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Wu Y, Xian D, Liu Y, Huang D, Liu Q, Yang S. USP8-Dependent Family Tyrosine Kinase Promotes the Malignant Progression of Esophageal Squamous Cell Carcinoma by Upregulating Protein Tyrosine Kinase 2 Expression. Thorac Cancer 2025; 16:e15489. [PMID: 39702934 PMCID: PMC11739124 DOI: 10.1111/1759-7714.15489] [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: 07/24/2024] [Revised: 09/03/2024] [Accepted: 11/03/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy, and the molecular underpinnings of its aggressive behavior are not fully understood. FYN proto-oncogene, Src family tyrosine kinase (FYN) has been linked to cancer progression, yet its role in ESCC remains elusive. This study investigated the influence of FYN on ESCC malignancy. METHODS Quantitative real-time polymerase chain reaction was used to assess the mRNA expression of FYN, while western blotting and immunohistochemistry (IHC) assays were performed to detect the protein expression of FYN, ubiquitin specific peptidase 8 (USP8) and protein tyrosine kinase 2 (PTK2). Cell viability was measured with a cell counting kit-8 assay, and cell apoptosis was evaluated using flow cytometry. RESULTS FYN expression was increased in ESCC tissues and cells when compared with normal esophageal tissues and normal esophageal epithelial cells. Knockdown of FYN inhibited cell invasion, migration, stem-like traits, and glycolysis, while promoting apoptosis. USP8 was shown to stabilize FYN protein expression through its deubiquitinating activity in ESCC cells. Overexpression of FYN reversed the effects of USP8 silencing on the malignant phenotypes of ESCC cells in vitro and in vivo. FYN upregulated PTK2 expression in both TE1 and KYSE150 cell lines. Furthermore, PTK2 overexpression reversed the effects of FYN silencing on the malignant phenotypes of ESCC cells. Further, USP8 silencing-induced inhibitory effect on PTK2 protein expression was counteracted after FYN overexpression. CONCLUSION USP8-dependent FYN contributed to the malignant progression of ESCC by interacting with PTK2. Targeting this pathway may offer a novel therapeutic strategy for ESCC treatment.
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Affiliation(s)
- Yuechang Wu
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
| | - Dubiao Xian
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
| | - Yunzhong Liu
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
| | - Ding Huang
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
| | - Qingfeng Liu
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
| | - Shubo Yang
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Hainan Medical CollegeHaikouChina
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Yang Y, Zhang M, Cai F, Ma G, Zhang RP, Yin Y, Deng J. CLEC4D as a Novel Prognostic Marker Boosts the Proliferation and Migration of Gastric Cancer via the NF-κB/AKT Signaling Pathway. Int J Gen Med 2024; 17:1923-1935. [PMID: 38736669 PMCID: PMC11088047 DOI: 10.2147/ijgm.s458228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/29/2024] [Indexed: 05/14/2024] Open
Abstract
Purpose The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.
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Affiliation(s)
- Yang Yang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
| | - Mengmeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
| | - Fenglin Cai
- Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, 300070, People’s Republic of China
| | - Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
| | - Ru-Peng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
| | - Yiqing Yin
- Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China
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Ma G, Liu S, Cai F, Liang H, Deng J, Zhang R, Cai M. Ketohexokinase-A deficiency attenuates the proliferation via reducing β-catenin in gastric cancer cells. Exp Cell Res 2024; 438:114038. [PMID: 38614422 DOI: 10.1016/j.yexcr.2024.114038] [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: 04/13/2023] [Revised: 02/20/2024] [Accepted: 04/08/2024] [Indexed: 04/15/2024]
Abstract
Overconsumption of fructose is closely related to cancer. Ketohexokinase (KHK) catalyzes the conversion from fructose to fructose-1-phosphate (F1P), which is the first and committed step of fructose metabolism. Recently, aberrant KHK activation has been identified in multiple malignancies. However, the roles of KHK in gastric cancer (GC) cells are largely unclear. Herein, we reveal that the expression of ketohexokinase-A (KHK-A), one alternatively spliced KHK isoform that possesses low affinity for fructose, was markedly increased in GC cells. Depletion of endogenous KHK-A expression using lentiviruses encoding short hairpin RNAs (shRNAs) or pharmaceutical disruption of KHK-A activity using KHK-IN-1 hydrochloride in GC NCI-N87 and HGC-27 cells inhibited the proliferation in vitro and in vivo. Additionally, the mitochondrial respiration in the GC cells with KHK-A deficiency compared with the control cells was significantly impaired. One commercially-available antibody array was used to explore the effects of KHK-A knockdown on signaling pathways, showing that β-catenin was remarkably reduced in the KHK-A deficient GC cells compared with the control ones. Pharmaceutical reduction in β-catenin levels slowed down the proliferation of GC cells. These data uncover that KHK-A promotes the proliferation in GC cells, indicating that this enzyme might be a promising therapeutical target for GC treatment.
