|
1
|
Wu C, Gao Y, Jin Z, Huang Z, Wang H, Lu S, Guo S, Zhang F, Zhang J, Huang J, Tao X, Liu X, Zhang X, You L, Li Q, Wu J. PTPRG-AS1 regulates the KITLG/KIT pathway through the ceRNA axis to promote the malignant progression of gastric cancer and the intervention effect of Compound Kushen injection on it. Pharmacol Res 2025; 215:107743. [PMID: 40250508 DOI: 10.1016/j.phrs.2025.107743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 04/20/2025]
Abstract
Gastric cancer (GC) is a common malignant tumor with high mortality, recurrence, and metastasis rates. Compound Kushen injection (CKI) combination chemotherapy has been clinically used for the treatment of GC in China for many years, but its underlying mechanisms of action remain unclear. Recent reports have highlighted the important role of the competing endogenous RNA (ceRNA) mechanism of noncoding RNA (ncRNA) and messenger RNA (mRNA) formation in GC and other tumors. This study aimed to investigate the effects of CKI on GC from the ceRNA perspective. We confirmed the inhibitory effect of CKI on GC in mouse models and cell lines. By examining the GC cell lines sensitive to CKI treatment, we developed the CNScore method to analyze the ceRNA network, revealing that the CKI-GC ceRNA network promotes GC proliferation and metastasis through the PTPRG-AS1/hsa-miR-421/KITLG axis. Finally, we constructed GC cell models with PTPRG-AS1 overexpression or knockdown and GC liver metastasis models and found that PTPRG-AS1 can sponge hsa-miR-421, releasing KITLG and promoting GC proliferation and metastasis through the KITLG/KIT pathway. Taken together, CKI can suppress these malignant phenotypes by regulating the PTPRG-AS1/hsa-miR-421/KITLG axis.
Collapse
Affiliation(s)
- Chao Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Yifei Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhengsen Jin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhihong Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Haojia Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shan Lu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Siyu Guo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Fanqin Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jingyuan Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jiaqi Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaoyu Tao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xinkui Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China; Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Xiaomeng Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Leiming You
- School of Life Science, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang Province 310022, China.
| | - Jiarui Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| |
Collapse
|
|
2
|
Huang Y, Wang X, Liu H, Meng X, Yin H, Hou R, Lin W, Zhang X, Ma J, Zhang X, Zhang F, Miao Y. Knocking Down HN1 Blocks Helicobacter pylori-Induced Malignant Phenotypes in Gastric Mucosal Cells and Inhibits Gastric Cancer Cell Proliferation, Cytoskeleton Remodeling, and Migration. Biochem Genet 2025; 63:875-895. [PMID: 38526710 DOI: 10.1007/s10528-024-10731-7] [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: 11/14/2023] [Accepted: 02/02/2024] [Indexed: 03/27/2024]
Abstract
Helicobacter pylori (H. pylori) is implicated in the aberrant proliferation and malignant transformation of gastric mucosal cells, heightening the risk of gastric cancer (GC). HN1 is involved in the development of various tumors. However, precise mechanistic underpinnings of HN1 promoting GC progression in H. pylori remain elusive. The study collected 79 tissue samples of GC patients, including 47 with H. pylori-positive GC and 32 H. pylori-negative controls. Using human gastric epithelial cells (GES-1) and human gastric adenocarcinoma cells (HGC-27), the effect of overexpression / knocking down of HN1 and H. pylori infection was evaluated on cell function (proliferation, migration, apoptosis), cytoskeleton, and expression of cell malignant phenotype factors that promote the malignant biological behavior of cancer cells. The expression of HN1 in GC tissues is higher than that in paracancerous tissue and is closely related to infiltration, lymphatic metastasis, distant metastasis, survival, and H. pylori infection. Downregulation of HN1 effectively hinders the ability of H. pylori strains 26695 and SS1 to promote migration of GES-1 and HGC-27 cells, while lowering the expression of key indicators associated with malignant phenotype. Downregulated GSK3B, β-catenin, and Vimentin after knockdown Integrinβ1, but HN1 expression remained largely unchanged, when HN1 and Integrinβ1 were knocked down, GSK3B, β-catenin, and Vimentin expression were considerably reduced. Our research demonstrated the crucial role of HN1 in H. pylori-induced acquisition of a malignant phenotype in GES-1 cells. Knockdown of HN1 blocked the pathogenic mechanism of H. pylori-induced GC and downregulated the expression of GSK3Β, β-catenin and Vimentin via Integrin β1.
