|
1
|
Tomioka Y, Suetsugu T, Seki N, Tanigawa K, Hagihara Y, Shinmura M, Asai S, Kikkawa N, Inoue H, Mizuno K. The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma. Cells 2023; 12:1885. [PMID: 37508549 PMCID: PMC10378275 DOI: 10.3390/cells12141885] [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: 06/20/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.
Collapse
Affiliation(s)
- Yuya Tomioka
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Kengo Tanigawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoko Hagihara
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Masahiro Shinmura
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Shunichi Asai
- Head and Neck Surgery, Chiba Cancer Center, Nitona, Chiba 260-8717, Japan
| | - Naoko Kikkawa
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| |
Collapse
|
|
2
|
Zhang Z, Fu J, Zhang Y, Qin X, Wang Y, Xing C. METTL3 regulates N6-methyladenosine modification of ANGPTL3 mRNA and potentiates malignant progression of stomach adenocarcinoma. BMC Gastroenterol 2023; 23:217. [PMID: 37344779 PMCID: PMC10283274 DOI: 10.1186/s12876-023-02844-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) is associated with mammalian mRNA biogenesis, decay, translation and metabolism, and also contributes greatly to gastrointestinal tumor formation and development. Therefore, the specific mechanisms and signaling pathways mediated by methyltransferase-like 3 (METTL3), which catalyzes the formation of m6A chemical labeling in stomach adenocarcinoma (STAD), are still worth exploring. METHODS Quantitative real-time PCR (qRT-PCR) was constructed to detect the expression of METTL3 in gastric cancer cell lines and patient tissues. The biological function of METTL3 was investigated in vitro/in vivo by Cell Counting Kit-8, colony formation assay, Transwell assay and nude mouse tumorigenesis assay. Based on the LinkedOmics database, the genes co-expressed with METTL3 in the TCGA STAD cohort were analyzed to clarify the downstream targets of METTL3. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and RNA stability analysis were employed to explore the mechanism of METTL3 in gastric cancer progression. RESULTS We analyzed TCGA data and found that METTL3 was frequently elevated in STAD, and demonstrated that METTL3 was present at high levels in clinical STAD tissues and cells. High METTL3 expression was more likely to have advanced TNM tumors and distant metastasis. On the other hand, METTL3 silencing effectively impeded the higher oncogenic capacity of AGS and HGC27 cells in vivo and in vitro, as reflected by slowed cell growth and diminished migration and invasion capacities. Continued mining of the TCGA dataset identified the co-expression of angiopoietin-like 3 (ANGPTL3) and METTL3 in STAD. Lower level of ANGPTL3 was related to increased level of METTL3 in STAD samples and shorter survival times in STAD patients. ANGPTL3 enrichment limited the growth and metastasis of STAD cells. Besides, ANGPTL3 mRNA levels could be decreased by METTL3-dominated m6A modifications, a result derived from a combination of MeRIP-qPCR and RNA half-life experiments. Importantly, the inhibitory effect of METTL3 silencing on cancer could be reversed to some extent by ANGPTL3 inhibition. CONCLUSIONS Overall, our findings suggested that METTL3 functioned an oncogenic role in STAD by reducing ANGPTL3 expression in an m6A-dependent manner. The discovery of the METTL3-ANGPTL3 axis and its effect on STAD tumor growth will contribute to further studies on the mechanisms of gastric adenocarcinoma development.
Collapse
Affiliation(s)
- Zhijin Zhang
- Department of General Surgery, the Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Jun Fu
- Department of General Surgery, Shanghai Eighth People Hospital, Shanghai, 200235, China
| | - Yuhao Zhang
- Department of General Surgery, Shanghai Eighth People Hospital, Shanghai, 200235, China
| | - Xianju Qin
- Department of General Surgery, Shanghai Eighth People Hospital, Shanghai, 200235, China
| | - Yuexia Wang
- Department of General Surgery, Shanghai Eighth People Hospital, Shanghai, 200235, China
| | - Chungen Xing
- Department of General Surgery, the Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China.
| |
Collapse
|
|
3
|
Shan DD, Zheng QX, Chen Z. Go-Ichi-Ni-San 2: A potential biomarker and therapeutic target in human cancers. World J Gastrointest Oncol 2022; 14:1892-1902. [PMID: 36310704 PMCID: PMC9611433 DOI: 10.4251/wjgo.v14.i10.1892] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/15/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
Cancer incidence and mortality are increasing globally, leading to its rising status as a leading cause of death. The Go-Ichi-Ni-San (GINS) complex plays a crucial role in DNA replication and the cell cycle. The GINS complex consists of four subunits encoded by the GINS1, GINS2, GINS3, and GINS4 genes. Recent findings have shown that GINS2 expression is upregulated in many diseases, particularly tumors. For example, increased GINS2 expression has been found in cervical cancer, gastric adenocarcinoma, glioma, non-small cell lung cancer, and pancreatic cancer. It correlates with the clinicopathological characteristics of the tumors. In addition, high GINS2 expression plays a pro-carcinogenic role in tumor development by promoting tumor cell proliferation and migration, inhibiting tumor cell apoptosis, and blocking the cell cycle. This review describes the upregulation of GINS2 expression in most human tumors and the pathway of GINS2 in tumor development. GINS2 may serve as a new marker for tumor diagnosis and a new biological target for therapy.
Collapse
Affiliation(s)
- Dan-Dan Shan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Qiu-Xian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
4
|
Zhou C, Chen Z, Xiao B, Xiang C, Li A, Zhao Z, Li H. Comprehensive analysis of GINS subunits prognostic value and ceRNA network in sarcoma. Front Cell Dev Biol 2022; 10:951363. [PMID: 36092720 PMCID: PMC9462653 DOI: 10.3389/fcell.2022.951363] [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: 05/23/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The GINS complex, composed of GINS1/2/3/4 subunits, is an essential structure of Cdc45-MCM-GINS (CMG) helicase and plays a vital role in establishing the DNA replication fork and chromosome replication. Meanwhile, GINS genes have been associated with the poor prognosis of various malignancies. However, the abnormal expression of GINS genes and their diagnostic and prognostic value in sarcomas (SARC) remain unclear. Methods: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, Cancer cell line encyclopedia (CCLE), The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), R studio, and Tumor Immune Estimation Resource (TIMER) were used to analyze the expression profiles, prognostic value, biological function, ceRNA, and immune infiltration associated with GINS genes in sarcomas. Results: We found that GINS1/2/3/4 genes exhibited significantly upregulated transcription levels in SARC samples compared to non-tumor tissues and exhibited high expression levels in sarcoma cell lines. In addition, SARC patients with increased expression levels of GINS1/2/3/4 showed poorer survival rates. Immune infiltration analysis showed that GINS subunits were closely associated with the infiltration of immune cells in sarcomas. Conclusion: Our research identified GINS subunits as potential diagnostic and prognostic biological targets in SARC and elucidated their underlying effects in the genesis and progression of SARC. These results may provide new opportunities and research directions for targeted sarcoma therapy.
Collapse
Affiliation(s)
- Chuqiao Zhou
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Zhuoyuan Chen
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Bo Xiao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Cheng Xiang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Aoyu Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Ziyue Zhao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Hui Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
- *Correspondence: Hui Li,
| |
Collapse
|