therapeutic targets for CM.
Collapse
Affiliation(s)
- Manman Ying
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Hao Feng
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaonan Zhang
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Ran Liu
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Hong Ning
- Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| |
Collapse
|
43
|
Wang L, Cui M, Cheng D, Qu F, Yu J, Wei Y, Cheng L, Wu X, Liu X. miR-9-5p facilitates hepatocellular carcinoma cell proliferation, migration and invasion by targeting ESR1. Mol Cell Biochem 2020; 476:575-583. [PMID: 33106914 DOI: 10.1007/s11010-020-03927-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022]
Abstract
The study aimed to explore the relationship between miR-9-5p and ESR1, and clarify the underlying functional mechanism in the occurrence and development of hepatocellular carcinoma (HCC). Expression data including miRNAs and mRNAs of HCC downloaded from TCGA database were processed for differential analysis, and corresponding clinical data were collected for survival analysis to identify the target miRNA miR-9-5p. Bioinformatics databases were applied for predicting downstream target mRNAs of miR-9-5p. qRT-PCR was used to evaluate expression of miR-9-5p. Western blot was used to detect protein expression of ESR1. MTT, wound healing assay and Transwell assay were used to detect HCC cell proliferation, migration and invasion, respectively. Dual-luciferase reporter gene assay was used to identify the targeting relationship between miR-9-5p and ESR1. Research suggested that miR-9-5p was highly expressed in HCC cells but ESR1 was poorly expressed. Overexpression of miR-9-5p could improve the proliferation, invasion and migration of cells. Dual-luciferase reporter assay showed that ESR1 was the downstream target of miR-9-5p in HCC. Overexpression of miR-9-5p markedly reduced ESR1 mRNA and protein levels in HCC cells, whereas inhibition of miR-9-5p expression produced the contrary results. Silencing ESR1 could noticeably reverse the effect of miR-9-5p knockdown on the proliferation, migration and invasion of HCC cells. As an oncogene, miR-9-5p fostered the proliferation, migration and invasion of HCC cells by targeting and inhibiting ESR1 expression.
Collapse
Affiliation(s)
- Libing Wang
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China
| | - Mingxin Cui
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China
| | - Daming Cheng
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China
| | - Fengzhi Qu
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China
| | - Jingkun Yu
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China
| | - Yanbin Wei
- Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, 200231, China
| | - Ling Cheng
- Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, 200231, China
| | - Xiaotang Wu
- Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, 200231, China
| | - Xiaogang Liu
- Department of Hepatobiliary Surgery, Tangshan Gongren Hospital, No. 27 Cultural Road, Lubei District, Tangshan, 063000, Hebei, China.
| |
Collapse
|
44
|
Xu R, Yang J, Ren B, Wang H, Yang G, Chen Y, You L, Zhao Y. Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies. Front Oncol 2020; 10:572722. [PMID: 33117704 PMCID: PMC7550743 DOI: 10.3389/fonc.2020.572722] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/31/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.
Collapse
Affiliation(s)
- Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jinshou Yang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
45
|
Hipólito A, Nunes SC, Vicente JB, Serpa J. Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer. Molecules 2020; 25:molecules25173984. [PMID: 32882966 PMCID: PMC7504796 DOI: 10.3390/molecules25173984] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/26/2020] [Accepted: 08/29/2020] [Indexed: 12/16/2022] Open
Abstract
Metabolic remodeling is a critical skill of malignant cells, allowing their survival and spread. The metabolic dynamics and adaptation capacity of cancer cells allow them to escape from damaging stimuli, including breakage or cross-links in DNA strands and increased reactive oxygen species (ROS) levels, promoting resistance to currently available therapies, such as alkylating or oxidative agents. Therefore, it is essential to understand how metabolic pathways and the corresponding enzymatic systems can impact on tumor behavior. Cysteine aminotransferase (CAT) per se, as well as a component of the CAT: 3-mercaptopyruvate sulfurtransferase (MST) axis, is pivotal for this metabolic rewiring, constituting a central mechanism in amino acid metabolism and fulfilling the metabolic needs of cancer cells, thereby supplying other different pathways. In this review, we explore the current state-of-art on CAT function and its role on cancer cell metabolic rewiring as MST partner, and its relevance in cancer cells' fitness.