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Affiliation(s)
- Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Siya Liu
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Mingzhi Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Tianjin Key Laboratory of Digestive Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Duan Y, Zhou M, Ye B, Yue K, Qiao F, Wang Y, Lai Q, Wu Y, Cao J, Wu Y, Wang X, Jing C. Hypoxia-induced miR-5100 promotes exosome-mediated activation of cancer-associated fibroblasts and metastasis of head and neck squamous cell carcinoma. Cell Death Dis 2024; 15:215. [PMID: 38485986 PMCID: PMC10940661 DOI: 10.1038/s41419-024-06587-9] [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: 09/11/2023] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 03/18/2024]
Abstract
The invasion-metastasis cascade in head and neck squamous cell carcinoma (HNSCC) is predominantly caused by the interaction between tumor cells and tumor microenvironment, including hypoxia as well as stromal cells. However, the mechanism of hypoxia-activated tumor-stroma crosstalk in HNSCC metastasis remains to be deciphered. Here, we demonstrated that HIF1α was upregulated in HNSCC specimens compared with adjacent normal tissues, whose overexpression was associated with lymph node metastasis and predicted unfavorable prognosis. HIF1α expression correlated positively with the levels of miR-5100 as well as α-SMA, the marker of CAFs. Hypoxia/HIF1α regulated transcriptionally miR-5100 to promote the degradation of its target gene QKI, which acts as a tumor suppressor in HNSCC. Hypoxic HNSCC-derived exosomal miR-5100 promoted the activation of CAFs by orchestrating QKI/AKT/STAT3 axis, which further facilitated HNSCC metastasis. Additionally, miR-5100 derived from plasma exosomes indicated HNSCC malignant progression. In conclusion, our findings illuminate a novel HIF1α/miR-5100/QKI pathway in HNSCC metastasis, and suggest that miR-5100 might be a potential biomarker and therapeutic target for HNSCC.
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Affiliation(s)
- Yuansheng Duan
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Mengqian Zhou
- Department of Thyroid and Breast Surgery, The Second Hospital of Anhui Medical University, Anhui, 230601, China
| | - Beibei Ye
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Kai Yue
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Feng Qiao
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Yuxuan Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Qingchuan Lai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Yue Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Jiayan Cao
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China
| | - Yansheng Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China.
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China.
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China.
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Cai F, Yang X, Ma G, Wang P, Zhang M, Zhang N, Zhang R, Liang H, Nie Y, Dong C, Deng J. EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity. Br J Cancer 2024; 130:597-612. [PMID: 38184692 PMCID: PMC10876699 DOI: 10.1038/s41416-023-02546-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] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 01/08/2024] Open
Abstract
BACKGROUND The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. METHODS This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. RESULTS EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. CONCLUSIONS EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.
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Affiliation(s)
- Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
- Department of Biochemistry and Molecular Biology, Tianjin Medical University, 300070, Tianjin, China
| | - Xiuding Yang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Pengliang Wang
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Mengmeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Nannan Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Cheng Dong
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
- Department of Biochemistry and Molecular Biology, Tianjin Medical University, 300070, Tianjin, China.
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Zhao Y, Li Y, Zhu R, Feng R, Cui H, Yu X, Huang F, Zhang R, Chen X, Li L, Chen Y, Liu Y, Wang J, Du G, Liu Z. RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m 6A modification. Signal Transduct Target Ther 2023; 8:224. [PMID: 37264021 DOI: 10.1038/s41392-023-01428-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 02/23/2023] [Accepted: 03/24/2023] [Indexed: 06/03/2023] Open
Abstract
Increased rates of ribosome biogenesis have been recognized as hallmarks of many cancers and are associated with poor prognosis. Using a CRISPR synergistic activation mediator (SAM) system library targeting 89 ribosomal proteins (RPs) to screen for the most oncogenic functional RPs in human esophageal squamous cell carcinoma (ESCC), we found that high expression of RPS15 correlates with malignant phenotype and poor prognosis of ESCC. Gain and loss of function models revealed that RPS15 promotes ESCC cell metastasis and proliferation, both in vitro and in vivo. Mechanistic investigations demonstrated that RPS15 interacts with the K homology domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which recognizes and directly binds the 3'-UTR of MKK6 and MAPK14 mRNA in an m6A-dependent manner, and promotes translation of core p38 MAPK pathway proteins. By combining targeted drug virtual screening and functional assays, we found that folic acid showed a therapeutic effect on ESCC by targeting RPS15, which was augmented by the combination with cisplatin. Inhibition of RPS15 by folic acid, IGF2BP1 ablation, or SB203580 treatment were able to suppress ESCC metastasis and proliferation via the p38 MAPK signaling pathway. Thus, RPS15 promotes ESCC progression via the p38 MAPK pathway and RPS15 inhibitors may serve as potential anti-ESCC drugs.
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Affiliation(s)
- Yahui Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yang Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Rui Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Riyue Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Heyang Cui
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, 518035, China
| | - Xiao Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Furong Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ruixiang Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Xiankai Chen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Lei Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Yinghui Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuhao Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Jinhua Wang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Guanhua Du
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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7
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Ma G, Sun Y, Cai F, Zhang M, Liang H, Deng J, Zhang R, Zhang L. DEPTOR as a novel prognostic marker inhibits the proliferation via deactivating mTOR signaling pathway in gastric cancer cells. Exp Cell Res 2023; 427:113598. [PMID: 37054772 DOI: 10.1016/j.yexcr.2023.113598] [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: 08/17/2022] [Revised: 02/15/2023] [Accepted: 04/09/2023] [Indexed: 04/15/2023]
Abstract
Aberrantly activated mTOR signaling pathway is commonly found in malignancies including gastric cancer (GC). DEPTOR, as a naturally occurred inhibitor of mTOR, functions in the pro- or anti-tumor manner depending on distinct tumor contexts. However, the roles of DEPTOR in GC remain largely unknown. In this study, DEPTOR expression was identified to be significantly decreased in GC tissues compared with matched normal gastric tissues, and reduced DEPTOR level was indicative of poor prognosis in patients. Restored DEPTOR expression inhibited the propagation in AGS and NCI-N87 cells, whose DEPTOR levels are low, via deactivating mTOR signaling pathway. Likewise, cabergoline (CAB) attenuated the proliferation in AGS and NCI-N87 cells via partially rescuing DEPTOR protein level. Targeted metabolomics analysis showed that several key metabolites, such as l-serine, significantly changed in AGS cells with DEPTOR restoration. These results revealed the anti-proliferation function of DEPTOR in GC cells, suggesting that restored DEPTOR expression using CAB may be a potential therapeutic approach for patients with GC.