Collapse
Affiliation(s)
- Ying Huang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Xiaofei Wang
- Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, 063000, Hebie Province, China
| | - Hao Liu
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Xiangkun Meng
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Hua Yin
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Ruirui Hou
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Wan Lin
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Xu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Jun Ma
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Xiaoxu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Feixiong Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China
| | - Yu Miao
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Hui Autonomous Region, 804 Shengli South Street, Xingqing District, Yinchuan, 750004, Ningxia, China.
| |
Collapse
|
|
3
|
Hu M, Zhang Y, Zhang P, Liu K, Zhang M, Li L, Yu Z, Zhang X, Zhang W, Xu Y. Targeting APE1: Advancements in the Diagnosis and Treatment of Tumors. Protein Pept Lett 2025; 32:18-33. [PMID: 39648425 DOI: 10.2174/0109298665338519241114103223] [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: 07/11/2024] [Revised: 10/07/2024] [Accepted: 10/16/2024] [Indexed: 12/10/2024]
Abstract
With the emergence of the precision medicine era, targeting specific proteins has emerged as a pivotal breakthrough in tumor diagnosis and treatment. Apurinic/apyrimidinic Endonuclease 1 (APE1) is a multifunctional protein that plays a crucial role in DNA repair and cellular redox regulation. This article comprehensively explores the fundamental mechanisms of APE1 as a multifunctional enzyme in biology, with particular emphasis on its potential significance in disease diagnosis and strategies for tumor treatment. Firstly, this article meticulously analyzes the intricate biological functions of APE1 at a molecular level, establishing a solid theoretical foundation for subsequent research endeavors. In terms of diagnostic applications, the presence of APE1 can be detected in patient serum samples, biopsy tissues, and through cellular in situ testing. The precise detection methods enable changes in APE1 levels to serve as reliable biomarkers for predicting tumor occurrence, progression, and patient prognosis. Moreover, this article focuses on elucidating the potential role of APE1 in tumor treatment by exploring various inhibitors, including nucleic acid-based inhibitors and small molecule drug inhibitors categories, and revealing their unique advantages in disrupting DNA repair function and modulating oxidative-reduction activity. Finally, the article provides an outlook on future research directions for APE1 while acknowledging major technical difficulties and clinical challenges that need to be overcome despite its immense potential as a target for tumor therapy.
Collapse
Affiliation(s)
- Minghui Hu
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Yingyu Zhang
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pin Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Kangbo Liu
- Henan Institute for Drug and Medical Device Inspection (Henan Vaccine Issuance Center), Zhengzhou, 450018, China
| | - Mengxin Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Lifeng Li
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Zhidan Yu
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Xianwei Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Wancun Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Ying Xu
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| |
Collapse
|
|
4
|
Kuang W, Xu J, Xu F, Huang W, Majid M, Shi H, Yuan X, Ruan Y, Hu X. Current study of pathogenetic mechanisms and therapeutics of chronic atrophic gastritis: a comprehensive review. Front Cell Dev Biol 2024; 12:1513426. [PMID: 39720008 PMCID: PMC11666564 DOI: 10.3389/fcell.2024.1513426] [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: 10/18/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Chronic atrophic gastritis (CAG) is a prevalent digestive system disease characterized by atrophy of the gastric mucosa and the disappearance of inherent gastric glands. According to the theory of Correa's cascade, CAG is an important pathological stage in the transformation from normal condition to gastric carcinoma. In recent years, the global incidence of CAG has been increasing due to pathogenic factors, including Helicobacter pylori infection, bile reflux, and the consumption of processed meats. In this review, we comprehensively described the etiology and clinical diagnosis of CAG. We focused on elucidating the regulatory mechanisms and promising therapeutic targets in CAG, with the expectation of providing insights and theoretical support for future research on CAG.
Collapse
Affiliation(s)
- Weihong Kuang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Jialin Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Fenting Xu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Weizhen Huang
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Muhammad Majid
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Hui Shi
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
| | - Xia Yuan
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Cancer Center, The First Huizhou Affiliated Hospital, Guangdong Medical University, Huizhou, China
| | - Xianjing Hu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Traditional Chinese Medicines for Prevention and Treatment of Digestive Diseases, Guangdong Medical University, Dongguan, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Department of Acupuncture, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| |
Collapse
|
|
5
|
Li Y, Liu J, Wu S, Xiao J, Zhang Z. Ferroptosis: opening up potential targets for gastric cancer treatment. Mol Cell Biochem 2024; 479:2863-2874. [PMID: 38082184 DOI: 10.1007/s11010-023-04886-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/24/2023] [Indexed: 10/15/2024]
Abstract
The fifth most frequent cancer in the world is gastric cancer. It ranks as the fourth most common reason for cancer-related deaths. Even though surgery is the only curative treatment for stomach cancer, adding adjuvant radiotherapy and chemotherapy is preferable than only surgery. The majority of patients, however, are discovered to be extremely tardy the first time and have a terrible prognosis. Therefore, it is necessary to create more viable therapy modalities. A growing number of studies in recent years have shown that ferroptosis and many cancer types are related. This gives our treatment a fresh viewpoint. We investigated the relationship between different signal pathways and non-coding RNA on ferroptosis in gastric cancer cells. Also discussed the targets cause ferroptosis resistance increased or reduced to the influence of the chemoresistance,proliferation and metastasis.