Collapse
Affiliation(s)
- Ana Hipólito
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Sofia C. Nunes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - João B. Vicente
- Institute of Technology, Chemistry and Biology António Xavier (ITQB NOVA), Avenida da República (EAN), 2780-157 Oeiras, Portugal
- Correspondence: (J.B.V.); (J.S.)
| | - Jacinta Serpa
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
- Correspondence: (J.B.V.); (J.S.)
| |
Collapse
|
46
|
Zhou L, Zhang Z, Huang Z, Nice E, Zou B, Huang C. Revisiting cancer hallmarks: insights from the interplay between oxidative stress and non-coding RNAs. MOLECULAR BIOMEDICINE 2020; 1:4. [PMID: 35006436 PMCID: PMC8603983 DOI: 10.1186/s43556-020-00004-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/21/2020] [Indexed: 02/08/2023] Open
Abstract
Cancer is one of the most common disease worldwide, with complex changes and certain traits which have been described as “The Hallmarks of Cancer.” Despite increasing studies on in-depth investigation of these hallmarks, the molecular mechanisms associated with tumorigenesis have still not yet been fully defined. Recently, accumulating evidence supports the observation that microRNAs and long noncoding RNAs (lncRNAs), two main classes of noncoding RNAs (ncRNAs), regulate most cancer hallmarks through their binding with DNA, RNA or proteins, or encoding small peptides. Reactive oxygen species (ROS), the byproducts generated during metabolic processes, are known to regulate every step of tumorigenesis by acting as second messengers in cancer cells. The disturbance in ROS homeostasis leads to a specific pathological state termed “oxidative stress”, which plays essential roles in regulation of cancer progression. In addition, the interplay between oxidative stress and ncRNAs is found to regulate the expression of multiple genes and the activation of several signaling pathways involved in cancer hallmarks, revealing a potential mechanistic relationship involving ncRNAs, oxidative stress and cancer. In this review, we provide evidence that shows the essential role of ncRNAs and the interplay between oxidative stress and ncRNAs in regulating cancer hallmarks, which may expand our understanding of ncRNAs in the cancer development from the new perspective.
Collapse
Affiliation(s)
- Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China
| | - Edouard Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia
| | - Bingwen Zou
- Department of Thoracic Oncology and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China. .,School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P.R. China.
| |
Collapse
|
47
|
Mi S, Du J, Liu J, Hou K, Ji H, Ma S, Ba Y, Chen L, Xie R, Hu S. FtMt promotes glioma tumorigenesis and angiogenesis via lncRNA SNHG1/miR-9-5p axis. Cell Signal 2020; 75:109749. [PMID: 32858123 DOI: 10.1016/j.cellsig.2020.109749] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/08/2020] [Accepted: 08/19/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE This study is to investigate the effects and the mechanisms of mitochondrial ferritin (FtMt) on the glioma tumorigenesis and angiogenesis. METHODS FtMt expression was detected in glioma tissues and cells as well as in nude mouse tissues. Cell proliferation and apoptosis rate were observed following transfection of LV-FtMt or sh-FtMt in glioma cell line. Moreover, glioma cells with FtMt over-expression/knockdown were co-cultured with human umbilical vein endothelial cells (HUVECs) to observe its function on HUVEC proliferation, angiogenic ability and the vascular endothelial growth factor (VEGF) content. Gain and loss of function of small nucleolar RNA host gene 1 (SNHG1) and miR-9-5p were performed in glioma cells and GBM nude mice to observe its effect on glioma cell proliferation and HUVEC angiogenic ability. Luciferase reporter gene and RIP assay were employed to inspect the interactions among SNHG1, FtMt and miR-9-5p. Additionally, a xenograft mouse model was applied to determine the role of FtMt in glioma. RESULTS In this work, FtMt was strongly expressed in glioma tissues and cells as well as in nude mouse tumor tissues. The employment of the loss-of and gain-of functions assays illustrated that FtMt enhanced glioma tumorigenesis and angiogenesis. Mechanistically, our findings showed that FtMt positively related to SNHG1 while negatively correlated with miR-9-5p, and both SNHG1 and FtMt can competitively bind with miR-9-5p. Besides, the inhibition effects of sh-FtMt on glioma were surveyed in vivo experiments. CONCLUSION Evidence in this study suggested that FtMt promotes glioma tumorigenesis and angiogenesis via SNHG1 mediated miR-9-5p expression, which may provide a theoretical basis for glioma treatment.
Collapse
Affiliation(s)
- Shan Mi
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Jianyang Du
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Jie Liu
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Kuiyuan Hou
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Hang Ji
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Shuai Ma
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Yixu Ba
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China
| | - Lei Chen
- Northern Translational Medical Research and Cooperation Center, Heilongjiang Academy of Medical University, Harbin, Heilongjiang 150081, China.