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Affiliation(s)
- Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yi Sun
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Mengmeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Li Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Ye B, Duan Y, Zhou M, Wang Y, Lai Q, Yue K, Cao J, Wu Y, Wang X, Jing C. Hypoxic tumor-derived exosomal miR-21 induces cancer-associated fibroblast activation to promote head and neck squamous cell carcinoma metastasis. Cell Signal 2023; 108:110725. [PMID: 37230199 DOI: 10.1016/j.cellsig.2023.110725] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/30/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Both microRNA-21-5p (miR-21) and the tumor microenvironment, including hypoxia and cancer-associated fibroblasts (CAFs), play a vital role in head and neck squamous cell carcinoma (HNSCC), but whether there is an interaction and the specific regulatory mechanism between them in the process of metastasis is still unclear. In this study, we aimed to elucidate the connection and regulatory mechanism of miR-21, hypoxia, and CAFs in HNSCC metastasis. METHODS The underlying mechanisms of HIF1α regulating miR-21 transcription, promoting exosome secretion, CAFs activation, tumor invasion, and lymph node metastasis were determined through quantitative real-time PCR, immunoblotting, transwell, wound healing, immunofluorescence, ChIP, electron microscopy, nanoparticle tracking analysis, dual-luciferase reporter assay, co-culture model and xenografts experiments. RESULTS MiR-21 promoted the invasion and metastasis of HNSCC in vitro and in vivo, whereas HIF1α knockdown inhibited these processes. HIF1α upregulated transcription of miR-21 and promoted the release of exosomes from HNSCC cells. Exosomes derived from hypoxic tumor cells were rich in miR-21, which induced NFs activation towards CAFs by targeting YOD1. Knockdown the expression level of miR-21 in CAFs prevented lymph node metastasis in HNSCC. CONCLUSION Hypoxic tumor cell-derived exosomal miR-21 might be a therapeutic target to prevent or delay HNSCC invasion and metastasis.
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Affiliation(s)
- Beibei Ye
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Yuansheng Duan
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Mengqian Zhou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, China
| | - Yuxuan Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Qingchuan Lai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Kai Yue
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Jiayan Cao
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China
| | - Yansheng Wu
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
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9
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Ma G, Zhao Z, Qu Y, Cai F, Liu S, Liang H, Zhang R, Deng J. Cysteine dioxygenase 1 attenuates the proliferation via inducing oxidative stress and integrated stress response in gastric cancer cells. Cell Death Discov 2022; 8:493. [PMID: 36526626 PMCID: PMC9758200 DOI: 10.1038/s41420-022-01277-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Whereas cysteine dioxygenase 1 (CDO1) expression is lost due to its hypermethylated promoter across a range of cancer types including gastric cancer (GC), its functions and molecular underpinnings remain largely unknown. Here we demonstrate that reduced CDO1 expression is indicative of unfavorable prognosis in patients with GC. CDO1 overexpression in GC cells markedly inhibits cellular proliferation in vitro and in vivo. Mechanistically, CDO1 exerts this cytostatic effect via increasing oxidative stress and thus activating integrated stress response (ISR) in GC cells. High throughput screening (HTS) of antioxidants library identifies that Engeletin, a flavanonol glycoside, blunts oxidative stress and the ISR to relieve the inhibitory effect of CDO1 on the proliferation in GC cells. Additionally, genetic disruption or pharmaceutical inhibition of the ISR boosts the growth in the GC cells with CDO1 expression. Our data uncover the molecular mechanisms underlying the cytostatic function of CDO1 in the proliferation of GC cells.
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Affiliation(s)
- Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Zhenzhen Zhao
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Yang Qu
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Siya Liu
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China.
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10
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miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression. Cell Mol Life Sci 2022; 79:216. [PMID: 35348905 PMCID: PMC8964646 DOI: 10.1007/s00018-022-04228-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs about 22 nucleotides in length that regulate the expression of target genes post-transcriptionally, and are highly involved in cancer progression. They are able to impact a variety of cell processes such as proliferation, apoptosis and differentiation and can consequently control tumor initiation, tumor progression and metastasis formation. miRNAs can regulate, at the same time, metabolic gene expression which, in turn, influences relevant traits of malignancy such as cell adhesion, migration and invasion. Since the interaction between metabolism and adhesion or cell movement has not, to date, been well understood, in this review, we will specifically focus on miRNA alterations that can interfere with some metabolic processes leading to the modulation of cancer cell movement. In addition, we will analyze the signaling pathways connecting metabolism and adhesion/migration, alterations that often affect cancer cell dissemination and metastasis formation.