Collapse
Affiliation(s)
- Yuwei Li
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China
| | - Jiangrong Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China
| | - Shihua Wu
- Department of Pathology, The Second Affiliated Hospital, Shaoyang University, Shaoyang, 422000, Hunan, China
| | - Juan Xiao
- Department of Head and Neck Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhiwei Zhang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China.
| |
Collapse
|
|
6
|
Malfatti MC, Bellina A, Antoniali G, Tell G. Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons. Cells 2023; 12:1895. [PMID: 37508559 PMCID: PMC10378182 DOI: 10.3390/cells12141895] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/06/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.
Collapse
Affiliation(s)
- Matilde Clarissa Malfatti
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Alessia Bellina
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Giulia Antoniali
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| |
Collapse
|
|
7
|
Al-Mohammed Amin YMI, Faisal Hatem Al-Mugdadi S, Mahmood Mohammed M. Levels of APE1 Repair Gene and CLEC4M in Lung Cancer Patients Receiving Cisplatin Chemotherapy. ARCHIVES OF RAZI INSTITUTE 2023; 78:963-972. [PMID: 38028841 PMCID: PMC10657964 DOI: 10.22092/ari.2022.360397.2578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 12/01/2023]
Abstract
This study aimed to detect the levels of apurinic/apyrimidinic endonuclease 1 (APE1) gene expression and C-type lectin domain family 4 member M (CLEC4M) and their association with cisplatin chemotherapy in lung cancer patients. Overall, 105 individuals who attended the Al-Amal National Hospital for Cancer Management, Baghdad, Iraq, were enrolled in the study and divided into three equal groups. The groups included the patients newly diagnosed with lung cancer, cancer patients who received cisplatin, and the healthy control group. All study groups were subjected to the sampling of the venous blood for molecular analysis by real-time polymerase chain reaction (RT-PCR) to detect the APE1 gene and enzyme-linked immunosorbent assay (ELISA) for serological testing to measure the concentration of CLEC4M protein. Significantly, the values of both cancer groups were higher than those reported in the control group. The relative index revealed a significant difference in the mean fold change level of APE1 in the newly diagnosed group (3 fold) and cisplatin therapy patients group (2 fold), compared to the control group (P=0.005). No significant differences were detected between the two cancer groups in terms of fold change mean of expression, demographic characteristics, and cancer histological type. Regarding human CLEC4M protein level, cases receiving cisplatin (139.2±25.9) and newly diagnosed patients (331.0±38.1) had a highly significant difference with the control group (100.3±47.5, P<0.001). There was no significant difference between the concentration level of CLEC4M and all parameters in demographic characteristics and cancer histological type. This was the first study to demonstrate that higher expression levels of new APE1, CLEC4M, and glutathione, especially after chemotherapy, are beneficial as diagnostic and prognostic markers for resistance to platinum chemotherapy in Iraqi lung cancer patients.
Collapse
Affiliation(s)
- Y M I Al-Mohammed Amin
- Department of Clinical Laboratory Sciences, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
| | - S Faisal Hatem Al-Mugdadi
- Department of Clinical Laboratory Sciences, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
| | - M Mahmood Mohammed
- Department of Clinical Pharmacy , College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
| |
Collapse
|
|
8
|
Zhao H, Ding Y, Zhang L. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis. Open Med (Wars) 2023; 18:20220620. [PMID: 36820068 PMCID: PMC9938643 DOI: 10.1515/med-2022-0620] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 02/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with high mortality. Sirtuin 1 (SIRT1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) are abnormally expressed in GC cells and related to p53, which is involved in ferroptosis. Thus, we explore the mechanism via which SIRT1, APE1, and p53 impact ferroptosis in GC cells. Specifically, GC cells were transfected with small-interfering RNA for SIRT1 (SiSIRT1) or small-interfering RNA for APE1 (SiAPE1) or with short-hairpin RNA for p53, and the cell viability, Fe2+, malondialdehyde (MDA), and glutathione (GSH) contents were detected by cell counting kit-8 assay and enzyme-linked immunosorbent assay. Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were conducted to quantify SIRT1, APE1, p53, solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) levels in GC cells. Silencing of SIRT1 decreased viability, GSH content, and expressions of GPX4 and SLC7A11, while increased Fe2+, MDA content, and p53 expression in GC cells. Such aforementioned effects were reversed by APE1 overexpression. Also, SiAPE1 generated the same effects as SiSIRT1 on the above aspects, which was offset by p53 silencing. In short, SIRT1/APE1 promotes the growth of GC cells by targeting p53 to inhibit ferroptosis.