| | - Rui Xie
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
| | - Shaoshan Hu
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
| |
Collapse
|
48
|
Zhao X, Weng W, Long Y, Pan W, Li Z, Sun F. LINC00665/miR-9-5p/ATF1 is a novel axis involved in the progression of colorectal cancer. Hum Cell 2020; 33:1142-1154. [PMID: 32776307 DOI: 10.1007/s13577-020-00393-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/17/2020] [Indexed: 02/08/2023]
Abstract
Long noncoding RNAs (lncRNAs) are abnormally expressed in many malignant tumors and involved in regulating the malignant phenotypes of cancer cells. However, the role of LINC00665 in colorectal cancer (CRC) and its regulatory mechanism remain unclear. In this study, real-time polymerase chain reaction (RT-PCR) was used to detect the expressions of LINC00665, miR-9-5p and activating transcription factor 1 (ATF1) mRNA in CRC tissues. The expression of ATF1 in CRC tissues was also detected by immunohistochemistry and Western blot. CCK-8 and colony formation assays were employed to detect cell proliferation. Cell cycle and apoptosis were detected by flow cytometry analysis. Scratch healing assay and Transwell test were exploited to detect cell migration and invasion. The targeting relationships between LINC00665 and miR-9-5p, and miR-9-5p and ATF1 were validated by dual luciferase reporter assay. We found that LINC00665 was significantly overexpressed in CRC tissues, and it was also negatively correlated with the expression of miR-9-5p and positively associated with the expression of ATF1. Besides, LINC00665 promoted the proliferation, migration and invasion of CRC cells, and inhibited cell apoptosis by sponging miR-9-5p. ATF1 was proved to be the downstream target of miR-9-5p and was indirectly regulated by LINC00665. Collectively, it is concluded that LINC00665 contributes to the progression of CRC by regulating miR-9-5p/ATF1 axis.
Collapse
Affiliation(s)
- Xuhong Zhao
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, People's Republic of China
| | - Wenhao Weng
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, People's Republic of China
| | - Yin Long
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, People's Republic of China
| | - Weijie Pan
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, People's Republic of China
| | - Zhi Li
- Department of Clinical Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, People's Republic of China.
| | - Fenyong Sun
- Department of Clinical Laboratory, Shanghai 10th People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China.
| |
Collapse
|
49
|
Zhen J, Zhang H, Dong H, Tong X. miR-9-3p inhibits glioma cell proliferation and apoptosis by directly targeting FOXG1. Oncol Lett 2020; 20:2007-2015. [PMID: 32724447 DOI: 10.3892/ol.2020.11725] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 02/11/2020] [Indexed: 01/30/2023] Open
Abstract
There is accumulating evidence indicating that microRNA (miR)-9-3p expression is abnormal in patients with glioma; however, the role of miR-9-3p in glioma remains unclear. In the present study, reverse transcription-quantitative PCR and immunohistochemical assays were conducted to assess miR-9-3p and forkhead box G1 (FOXG1) expression, respectively. A luciferase reporter assay was performed to confirm the target of miR-9-3p. Moreover, cell counting kit-8 and flow cytometry assays were used to assess proliferation and apoptosis, respectively. The present study demonstrated that miR-9-3p is significantly downregulated, and FOXG1 is significantly upregulated, in patients with glioma. miR-9-3p overexpression inhibited proliferation and increased the apoptosis of both U87MG and TG-905 cells. In addition, FOXG1 was identified as a direct target of miR-9-3p, and FOXG1 silencing enhanced the inhibitory effect of miR-9-3p on proliferation and apoptosis in U87 MG and TG-905 cells. In conclusion, the present results suggest that miR-9-3p may suppress malignant biological properties by targeting FOXG1. Thus, miR-9-3p may serve as a diagnostic target and novel prognostic marker in patients with glioma.
Collapse
Affiliation(s)
- Jianwen Zhen
- Department of Cardio-cerebrovascular Diseases, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi 712082, P.R. China
| | - Hengxun Zhang
- Department of Cardio-cerebrovascular Diseases, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi 712082, P.R. China
| | - Hongzhi Dong
- Department of Cardio-cerebrovascular Diseases, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi 712082, P.R. China
| | - Xiaopeng Tong
- Department of Cardio-cerebrovascular Diseases, The Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi 712082, P.R. China
| |
Collapse
|
50
|
Zheng C, Zhang T, Li D, Huang C, Tang H, Ni XF, Chen B. Upregulation of CENPM facilitates tumor metastasis via the mTOR/p70S6K signaling pathway in pancreatic cancer. Oncol Rep 2020; 44:1003-1012. [PMID: 32705259 PMCID: PMC7388243 DOI: 10.3892/or.2020.7673] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 06/05/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is a severe disease with high morbidity and mortality. However, the primary molecular mechanisms of pancreatic tumor formation and progression remain unclear. The present study using sequencing technology revealed that the centromere protein M (CENPM) gene was overexpressed in pancreatic cancer tissues. CENPM is one of the components of a complex that plays a central role in kinetochore protein assembly, mitotic progression and chromosome segregation. However, the biological function of CENPM in pancreatic cancer has yet to be determined. Hence, two effective siRNAs were designed to knock down CENPM. Notably, downregulation of CENPM inhibited pancreatic cancer cell proliferation, altered the cell cycle and limited pancreatic cancer cell migration and invasion via the mTOR/p70S6K signaling pathway. This research provides new evidence that CENPM overexpression plays a significant role in the progression of pancreatic cancer. Overall, the present findings indicated that CENPM may be a significant biomarker for predicting the development and progression of pancreatic malignancy.
Collapse
Affiliation(s)
- Chenlei Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Tan Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ding Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chongchu Huang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Hengjie Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiao-Feng Ni
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| |
Collapse
|