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11
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Weidle UH, Nopora A. MicroRNAs and Corresponding Targets in Esophageal Cancer as Shown In Vitro and In Vivo in Preclinical Models. Cancer Genomics Proteomics 2022; 19:113-129. [PMID: 35181582 DOI: 10.21873/cgp.20308] [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: 11/23/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/08/2023] Open
Abstract
Squamous cell carcinoma of the esophagus is associated with a dismal prognosis. Therefore, identification of new targets and implementation of new treatment modalities are issues of paramount importance. Based on a survey of the literature, we identified microRNAs conferring antitumoral activity in preclinical in vivo experiments. In the category of miRs targeting secreted factors and transmembrane receptors, four miRs were up-regulated and 10 were down-regulated compared with five out of nine in the category transcription factors, and six miRs were down-regulated in the category enzymes, including metabolic enzymes. The down-regulated miRs have targets which can be inhibited by small molecules or antibody-related entities, or re-expressed by reconstitution therapy. Up-regulated miRs have targets which can be reconstituted with small molecules or inhibited with antagomirs.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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12
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Pang P, Fang H, Wu H, Wang S, Liu M, Jin S, Qi Z, Li Z, Liu F, Sun C. Specificity protein 1/microRNA-92b forms a feedback loop promoting the migration and invasion of head and neck squamous cell carcinoma. Bioengineered 2021; 12:11397-11409. [PMID: 34905435 PMCID: PMC8810166 DOI: 10.1080/21655979.2021.2008698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 11/09/2022] Open
Abstract
In this study we report a novel specificity protein 1 (SP1)/microRNA-92b (miR-92b) feedback loop regulating the migration and invasion of head and neck squamous cell carcinoma (HNSCC). Microarray and real-time Polymerase Chain Reaction (PCR) were used to detect gene expression in HNSCC tissues and cell lines. Transwell migration, invasion, wound healing and cell counting kit - 8 (CCK-8) cell assays were used to compare cell migration, invasion and proliferation abilities. Chromatin Immunoprecipitation (ChIP) assays were used to detect SP1 binding to the miR-92b promoter. Western blot was used to detect protein levels. An in vivo tumorigenesis experiment was used to evaluate the effect of SP1 knockdown on tumor growth and protein levels were evaluated by immunohistochemistry. We found that the miR-92b expression level was elevated in HNSCC primary focus tissue compared with adjacent normal tissue, and a higher level of miR-92b was related to a higher clinical stage and worse prognosis of HNSCC patients. MiR-92b and SP1 mutually promoted each expression and cooperatively facilitated the migration, invasion and proliferation of HNSCC cells. A decreased level of SP1/miR-92b resulted in a restraint of in vivo tumor growth. In conclusion, our results suggest that the SP1/miR-92b feedback loop generally promotes HNSCC invasion and metastasis, thus presenting a possible therapeutic target in the treatment of HNSCC patients.
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Affiliation(s)
- Pai Pang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Hui Fang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Hong Wu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Song Wang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Minda Liu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Shan Jin
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Zhongzheng Qi
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Zhenning Li
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Fayu Liu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Changfu Sun
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
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13
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Cui D, Cheung ALM. Roles of microRNAs in tumorigenesis and metastasis of esophageal squamous cell carcinoma. World J Clin Oncol 2021; 12:609-622. [PMID: 34513596 PMCID: PMC8394161 DOI: 10.5306/wjco.v12.i8.609] [Citation(s) in RCA: 4] [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: 01/27/2021] [Revised: 05/11/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer that is prevalent in Eastern Asia. Despite recent advances in therapy, the outcome of ESCC patients is still dismal. MicroRNAs (miRNAs) are non-coding RNAs which can negatively modulate gene expression at the post-transcriptional level. The involvement and roles of miRNAs have become one of the hot topics of cancer research in recent years. In ESCC, genetic variations within miRNA coding genes were found to have distinct epidemiological significance in different populations. Dysregulated expression of several miRNAs was reported to be associated with therapeutic response. Functionally, miRNAs can act either in an oncogenic or a tumor-suppressive manner during tumorigenesis of ESCC by interrupting signaling pathways associated with cell proliferation, metabolism, cancer stemness, and resistance to chemo- or radiotherapy. Moreover, miRNAs modulate metastasis of ESCC by targeting genes that regulate cytoskeleton dynamics, extracellular matrix remodeling, epithelial-mesenchymal transition, and tumor microenvironment. Most importantly, mounting evidence suggests that inhibiting oncogenic miRNAs or restoring the loss of tumor-suppressive miRNAs has therapeutic potential in the treatment of ESCC. Here, we review and discuss recent studies on the significance, biological functions, and therapeutic potential of miRNAs in tumorigenesis and metastasis of ESCC.