Collapse
Affiliation(s)
- Huijin Zhao
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Yuanyi Ding
- Department of No. 2 General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Lan Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| |
Collapse
|
|
9
|
Usman M, Beilerli A, Sufianov A, Kudryashov V, Ilyasova T, Balaev P, Danilov A, Lu H, Gareev I. Investigations into the impact of non-coding RNA on the sensitivity of gastric cancer to radiotherapy. Front Physiol 2023; 14:1149821. [PMID: 36909247 PMCID: PMC9998927 DOI: 10.3389/fphys.2023.1149821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/16/2023] [Indexed: 02/26/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a newly discovered functional RNA different from messenger RNA, which can participate in regulating the occurrence and development of tumors. More and more research results show that ncRNAs can participate in the regulation of gastric cancer (GC) radiotherapy response, and its mechanism may be related to its effect on DNA damage repair, gastric cancer cell stemness, cell apoptosis, activation of epidermal growth factor receptor signaling pathway, etc. This article summarizes the relevant mechanisms of ncRNAs regulating the response to radiotherapy in gastric cancer, which will be directly important for the introduction of ncRNAs particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) into clinical medicine as biomarkers and therapeutic targets.
Collapse
Affiliation(s)
- Muhammad Usman
- Department of Medical Imaging, Central Hospital Affiliated to Chongqing University of Technology, Chongqing, China
| | - Aferin Beilerli
- Department of Obstetrics and Gynecology, Tyumen State Medical University, Tyumen, Russia
| | - Albert Sufianov
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.,Department of Internal Diseases, Bashkir State Medical University, Ufa, Russia
| | - Valentin Kudryashov
- Gastric Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Tatiana Ilyasova
- Department of Internal Diseases, Bashkir State Medical University, Ufa, Russia
| | - Pavel Balaev
- Department of Oncology and Radiology, Ural State Medical University, Yekaterinburg, Russia
| | - Andrei Danilov
- Department of Clinical Pharmacology, Smolensk State Medical University, Smolensk, Russia
| | - Hong Lu
- Department of Medical Imaging, Central Hospital Affiliated to Chongqing University of Technology, Chongqing, China
| | - Ilgiz Gareev
- Educational and Scientific Institute of Neurosurgery, Рeoples' Friendship University of Russia (RUDN University), Moscow, Russia
| |
Collapse
|
|
10
|
Li J, Zhao H, McMahon A, Yan S. APE1 assembles biomolecular condensates to promote the ATR-Chk1 DNA damage response in nucleolus. Nucleic Acids Res 2022; 50:10503-10525. [PMID: 36200829 PMCID: PMC9561277 DOI: 10.1093/nar/gkac853] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 09/14/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Multifunctional protein APE1/APEX1/HAP1/Ref-1 (designated as APE1) plays important roles in nuclease-mediated DNA repair and redox regulation in transcription. However, it is unclear how APE1 regulates the DNA damage response (DDR) pathways. Here we show that siRNA-mediated APE1-knockdown or APE1 inhibitor treatment attenuates the ATR–Chk1 DDR under stress conditions in multiple immortalized cell lines. Congruently, APE1 overexpression (APE1-OE) activates the ATR DDR under unperturbed conditions, which is independent of APE1 nuclease and redox functions. Structural and functional analysis reveals a direct requirement of the extreme N-terminal motif within APE1 in the assembly of distinct biomolecular condensates in vitro and DNA/RNA-independent activation of the ATR DDR. Overexpressed APE1 co-localizes with nucleolar NPM1 and assembles biomolecular condensates in nucleoli in cancer but not non-malignant cells, which recruits ATR and activator molecules TopBP1 and ETAA1. APE1 protein can directly activate ATR to phosphorylate its substrate Chk1 in in vitro kinase assays. W119R mutant of APE1 is deficient in nucleolar condensation, and is incapable of activating nucleolar ATR DDR in cells and ATR kinase in vitro. APE1-OE-induced nucleolar ATR DDR activation leads to compromised ribosomal RNA transcription and reduced cell viability. Taken together, we propose distinct mechanisms by which APE1 regulates ATR DDR pathways.
Collapse
Affiliation(s)
- Jia Li
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
| | - Haichao Zhao
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
| | - Anne McMahon
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
| | - Shan Yan
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.,School of Data Science, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.,Center for Biomedical Engineering and Science, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
| |
Collapse
|
|
11
|
Rossi AFT, da Silva Manoel-Caetano F, Biselli JM, Cabral ÁS, Saiki MDFC, Ribeiro ML, Silva AE. Downregulation of TNFR2 decreases survival gene expression, promotes apoptosis and affects the cell cycle of gastric cancer cells. World J Gastroenterol 2022; 28:2689-2704. [PMID: 35979166 PMCID: PMC9260869 DOI: 10.3748/wjg.v28.i24.2689] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/21/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic inflammation due to Helicobacter pylori (H. pylori) infection promotes gastric carcinogenesis. Tumour necrosis factor-α (TNF-α), a key mediator of inflammation, induces cell survival or apoptosis by binding to two receptors (TNFR1 and TNFR2). TNFR1 can induce both survival and apoptosis, while TNFR2 results only in cell survival. The dysregulation of these processes may contribute to carcinogenesis.
