1
|
Xu L, Wen B, Wu Q, Lu S, Liao J, Mo L, Li Q, Tong X, Yan H. Long non-coding RNA KB-1460A1.5 promotes ferroptosis by inhibiting mTOR/SREBP-1/SCD1-mediated polyunsaturated fatty acid desaturation in glioma. Carcinogenesis 2024; 45:487-499. [PMID: 38422369 DOI: 10.1093/carcin/bgae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 02/03/2024] [Accepted: 02/28/2024] [Indexed: 03/02/2024] Open
Abstract
Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.
Collapse
Affiliation(s)
- Lixia Xu
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Binli Wen
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Qiaoli Wu
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Shan Lu
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Jianwen Liao
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Lidong Mo
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
| | - Qingguo Li
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin 300350, China
| | - Xiaoguang Tong
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin 300350, China
| | - Hua Yan
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumour New Technology Translation, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, China
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin 300070, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin 300350, China
| |
Collapse
|
2
|
Dong N, Qi W, Wu L, Li J, Zhang X, Wu H, Zhang W, Jiang J, Zhang S, Fu W, Liu Q, Qi G, Wang L, Lu Y, Luo J, Kong Y, Liu Y, Zhao RC, Wang J. LINC00606 promotes glioblastoma progression through sponge miR-486-3p and interaction with ATP11B. J Exp Clin Cancer Res 2024; 43:139. [PMID: 38725030 PMCID: PMC11080186 DOI: 10.1186/s13046-024-03058-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown. METHODS The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay. RESULTS We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein. CONCLUSIONS Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM.
Collapse
Affiliation(s)
- Naijun Dong
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
- School of Medicine, Shanghai University, Shanghai, China
| | - Wenxin Qi
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
- School of Medicine, Shanghai University, Shanghai, China
| | - Lingling Wu
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
- School of Medicine, Shanghai University, Shanghai, China
| | - Jie Li
- Shanghai Institute of Phage, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xueqi Zhang
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Hao Wu
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Wen Zhang
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Jiawen Jiang
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Shibo Zhang
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Wenjun Fu
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Qian Liu
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Guandong Qi
- Residential College, Shanghai University, Shanghai, China
| | - Lukai Wang
- Residential College, Shanghai University, Shanghai, China
| | - Yanyuan Lu
- Residential College, Shanghai University, Shanghai, China
| | - Jingyi Luo
- Residential College, Shanghai University, Shanghai, China
| | - Yanyan Kong
- PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Yihao Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
| | - Robert Chunhua Zhao
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China.
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, China.
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
- Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, China.
| | - Jiao Wang
- School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China.
| |
Collapse
|
3
|
Yang E, Hong B, Wang Y, Wang Q, Zhao J, Cui X, Wu Y, Yang S, Su D, Liu X, Kang C. EPIC-0628 abrogates HOTAIR/EZH2 interaction and enhances the temozolomide efficacy via promoting ATF3 expression and inhibiting DNA damage repair in glioblastoma. Cancer Lett 2024; 588:216812. [PMID: 38490327 DOI: 10.1016/j.canlet.2024.216812] [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: 10/03/2023] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/17/2024]
Abstract
The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O6-methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non-coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small-molecule inhibitor called EPIC-0628 that selectively disrupted the HOTAIR-EZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p-p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC-0628 silenced MGMT expression. Besides, EPIC-0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double-strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC-0628 enhanced TMZ efficacy in GBM in vitro and vivo. Hence, this study provided evidence for the combination of epigenetic drugs EPIC-0628 with TMZ for GBM treatment through the above mechanisms.
Collapse
Affiliation(s)
- Eryan Yang
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Biao Hong
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yunfei Wang
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Qixue Wang
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Jixing Zhao
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xiaoteng Cui
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Ye Wu
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Shixue Yang
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Dongyuan Su
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xiaomin Liu
- Neuro-Oncology Center, Tianjin Huanhu Hospital, Nankai University, Tianjin, 300350, China
| | - Chunsheng Kang
- Lab of Neuro- Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| |
Collapse
|
4
|
Wei H, Li W, Yang M, Fang Q, Nian J, Huang Y, Wei Q, Huang Z, Liu G, Xu Z, Hu A, Pu J. METTL3/16-mediated m 6A modification of ZNNT1 promotes hepatocellular carcinoma progression by activating ZNNT1/osteopontin/S100A9 positive feedback loop-mediated crosstalk between macrophages and tumour cells. Clin Immunol 2024; 261:109924. [PMID: 38310994 DOI: 10.1016/j.clim.2024.109924] [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: 09/06/2023] [Accepted: 02/01/2024] [Indexed: 02/06/2024]
Abstract
Macrophages are the major components of tumour microenvironment, which play critical roles in tumour development. N6-methyladenosine (m6A) also contributes to tumour progression. However, the potential roles of m6A in modulating macrophages in hepatocellular carcinoma (HCC) are poorly understood. Here, we identified ZNNT1 as an HCC-related m6A modification target, which was upregulated and associated with poor prognosis of HCC. METTL3 and METTL16-mediated m6A modification contributed to ZNNT1 upregulation through stabilizing ZNNT1 transcript. ZNNT1 exerted oncogenic roles in HCC. Furthermore, ZNNT1 recruited and induced M2 polarization of macrophages via up-regulating osteopontin (OPN) expression and secretion. M2 Macrophages-recruited by ZNNT1-overexpressed HCC cells secreted S100A9, which further upregulated ZNNT1 expression in HCC cells via AGER/NF-κB signaling. Thus, this study demonstrates that m6A modification activated the ZNNT1/OPN/S100A9 positive feedback loop, which promoted macrophages recruitment and M2 polarization, and enhanced malignant features of HCC cells. m6A modification-triggered ZNNT1/OPN/S100A9 feedback loop represents potential therapeutic target for HCC.