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Affiliation(s)
- Di Cui
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China
| | - Annie LM Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China
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14
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Kiss D, Machackova T, Souckova K, Fabian P, Krepelkova I, Svoboda M, Kiss I. An Independent Validation Study of Candidate microRNAs as Predictive Biomarkers for Bevacizumab-based Therapy in Patients With Metastatic Colorectal Cancer. In Vivo 2021; 35:2809-2814. [PMID: 34410972 DOI: 10.21873/invivo.12567] [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: 04/08/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM The monoclonal antibody bevacizumab is a standard drug used in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) based chemotherapy in the first or second-line treatment of metastatic colorectal cancer (mCRC). Our previous study identified and subsequently validated 4 microRNAs in a small group of patients as predictors of the therapeutic response to bevacizumab combined with chemotherapy. The aim of this follow-up study is to confirm the predictive ability of these tissue miRNAs in a larger independent cohort of mCRC patients. PATIENTS AND METHODS The retrospective study included 92 patients with generalized-radically inoperable tumors treated with the combined therapy of bevacizumab/FOLFOX in a standard regimen. RESULTS Expression levels of candidate miRNA biomarkers (miR-92b-3p, miR-3156-5p, miR-10a-5p and miR-125a-5p) were determined in tumor tissue specimens and statistically evaluated. MiR-92b-3p and miR-125a-5p were confirmed to be associated with radiological response according to RECIST criteria (p=0.005 and 0.05, respectively) and to be up-regulated in responders to bevacizumab/FOLFOX therapy. Higher levels of miR-92b-3p were also significantly associated with extended progression-free survival (p=0.024). CONCLUSION We have successfully confirmed miR-92b-3p to be up-regulated in tumor tissue of mCRC patients with good response to bevacizumab/FOLFOX therapy.
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Affiliation(s)
- David Kiss
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Department of Cardiology and Internal Medicine, University Hospital Brno, Brno, Czech Republic
| | - Tana Machackova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Kamila Souckova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Pavel Fabian
- Department of Clinical and Experimental Pahology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | - Marek Svoboda
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Igor Kiss
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic; .,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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15
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Zhao F, Yang Z, Gu X, Feng L, Xu M, Zhang X. miR-92b-3p Regulates Cell Cycle and Apoptosis by Targeting CDKN1C, Thereby Affecting the Sensitivity of Colorectal Cancer Cells to Chemotherapeutic Drugs. Cancers (Basel) 2021; 13:cancers13133323. [PMID: 34283053 PMCID: PMC8268555 DOI: 10.3390/cancers13133323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/19/2021] [Accepted: 06/24/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Multidrug resistance (MDR) limits the effectiveness of colorectal cancer (CRC) treatment and miRNAs play an important role in drug resistance. To search for miRNA targets that may be involved in the CRC MDR phenotype, this study used small RNAomic screens to analyze the expression profiles of miRNAs in CRC HCT8 cell line and its chemoresistant counterpart HCT8/T cell line. It was found that miR-92b-3p was highly expressed in HCT8/T cells and chemotherapeutic drugs could stimulate CRC cells to up-regulate miR-92b-3p expression and conferred cellular resistance to chemotherapeutic drugs. This study revealed a new mechanism of MDR in CRC, elucidating for the first time the direct link between miR-92b-3p/CDKN1C and chemoresistance. In summary, this study suggested that miR-92b-3p could be used as a potential therapeutic target for reversing MDR in chemotherapy and as a candidate biomarker for predicting the efficacy of chemotherapy. Abstract Colorectal cancer (CRC) is the third most common malignant tumor in the world and the second leading cause of cancer death. Multidrug resistance (MDR) has become a major obstacle in the clinical treatment of CRC. The clear molecular mechanism of MDR is complex, and miRNAs play an important role in drug resistance. This study used small RNAomic screens to analyze the expression profiles of miRNAs in CRC HCT8 cell line and its chemoresistant counterpart HCT8/T cell line. It was found that miR-92b-3p was highly expressed in HCT8/T cells. Knockdown of miR-92b-3p reversed the resistance of MDR HCT8/T cells to chemotherapeutic drugs in vitro and in vivo. Paclitaxel (PTX, a chemotherapy medication) could stimulate CRC cells to up-regulate miR-92b-3p expression and conferred cellular resistance to chemotherapeutic drugs. In studies on downstream molecules, results suggested that miR-92b-3p directly targeted Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, which encodes a cell cycle inhibitor p57Kip2) to inhibit its expression and regulate the sensitivity of CRC cells to chemotherapeutic drugs. Mechanism study revealed that the miR-92b-3p/CDKN1C axis exerted a regulatory effect on the sensitivity of CRC cells via the regulation of cell cycle and apoptosis. In conclusion, these findings showed that miR-92b-3p/CDKN1C was an important regulator in the development of drug resistance in CRC cells, suggesting its potential application in drug resistance prediction and treatment.