AIM To evaluate the effects of TNFR1 and TNFR2 downregulation in AGS cells treated with H. pylori extract on the TNF-α pathway.
METHODS AGS cell lines containing TNFR1 and TNFR2 receptors downregulated by specific shRNAs and nonsilenced AGS cells were treated with H. pylori extract for 6 h. Subsequently, quantitative polymerase chain reaction with TaqMan® assays was used for the relative quantification of the mRNAs (TNFA, TNFR1, TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3) and miRNAs (miR-19a, miR-34a, miR-103a, miR-130a, miR-181c) related to the TNF-α signalling pathway. Flow cytometry was employed for cell cycle analysis and apoptosis assays.
RESULTS In nonsilenced AGS cells, H. pylori extract treatment increased the expression of genes involved in cell survival and inhibited both apoptosis (NFKB1, NFKB2 and CFLIP) and the TNFR1 receptor. TNFR1 downregulation significantly decreased the expression of the TRADD and CFLIP genes, although no change was observed in the cellular process or miRNA expression. In contrast, TNFR2 downregulation decreased the expression of the TRADD and TRAF2 genes, which are both important downstream mediators of the TNFR1-mediated pathway, as well as that of the NFKB1 and CFLIP genes, while upregulating the expression of miR-19a and miR-34a. Consequently, a reduction in the number of cells in the G0/G1 phase and an increase in the number of cells in the S phase were observed, as well as the promotion of early apoptosis.
CONCLUSION Our findings mainly highlight the important role of TNFR2 in the TNF-α pathway in gastric cancer, indicating that silencing it can reduce the expression of survival and anti-apoptotic genes.
Collapse
Affiliation(s)
- Ana Flávia Teixeira Rossi
- Department of Biological Sciences, Sao Paulo State University (UNESP), São José do Rio Preto 15054-000, São Paulo, Brazil
| | | | - Joice Matos Biselli
- Department of Biological Sciences, Sao Paulo State University (UNESP), São José do Rio Preto 15054-000, São Paulo, Brazil
| | - Ágata Silva Cabral
- Department of Biological Sciences, Sao Paulo State University (UNESP), São José do Rio Preto 15054-000, São Paulo, Brazil
| | | | - Marcelo Lima Ribeiro
- Clinical Pharmacology and Gastroenterology Unit, São Francisco University (USF), Bragança Paulista 12916-900, São Paulo, Brazil
| | - Ana Elizabete Silva
- Department of Biological Sciences, Sao Paulo State University (UNESP), São José do Rio Preto 15054-000, São Paulo, Brazil
| |
Collapse
|
|
12
|
Yang Y, Zhou L, Gou X, Wu G, Zheng Y, Liu M, Chen Z, Wang Y, Ji R, Guo Q, Zhou Y. Comprehensive analysis to identify DNA damage response-related lncRNA pairs as a prognostic and therapeutic biomarker in gastric cancer. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:595-611. [PMID: 34903003 DOI: 10.3934/mbe.2022026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
OBJECTIVE Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide. The identification of valuable predictive signatures to improve the prognosis of patients with GC is becoming a realistic prospect. DNA damage response-related long noncoding ribonucleic acids (drlncRNAs) play an important role in the development of cancers. However, their prognostic and therapeutic values remain sparse in gastric cancer (GC). METHODS We obtained the transcriptome data and clinical information from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort. Co-expression network analyses were performed to discover functional modules using the igaph package. Subsequently, lncRNA pairs were identified by bioinformation analysis, and prognostic pairs were determined by univariate analysis, respectively. In addition, we utilized least absolute shrinkage and selection operator (LASSO) cox regression analysis to construct the risk model based on lncRNA pairs. Then, we distinguished between the high- or low- risk groups from patients with GC based on the optimal model. Finally, we reevaluated the association between risk score and overall survival, tumor immune microenvironment, specific tumor-infiltrating immune cells related biomarkers, and the sensitivity of chemotherapeutic agents. RESULTS 32 drlncRNA pairs were obtained, and a 17-drlncRNA pairs signature was constructed to predict the overall survival of patients with GC. The ROC was 0.797, 0.812 and 0.821 at 1, 2, 3 years, respectively. After reclassifying these patients into different risk-groups, we could differentiate between them based on negative overall survival outcome, specialized tumor immune infiltration status, higher expressed immune cell related biomarkers, and a lower chemotherapeutics sensitivity. Compared with previous models, our model showed better performance with a higher ROC value. CONCLUSION The prognostic and therapeutic signature established by novel lncRNA pairs could provide promising prediction value, and guide individual treatment strategies in the future.