Collapse
Affiliation(s)
- Huamei Wei
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Meng Yang
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Quan Fang
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Jiahui Nian
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Youguan Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Qing Wei
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Zihua Huang
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Guoman Liu
- Graduate College of Youjiang Medical University for Nationalities, Baise, China
| | - Zuoming Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Anbin Hu
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China; The Guangxi Clinical Medical Research Center for Hepatobiliary Diseases, No. 18 Zhongshan two Road, Baise 533000, China.
| |
Collapse
|
5
|
Zhang Y, Zhang Y, Tao H, Zhu J, Lu Y, Cheng F, Xiong Y, Liu J, Cai G, Zhang Z, Liang H, Chen Y, Zhang W. Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy. Cancer Lett 2023; 576:216405. [PMID: 37783391 DOI: 10.1016/j.canlet.2023.216405] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/08/2023] [Accepted: 09/18/2023] [Indexed: 10/04/2023]
Abstract
Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.
Collapse
Affiliation(s)
- Yuxin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yujie Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haisu Tao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China; Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Jinghan Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Yuanxiang Lu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Fangling Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Yixiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Junjie Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Guangzhen Cai
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Yifa Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Hepato-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| |
Collapse
|
6
|
Chao C, Tang R, Zhao J, Di D, Qian Y, Wang B. Oncogenic roles and related mechanisms of the long non-coding RNA MINCR in human cancers. Front Cell Dev Biol 2023; 11:1087337. [PMID: 37215074 PMCID: PMC10196036 DOI: 10.3389/fcell.2023.1087337] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) play vital roles in regulating epigenetic mechanisms and gene expression levels, and their dysregulation is closely associated with a variety of diseases such as cancer. Several studies have demonstrated that lncRNAs are dysregulated during tumor progression. Recently, the MYC-induced long non-coding RNA MINCR, a newly identified lncRNA, has been demonstrated to act as an oncogene in different cancers, including gallbladder cancer, hepatocellular cancer, colorectal cancer, non-small cell lung cancer, oral squamous cell carcinoma, nasopharyngeal cancer, and glioma. Moreover, MINCR has been reported to act as a biomarker in the prognosis of patients with different cancers. In this review, we summarize and analyze the oncogenic roles of MINCR in a variety of human cancers in terms of its clinical significance, biological functions, cellular activities, and regulatory mechanism. Our analysis of the literature suggests that MINCR has potential as a novel biomarker and therapeutic target in human cancers.
Collapse
Affiliation(s)
- Ce Chao
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Renzhe Tang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jiamin Zhao
- Department of Respiratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dongmei Di
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yongxiang Qian
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Bin Wang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| |
Collapse
|
7
|
Wu S, Ballah AK, Che W, Wang X. M7G-related LncRNAs: A comprehensive analysis of the prognosis and immunity in glioma. Front Genet 2022; 13:961278. [DOI: 10.3389/fgene.2022.961278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 11/02/2022] [Indexed: 11/17/2022] Open
Abstract
Today, numerous international researchers have demonstrated that N7-methylguanosine (m7G) related long non-coding RNAs (m7G-related lncRNAs) are closely linked to the happenings and developments of various human beings’ cancers. However, the connection between m7G-related lncRNAs and glioma prognosis has not been investigated. We did this study to look for new potential biomarkers and construct an m7G-related lncRNA prognostic signature for glioma. We identified those lncRNAs associated with DEGs from glioma tissue sequences as m7G-related lncRNAs. First, we used Pearson’s correlation analysis to identify 28 DEGs by glioma and normal brain tissue gene sequences and predicated 657 m7G-related lncRNAs. Then, eight lncRNAs associated with prognosis were obtained and used to construct the m7G risk score model by lasso and Cox regression analysis methods. Furthermore, we used Kaplan-Meier analysis, time-dependent ROC, principal component analysis, clinical variables, independent prognostic analysis, nomograms, calibration curves, and expression levels of lncRNAs to determine the model’s accuracy. Importantly, we validated the model with external and internal validation methods and found it has strong predictive power. Finally, we performed functional enrichment analysis (GSEA, aaGSEA enrichment analyses) and analyzed immune checkpoints, associated pathways, and drug sensitivity based on predictors. In conclusion, we successfully constructed the formula of m7G-related lncRNAs with powerful predictive functions. Our study provides instructional value for analyzing glioma pathogenesis and offers potential research targets for glioma treatment and scientific research.