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16
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Ju G, Zhu Y, Du T, Cao W, Lin J, Li C, Xu D, Wang Z. MiR-197 Inhibitor Loaded AbCD133@MSNs@GNR Affects the Development of Prostate Cancer Through Targeting ITGAV. Front Cell Dev Biol 2021; 9:646884. [PMID: 34195187 PMCID: PMC8238009 DOI: 10.3389/fcell.2021.646884] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/27/2021] [Indexed: 12/25/2022] Open
Abstract
Prostate cancer is one of the most severe male malignant tumors, which ranks second in mortality rate among all tumors. Traditional methods of treatment for prostate cancer produce obvious side effects and a high recurrence rate. Cancer stem cells are considered to be a group of cells that determine the proliferation, metastasis, and drug resistance of tumor. Prostate cancer therapy based on microRNAs and prostate cancer stem cells (PCSCs) has been a research hot spot in this field. Previous studies have reported that miR-197 plays an important role in the occurrence and development of prostate cancer, but the molecular mechanism of miR-197 on the development of prostate cancer has not been reported yet. In this study, we verified that miR-197 is significantly overexpressed in prostate cancer tissues and prostate cancer cells. Then, we verified that miR-197 expression affects the proliferation, invasion, and metastasis of prostate cancer cells by regulating integrin subunit alpha V (ITGAV) expression through STAT5 pathway, and the results indicated that the miR-197 inhibitor can be a prostate cancer suppressor. Then we synthesized the AbCD133@GNR@MSNs@miR-197 inhibitor drug carrier, in which 35.42 μg of the miR-197 inhibitor could be loaded in 1 mg of AbCD133@GNR@MSNs. The AbCD133@GNR@MSNs@miR-197 inhibitor demonstrated good photothermal properties and photothermal controlled-release properties. The modified CD133 antibodies on the surface of the nano drug carrier helped more drug carriers to enter the PCSCs. The pharmacodynamic effects of the AbCD133@GNR@MSNs@miR-197 inhibitor on PCSCs in vivo and in vitro were studied under near-infrared radiation. The results showed that the AbCD133@GNR@MSNs@miR-197 inhibitor prepared in this study could not only significantly suppress the development of PCSCs through ITGAV/STAT5 pathway but also significantly suppress the growth of PCSC solid tumors. In short, our study verified that miR-197 regulates the development of PCSCs through STAT5 pathway by targeting ITGAV, and the AbCD133@MSNs@GNR@miR-197 inhibitor could be a potential suppressor used in prostate cancer treatment. In short, our study found that miR-197 affected the development of prostate cancer by regulating ITGAV. The AbCD133@GNR@MSNs@miR-197 inhibitor prepared in this study could suppress the development and growth of PCSCs in vitro and in solid tumors not only by targeting the ITGAV but also through photothermal therapy. Our study not only provides a theoretical basis for the clinical treatment of prostate cancer but also provides a research scheme of drug loading and microRNA-based photothermal controlled therapy for prostate cancer.
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Affiliation(s)
- Guanqun Ju
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yingjian Zhu
- Department of Urology, Shanghai Jiangqiao Hospital, Shanghai General Hospital Jiading Branch, Shanghai, China
| | - Tao Du
- Department of Urology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Wanli Cao
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jianhai Lin
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Chun Li
- Key Laboratory of Functional Genomic and Molecular Diagnosis of Gansu Province, Lanzhou, China
| | - Dongliang Xu
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China.,Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhijun Wang
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
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17
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Li P, Butcher NJ, Minchin RF. Effect arylamine N-acetyltransferase 1 on morphology, adhesion, migration, and invasion of MDA-MB-231 cells: role of matrix metalloproteinases and integrin αV. Cell Adh Migr 2021; 14:1-11. [PMID: 31910058 PMCID: PMC6961680 DOI: 10.1080/19336918.2019.1710015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Reducted arylamine N-acetyltransferase (NAT1) in breast cancers is associated with poor patient survival. NAT1 has also been associated with changes in cancer cell survival and invasion both invitro and invivo. Here, we report the effects of NAT1 in cancer cell invasion by addressing its role in adherence, migration, and invasion in vitro. The NAT1 gene was deleted in MDA-MB-231, HT-29 and HeLa cells using CRISPR/Cas9 gene editing. Loss of NAT1 increased adherence to collagen in all three cell-lines but migration was unaffected. NAT1 deletion decreased invasion and induced changes to cell morphology. These effects were independent of matrix metalloproteinases but were related to integrin ITGαV expression. The data suggest NAT1 is important in adhesion and invasion through integrin expression.
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Affiliation(s)
- Pengcheng Li
- School of Biomedical Sciences, University of Queensland, St Lucia, Australia
| | - Neville J Butcher
- School of Biomedical Sciences, University of Queensland, St Lucia, Australia
| | - Rodney F Minchin
- School of Biomedical Sciences, University of Queensland, St Lucia, Australia
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18
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Jing C, Li X, Zhou M, Zhang S, Lai Q, Liu D, Ye B, Li L, Wu Y, Li H, Yue K, Chen P, Yao X, Wu Y, Duan Y, Wang X. The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation. Theranostics 2021; 11:5847-5862. [PMID: 33897885 PMCID: PMC8058732 DOI: 10.7150/thno.46109] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 03/11/2021] [Indexed: 12/13/2022] Open
Abstract
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Methods: Through 4-NQO-induced murine ESCC model, we investigated the expression of PSMD14 in esophageal tumorigenesis. Ubiquitin-AMC assay was performed to evaluate DUB activity of PSMD14 with THL treatment. The effect of THL on epithelial-to-mesenchymal transition (EMT), invasion, stemness and chemosensitivity was detected by using in vitro and in vivo experiments. Immunoprecipitation and in vivo ubiquitination assay were conducted to examine whether THL could impair the deubiquitination and stability of SNAIL regulated by PSMD14. Results: Compared with normal esophageal epithelium, PSMD14 was upregulated in 4-NQO-induced murine esophageal epithelium dysplasia and ESCC tissues. THL could significantly weaken DUB activity of PSMD14. Furthermore, the results of in vitro and in vivo assays showed that THL efficiently suppressed motility and stemness and increased sensitivity to cisplatin in ESCC. Mechanically, THL impaired the interaction between PSMD14 and SNAIL, then promoted the ubiquitination and degradation of SNAIL to inhibit EMT which plays a crucial role in ESCC metastasis, stemness and chemosensitivity. TCGA database analysis revealed that high concomitant PSMD14/SNAIL expression predicted shorter overall survival in esophageal cancer. Conclusion: Our findings demonstrate for the first time that suppression of PSMD14/SNAIL axis by THL could be a novel and promising therapeutic approach for ESCC clinical therapy.