Collapse
Affiliation(s)
- Yuan Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Lingshan Zhou
- Department of Geriatrics Ward 2, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Xi Gou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Guozhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Min Liu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Zhaofeng Chen
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Rui Ji
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Qinghong Guo
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China
- Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou 730000, China
| |
Collapse
|
|
13
|
Liu D, Cheng Y, Tang Z, Mei X, Cao X, Liu J. Toxicity mechanism of acrolein on DNA damage and apoptosis in BEAS-2B cells: Insights from cell biology and molecular docking analyses. Toxicology 2021; 466:153083. [PMID: 34958888 DOI: 10.1016/j.tox.2021.153083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/16/2021] [Accepted: 12/23/2021] [Indexed: 02/08/2023]
Abstract
Acrolein is a hazardous air pollutant for humans and is responsible for many pulmonary diseases, but the underlying mechanisms have not been completely elucidated. This work is focused on the genotoxicity effects of human bronchial epithelial (BEAS-2B) cells induced by acrolein (20, 40, 80 μM). The molecular mechanism was investigated base on DNA damage and mitochondrial apoptosis pathways. The results showed that after exposure to acrolein, the cell viability, glutathione (GSH) of BEAS-2B cells were reduced. Reactive oxygen species (ROS) level significantly increased, accompanied by increased levels of DNA damage-related indicators 8-hydroxy-2 deoxyguanosine (8-OHdG), DNA content of comet tail (Tail DNA%), olive tail moment (OTM), and nucleus morphology. Cell arrested at the G2/M phase. Then, the DNA damage response (DDR) signaling pathway (Ataxia-telangiectasia-mutated (ATM) and Rad-3-related (ATR)/Chk1 and ATM/Chk2) and the consequent cell cycle checkpoints were activated. The expression of γ-H2AX was significantly increased, indicating that acrolein induced DNA double-strand breaks. Molecular docking assay showed that acrolein bound to DNA in a spontaneous process. Moreover, mitochondrial apoptosis pathway involved in apoptosis, mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) content of BEAS-2B cells were significantly reduced, and the apoptosis rate was significantly increased. The protein expression of Bax/Bcl-2 and Cleaved Caspase-3 were increased, and JNK signaling pathway was activated. All the results indicated that acrolein induced DNA damage, activated DDR and mitochondrial apoptosis pathways, which might be the pivotal factors to mediate cytotoxicity in BEAS-2B cells.
Collapse
Affiliation(s)
- Dan Liu
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China
| | - Ye Cheng
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China
| | - Zhipeng Tang
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China
| | - Xueying Mei
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China
| | - Xiangyu Cao
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China.
| | - Jianli Liu
- Department of Biological Sciences, School of Life Science, Liaoning University, Shenyang, 110036, PR China.
| |
Collapse
|
|
14
|
Arghiani N, Matin MM. miR-21: A Key Small Molecule with Great Effects in Combination Cancer Therapy. Nucleic Acid Ther 2021; 31:271-283. [PMID: 33891511 DOI: 10.1089/nat.2020.0914] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The increasing incidence of various cancers indicates the urgent need for finding accurate early diagnostic markers and more effective treatments for these malignancies. MicroRNAs (miRNAs) are small noncoding RNAs with great potentials to enter into cancer clinics as both diagnostic markers and therapeutic targets. miR-21 is elevated in many cancers, and promotes cell proliferation, metastasis, and drug resistance. In recent years, many studies have shown that targeting miR-21 combined with conventional chemotherapeutic agents could enhance their therapeutic efficacy, and overcome drug resistance and cancer recurrence both in vitro and in animal models. In this review, we first summarize the effects and importance of miR-21 in various cancers, and explore its function in drug resistance of cancer cells. Next, the challenges and prospects for clinical translation of anti-miR-21, as a therapeutic agent, will be discussed in combination cancer therapy.
Collapse
Affiliation(s)
- Nahid Arghiani
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.,Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| |
Collapse
|
|
15
|
Hydrogen peroxide and Helicobacter pylori extract treatment combined with APE1 knockdown induce DNA damage, G2/M arrest and cell death in gastric cancer cell line. DNA Repair (Amst) 2020; 96:102976. [DOI: 10.1016/j.dnarep.2020.102976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 08/28/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023]
|
|
16
|
Yi R, Yang S, Lin X, Zhong L, Liao Y, Hu Z, Huang T, Long H, Lin J, Wu Z, Xie C, Ding S, Luo J, Luo Q, Song Y. miR-5188 augments glioma growth, migration and invasion through an SP1-modulated FOXO1-PI3K/AKT-c-JUN-positive feedback circuit. J Cell Mol Med 2020; 24:11800-11813. [PMID: 32902145 PMCID: PMC7579714 DOI: 10.1111/jcmm.15794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/14/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
The biological effect and molecular mechanism of miR-5188 have not been thoroughly investigated. The study aims at elucidating the role of miR-5188 in glioma progression. Human glioma cell lines and tissues were used for functional and expression analysis. Cellular and molecular techniques were performed to explore the functions and mechanisms of miR-5188 in glioma. In our investigation, we demonstrated that miR-5188 promoted cell proliferation, the G1/S transition of the cell cycle, migration and invasion in glioma and reduced the lifespan of glioma-bearing mice. miR-5188 directly targeted FOXO1 and activated PI3K/AKT-c-JUN signalling, which enhanced miR-5188 expression. Moreover, the c-JUN transcription factor functionally bound to the miR-5188 promoter region, forming the positive feedback loop. The feedback loop promoted glioma progression through activating the PI3K/AKT signalling, and this loop is augmented by the interaction between SP1 and c-JUN. Moreover, it was also found that the miR-5188/FOXO1 axis is facilitated by SP1-activated PI3K/AKT/c-JUN signalling. In glioma samples, miR-5188 expression was found to be an unfavourable factor and was positively associated with the mRNA levels of SP1 and c-JUN, whereas negatively associated with the mRNA levels of FOXO1. Our investigation demonstrates that miR-5188 could function as a tumour promoter by directly targeting FOXO1 and participating in SP1-mediated promotion of cell growth and tumorigenesis in glioma.