Collapse
|
8
|
Cheng C, Liu D, Liu Z, Li M, Wang Y, Sun B, Kong R, Chen H, Wang G, Li L, Hu J, Li Y, Chen H, Zhao Z, Zhang T, Zhu S, Pan S. Positive feedback regulation of lncRNA TPT1-AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer. Cancer Sci 2022; 113:2986-3001. [PMID: 35534983 PMCID: PMC9459417 DOI: 10.1111/cas.15388] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/08/2022] [Accepted: 04/18/2022] [Indexed: 11/29/2022] Open
Abstract
Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin β3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.
Collapse
Affiliation(s)
- Chundong Cheng
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Danxi Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zonglin Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Mengyang Li
- Department of Medical OncologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yongwei Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Bei Sun
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Rui Kong
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hua Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Gang Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Le Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Jisheng Hu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Yilong Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hongze Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zhongjie Zhao
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Tao Zhang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Siqiang Zhu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Shangha Pan
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| |
Collapse
|
9
|
Wu H, Wei M, Li Y, Ma Q, Zhang H. Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma. Front Mol Neurosci 2022; 15. [DOI: https:/doi.org/10.3389/fnmol.2022.910543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023] Open
Abstract
As is known to all, glioma, a global difficult problem, has a high malignant degree, high recurrence rate and poor prognosis. We analyzed and summarized signal pathway of the Hippo/YAP, PI3K/AKT/mTOR, miRNA, WNT/β-catenin, Notch, Hedgehog, TGF-β, TCS/mTORC1 signal pathway, JAK/STAT signal pathway, MAPK signaling pathway, the relationship between BBB and signal pathways and the mechanism of key enzymes in glioma. It is concluded that Yap1 inhibitor may become an effective target for the treatment of glioma in the near future through efforts of generation after generation. Inhibiting PI3K/Akt/mTOR, Shh, Wnt/β-Catenin, and HIF-1α can reduce the migration ability and drug resistance of tumor cells to improve the prognosis of glioma. The analysis shows that Notch1 and Sox2 have a positive feedback regulation mechanism, and Notch4 predicts the malignant degree of glioma. In this way, notch cannot only be treated for glioma stem cells in clinic, but also be used as an evaluation index to evaluate the prognosis, and provide an exploratory attempt for the direction of glioma treatment. MiRNA plays an important role in diagnosis, and in the treatment of glioma, VPS25, KCNQ1OT1, KB-1460A1.5, and CKAP4 are promising prognostic indicators and a potential therapeutic targets for glioma, meanwhile, Rheb is also a potent activator of Signaling cross-talk etc. It is believed that these studies will help us to have a deeper understanding of glioma, so that we will find new and better treatment schemes to gradually conquer the problem of glioma.
Collapse
|
10
|
Wu H, Wei M, Li Y, Ma Q, Zhang H. Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma. Front Mol Neurosci 2022; 15:910543. [PMID: 35935338 PMCID: PMC9354928 DOI: 10.3389/fnmol.2022.910543] [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: 04/01/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022] Open
Abstract
As is known to all, glioma, a global difficult problem, has a high malignant degree, high recurrence rate and poor prognosis. We analyzed and summarized signal pathway of the Hippo/YAP, PI3K/AKT/mTOR, miRNA, WNT/β-catenin, Notch, Hedgehog, TGF-β, TCS/mTORC1 signal pathway, JAK/STAT signal pathway, MAPK signaling pathway, the relationship between BBB and signal pathways and the mechanism of key enzymes in glioma. It is concluded that Yap1 inhibitor may become an effective target for the treatment of glioma in the near future through efforts of generation after generation. Inhibiting PI3K/Akt/mTOR, Shh, Wnt/β-Catenin, and HIF-1α can reduce the migration ability and drug resistance of tumor cells to improve the prognosis of glioma. The analysis shows that Notch1 and Sox2 have a positive feedback regulation mechanism, and Notch4 predicts the malignant degree of glioma. In this way, notch cannot only be treated for glioma stem cells in clinic, but also be used as an evaluation index to evaluate the prognosis, and provide an exploratory attempt for the direction of glioma treatment. MiRNA plays an important role in diagnosis, and in the treatment of glioma, VPS25, KCNQ1OT1, KB-1460A1.5, and CKAP4 are promising prognostic indicators and a potential therapeutic targets for glioma, meanwhile, Rheb is also a potent activator of Signaling cross-talk etc. It is believed that these studies will help us to have a deeper understanding of glioma, so that we will find new and better treatment schemes to gradually conquer the problem of glioma.
Collapse
Affiliation(s)
- Hao Wu
- Graduate School of Dalian Medical University, Dalian, China
- Department of Neurosurgery, The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian, China
| | - Min Wei
- Graduate School of Dalian Medical University, Dalian, China
- Department of Neurosurgery, The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian, China
| | - Yuping Li
- Department of Neurosurgery, The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian, China
| | - Qiang Ma
- Department of Neurosurgery, The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian, China
| | - Hengzhu Zhang
- Graduate School of Dalian Medical University, Dalian, China
- Department of Neurosurgery, The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian, China
| |
Collapse
|