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Jing C, Duan Y, Zhou M, Yue K, Zhuo S, Li X, Liu D, Ye B, Lai Q, Li L, Yao X, Wei H, Zhang W, Wu Y, Wang X. Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness. Theranostics 2021; 11:2655-2669. [PMID: 33456565 PMCID: PMC7806466 DOI: 10.7150/thno.48375] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 12/03/2020] [Indexed: 12/25/2022] Open
Abstract
Increasing evidence reveals a close relationship between deubiquitinating enzymes (DUBs) and cancer progression. In this study, we attempted to identify the roles and mechanisms of critical DUBs in head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatics analysis was performed to screen differentially expressed novel DUBs in HNSCC. Immunohistochemistry assay was used to measure the expression of DUB PSMD14 in HNSCC specimens and adjacent normal tissues. The level of PSMD14 in HNSCC tumorigenesis was investigated using a 4-NQO-induced murine HNSCC model. The function of PSMD14 was determined through loss-of-function assays. Chromatin immunoprecipitation, immunoprecipitation and in vivo ubiquitination assay were conducted to explore the potential mechanism of PSMD14. The anti-tumor activity of PSMD14 inhibitor Thiolutin was assessed by in vitro and in vivo experiments. Results: We identified PSMD14 as one of significantly upregulated DUBs in HNSCC tissues. Aberrant expression of PSMD14 was associated with tumorigenesis and malignant progression of HNSCC and further indicated poor prognosis. The results of in vitro and in vivo experiments demonstrated PSMD14 depletion significantly undermined HNSCC growth, chemoresistance and stemness. Mechanically, PSMD14 inhibited the ubiquitination and degradation of E2F1 to improve the activation of Akt pathway and the transcription of SOX2. Furthermore, PSMD14 inhibitor Thiolutin exhibited a potent anti-tumor effect on HNSCC in vivo and in vitro by impairing DUB activity of PSMD14. Conclusion: Our findings demonstrate the role and mechanism of PSMD14 in HNSCC, and provide a novel and promising target for diagnosis and clinical therapy of HNSCC.
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20
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Chen Y, Sheng HG, Deng FM, Cai LL. Downregulation of the long noncoding RNA SNHG1 inhibits tumor cell migration and invasion by sponging miR-195 through targeting Cdc42 in oesophageal cancer. Kaohsiung J Med Sci 2020; 37:181-191. [PMID: 33171523 DOI: 10.1002/kjm2.12318] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/14/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022] Open
Abstract
Despite the poor prognosis of oesophageal cancer (EC), the molecular mechanisms of EC are still unclear. In recent years, role of lncRNA in cancer development attracted much attention. The present study aimed to investigate the effects of the long noncoding RNA SNHG1 on the migration and invasion of EC cells and the possible mechanisms involved. The effects of SNHG1 on cell proliferation, migration, and invasion were determined and its relationship with miR-195/Cdc42 axis was investigated. It was found SNHG1 and Cdc42 were significantly upregulated, and miR-195 was significantly downregulated in both EC tissues and cell lines. In addition, the inhibition of either SNHG1 or Cdc42 resulted in suppression of cell proliferation, migration, and invasion, while inhibition of miR-195 led to opposite results and reversed the effects of si-SNHG1. We also observed that higher SNHG1 predicted poorer prognosis of EC patients. In summary, inhibition of SNHG1 can suppress the cell migration and invasion of EC cells by sponging miR-195 through targeting Cdc42. This study might provide deeper insights into the SNHG1/miR-195/Cdc42 axis in EC.
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Affiliation(s)
- Yu Chen
- Jiangxi Provincial Key Laboratory of Laboratory Medicine, Nanchang, China.,Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hong-Guang Sheng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fu-Mou Deng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li-Ly Cai
- Jiangxi Provincial Key Laboratory of Laboratory Medicine, Nanchang, China.,Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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21
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Sun H, Tian J, Li J. MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells. Int Immunopharmacol 2020; 88:106691. [PMID: 32822908 DOI: 10.1016/j.intimp.2020.106691] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/20/2020] [Accepted: 06/08/2020] [Indexed: 02/08/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. Dysregulation of microRNAs (miRNAs) was involved in human diseases, including AP. However, the effects of miR-92b-3p on AP process and its mechanism remain not been fully clarified. The expression levels of miR-92b-3p and tumor necrosis factor receptor-associated factor-3 (TRAF3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of TRAF3, tumor necrosis factor α (TNF-α) TNF-α, interleukin-6 (IL-6), phosphorylated mitogen-activated protein kinase kinase 3 (p-MKK3), MKK3, p38 and phosphorylated p38 (p-p38) were detected by western blot. The concentration of TNF-α and IL-6 in the medium was measured using ELISA kits. The possible binding sites of miR-92b-3p and TRAF3 were predicted by TargetScan and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The expression level of miR-92b-3p was decreased and TRAF3 expression was increased in AR42J cells stimulated with caerulein. Moreover, the protein levels of pro-inflammatory cytokines (TNF-α and IL-6) were markedly elevated, and the expression levels of autophagy-related markers Beclin1 as well as the ratio of LC3-II/I were obviously increased in AR42J cells treated with caerulein. In addition, overexpression of miR-92b-3p or knockdown of TRAF3 significantly suppressed the release of pro-inflammatory cytokines and autophagy in caerulein-induced AR42J cells. Furthermore, TRAF3 was a direct target of miR-92b-3p and its upregulation reversed the effects of miR-92b-3p overexpression on inflammatory response and autophagy. Besides, overexpression of miR-92b-3p inhibited the activation of the MKK3-p38 pathway by affecting TRAF3 expression. In conclusion, miR-92b-3p attenuated inflammatory response and autophagy by downregulating TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells, providing a novel avenue for treatment of AP.