Collapse
Affiliation(s)
- Renhui Yi
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
- Department of NeurosurgeryFirst Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Shaochun Yang
- Department of NeurosurgeryFirst Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Xian Lin
- Department of OncologyFujian Provincial Cancer HospitalThe Affiliated Hospital of Fujian Medical UniversityFuzhouChina
| | - Liangying Zhong
- Department of Laboratory MedicineThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yuanyuan Liao
- Department of UltrasonographyFirst Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Zheng Hu
- Department of NeurosurgeryFirst Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Tengyue Huang
- Department of NeurosurgeryFirst Affiliated Hospital of Gannan Medical UniversityGanzhouChina
| | - Hao Long
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Jie Lin
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Zhiyong Wu
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Cheng Xie
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Shengfeng Ding
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Jie Luo
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Qisheng Luo
- Department of NeurosurgeryAffiliated Hospital of Youjiang Medical University for NationalitiesBaiseChina
| | - Ye Song
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhouChina
| |
Collapse
|
|
17
|
Liu YN, Yang JF, Huang DJ, Ni HH, Zhang CX, Zhang L, He J, Gu JM, Chen HX, Mai HQ, Chen QY, Zhang XS, Gao S, Li J. Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways. Front Immunol 2020; 11:1906. [PMID: 32973789 PMCID: PMC7472844 DOI: 10.3389/fimmu.2020.01906] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (TExh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a TExh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The TExh phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes MYC and fibroblast growth factor 11 (FGF11). Downregulation of MYC and FGF11 induces TExh differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of FGF11 and MFN1. In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.
Collapse
Affiliation(s)
- Yi-Na Liu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Jie-Feng Yang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Dai-Jia Huang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Huan-He Ni
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Chuan-Xia Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lin Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Jia He
- Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jia-Mei Gu
- Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hong-Xia Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Hai-Qiang Mai
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiu-Yan Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Shi Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Song Gao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Jiang Li
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen International Biological Valley-Life Science Industrial Park, Shenzhen, China
| |
Collapse
|
|
18
|
Li Y, Lv Y, Cheng C, Huang Y, Yang L, He J, Tao X, Hu Y, Ma Y, Su Y, Wu L, Yu G, Jiang Q, Liu S, Liu X, Liu Z. SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma. Cell Death Dis 2020; 11:509. [PMID: 32641685 PMCID: PMC7343777 DOI: 10.1038/s41419-020-2699-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023]
Abstract
SPEN family transcriptional repressor (SPEN), also known as the SMART/HDAC1-associated repressor protein (SHARP), has been reported to modulate the malignant phenotypes of breast cancer, colon cancer, and ovarian cancer. However, its role and the detail molecular basis in nasopharyngeal carcinoma (NPC) remain elusive. In this study, the SPEN mRNA and protein expression was found to be increased in NPC cells and tissues compared with nonmalignant nasopharyngeal epithelial cells and tissues. Elevated SPEN protein expression was found to promote the pathogenesis of NPC and lead to poor prognosis. Knockdown of SPEN expression resulted in inactivation ofPI3K/AKT and c-JUN signaling, thereby suppressing NPC migration and invasion. In addition, miR-4652-3p was found to be a downstream inducer of SPEN by targeting the homeodomain interacting protein kinase 2 (HIPK2) gene, a potential tumor suppressor that reduces the activation of epithelial-mesenchymal transition (EMT) signaling, thereby reducing its expression and leading to increased NPC migration, invasion, and metastasis. In addition, SPEN was found to induce miR-4652-3p expression by activating PI3K/AKT/c-JUN signaling to target HIPK2. Our data provided a new molecular mechanism for SPEN as a metastasis promoter through activation of PI3K/AKT signaling, thereby stimulating the c-JUN/miR-4652-3p axis to target HIPK2 in NPC.
Collapse
Affiliation(s)
- Yang Li
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Yumin Lv
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Chao Cheng
- Department of Pediatric Otorhinolaryngology, Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Yan Huang
- Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liu Yang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Jingjing He
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Xingyu Tao
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Yingying Hu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Yuting Ma
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Yun Su
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Liyang Wu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China
| | - Guifang Yu
- Department of Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qingping Jiang
- Department of Pathology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Shu Liu
- Department of Breast Surgery, Guiyang Maternal and Child Healthcare Hospital, Guiyang, 550003, Guizhou, China
| | - Xiong Liu
- E.N.T. Department of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Zhen Liu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510095, Guangdong, China.
| |
Collapse
|
|
19
|
Liu X, Tu Y, Wang Y, Zhou D, Chong Y, Shi L, Liu G, Zhang X, Wu S, Li H, Gao S, Niu M, Yu R. Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway. Cancer Cell Int 2020; 20:97. [PMID: 32256206 PMCID: PMC7106748 DOI: 10.1186/s12935-020-01186-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/23/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Activation of nuclear factor-kappa B (NF-κΒ) through DNA damage is one of the causes of tumor cell resistance to radiotherapy. Chromosome region 1 (CRM1) regulates tumor cell proliferation, drug resistance, and radiation resistance by regulating the nuclear-cytoplasmic translocation of important tumor suppressor proteins or proto-oncoproteins. A large number of studies have reported that inhibition of CRM1 suppresses the activation of NF-κΒ. Thus, we hypothesize that the reversible CRM1 inhibitor S109 may induce radiosensitivity in glioblastoma (GBM) by regulating the NF-κΒ signaling pathway. METHODS This study utilized the cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assay to evaluate the effect of S109 combined with radiotherapy on the proliferation and survival of GBM cells. The therapeutic efficacy of S109 combined with radiotherapy was evaluated in vivo to explore the therapeutic mechanism of S109-induced GBM radiosensitization. RESULTS We found that S109 combined with radiotherapy significantly inhibited GBM cell proliferation and colony formation. By regulating the levels of multiple cell cycle- and apoptosis-related proteins, the combination therapy induced G1 cell cycle arrest in GBM cells. In vivo studies showed that S109 combined with radiotherapy significantly inhibited the growth of intracranial GBM and prolonged survival. Importantly, we found that S109 combined with radiotherapy promoted the nuclear accumulation of IκΒα, and inhibited phosphorylation of p65 and the transcriptional activation of NF-κΒ. CONCLUSION Our findings provide a new therapeutic regimen for improving GBM radiosensitivity as well as a scientific basis for further clinical trials to evaluate this combination therapy.
Collapse
Affiliation(s)
- Xuejiao Liu
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Yiming Tu
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu China
| | - Yifeng Wang
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Di Zhou
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Yulong Chong
- Department of Neurosurgery, Suqian Hospital Affiliated to Xuzhou Medical University, Suqian, Jiangsu China
| | - Lin Shi
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Guanzheng Liu
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Xu Zhang
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Sijin Wu
- College of pharmacy, The Ohio State University, Columbus, OH USA
| | - Huan Li
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Shangfeng Gao
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Mingshan Niu
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu China
| | - Rutong Yu
- Insititute of Nervous System Diseases, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu China
- Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu China
| |
Collapse
|
|
20
|
Genomic alterations and abnormal expression of APE2 in multiple cancers. Sci Rep 2020; 10:3758. [PMID: 32111912 PMCID: PMC7048847 DOI: 10.1038/s41598-020-60656-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 02/13/2020] [Indexed: 12/26/2022] Open
Abstract
Although APE2 plays essential roles in base excision repair and ATR-Chk1 DNA damage response (DDR) pathways, it remains unknown how the APE2 gene is altered in the human genome and whether APE2 is differentially expressed in cancer patients. Here, we report multiple-cancer analyses of APE2 genomic alterations and mRNA expression from cancer patients using available data from The Cancer Genome Atlas (TCGA). We observe that APE2 genomic alterations occur at ~17% frequency in 14 cancer types (n = 21,769). Most frequent somatic mutations of APE2 appear in uterus (2.89%) and skin (2.47%) tumor samples. Furthermore, APE2 expression is upregulated in tumor tissue compared with matched non-malignant tissue across 5 cancer types including kidney, breast, lung, liver, and uterine cancers, but not in prostate cancer. We also examine the mRNA expression of 13 other DNA repair and DDR genes from matched samples for 6 cancer types. We show that APE2 mRNA expression is positively correlated with PCNA, APE1, XRCC1, PARP1, Chk1, and Chk2 across these 6 tumor tissue types; however, groupings of other DNA repair and DDR genes are correlated with APE2 with different patterns in different cancer types. Taken together, this study demonstrates alterations and abnormal expression of APE2 from multiple cancers.
Collapse
|