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Affiliation(s)
- Hongzhi Sun
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jiakun Tian
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jinliang Li
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China.
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22
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Zhang Y, Liu S, Zhou S, Yu D, Gu J, Qin Q, Cheng Y, Sun X. Focal adhesion kinase: Insight into its roles and therapeutic potential in oesophageal cancer. Cancer Lett 2020; 496:93-103. [PMID: 33038490 DOI: 10.1016/j.canlet.2020.10.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/10/2020] [Accepted: 10/02/2020] [Indexed: 12/26/2022]
Abstract
Oesophageal cancer is associated with high morbidity and mortality rates because it is highly invasive and prone to recurrence and metastasis, with a five-year survival rate of <20%. Therefore, there is an urgent need for new methods aimed at improving therapeutic intervention. Several studies have shown that targeted therapy may be effective for the treatment of oesophageal cancer. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase with kinase activity and scaffolding function, could be overexpressed in a variety of solid tumours, including oesophageal cancer. FAK participates in survival, proliferation, progression, adhesion, invasion, migration, epithelial-to-mesenchymal transition, angiogenesis, DNA damage repair, and other biological processes through multiple signalling pathways in cancer cells. It plays an important role in the occurrence and development of tumours and has been linked to the prognosis of oesophageal cancer. FAK has been suggested as a potential therapeutic target in oesophageal cancer; thus, the combination of FAK inhibitors with chemotherapy, radiotherapy, and immunotherapy is expected to prolong the survival of patients. This paper presents a brief overview of the structure of FAK and its potential role in oesophageal cancer, providing a rationale for the future application of FAK inhibitors in the treatment of the disease.
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Affiliation(s)
- Yumeng Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Shu Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Shu Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Dandan Yu
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Junjie Gu
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Qin Qin
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Yu Cheng
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China; The First School of Clinical Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu province, China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China.
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23
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Huang F, Ma G, Zhou X, Zhu X, Yu X, Ding F, Cao X, Liu Z. Depletion of LAMP3 enhances PKA-mediated VASP phosphorylation to suppress invasion and metastasis in esophageal squamous cell carcinoma. Cancer Lett 2020; 479:100-111. [PMID: 32200035 DOI: 10.1016/j.canlet.2020.03.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/29/2020] [Accepted: 03/15/2020] [Indexed: 11/26/2022]
Abstract
Metastasis is still a major cause of cancer-related mortality. Lysosome-associated membrane protein 3 (LAMP3) has been implicated in the invasiveness and metastasis of multiple cancer types; however, the underlying mechanisms are unclear. In this study, we found that LAMP3 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and that this increased expression positively correlated with lymph node metastasis. Depletion of LAMP3 dramatically suppressed the motility of ESCC cells in vitro and experimental pulmonary and lymph node metastasis in vivo. Importantly, knockdown of LAMP3 increased the level of phosphorylated VASP(Ser239), which attenuated the invasive and metastatic capability of ESCC cells. We identified that cAMP-dependent protein kinase A (PKA) was responsible for the phosphorylation of VASP at Ser239. Consistently, silencing of PKA regulatory subunits diminished Ser239 phosphorylation on VASP and restored the motility capacity of LAMP3-depleted ESCC cells. In conclusion, we uncovered a previously unknown role of LAMP3 in promoting cellular motility and metastasis in ESCC.
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Affiliation(s)
- Furong Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Gang Ma
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Xuantong Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaolin Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiao Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fang Ding
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiufeng Cao
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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24
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Zhao H, Yan G, Zheng L, Zhou Y, Sheng H, Wu L, Zhang Q, Lei J, Zhang J, Xin R, Jiang L, Zhang X, Chen Y, Wang J, Xu Y, Li D, Li Y. STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma. Theranostics 2020; 10:6483-6499. [PMID: 32483465 PMCID: PMC7255033 DOI: 10.7150/thno.44025] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca2+)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC via metabolic reprogramming is unclear. Methods: The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated via lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate in vitro and lung metastasis in vivo. Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. Results: STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, i.e., from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. Conclusions: Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis via reprogramming HCC metabolism.
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25
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Li M, Pan M, You C, Zhao F, Wu D, Guo M, Xu H, Shi F, Zheng D, Dou J. MiR-7 reduces the BCSC subset by inhibiting XIST to modulate the miR-92b/Slug/ESA axis and inhibit tumor growth. Breast Cancer Res 2020; 22:26. [PMID: 32143670 PMCID: PMC7060548 DOI: 10.1186/s13058-020-01264-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/26/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown. METHODS We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays. RESULTS MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-κB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7. CONCLUSIONS The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer.
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Affiliation(s)
- Miao Li
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China
| | - Meng Pan
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China.,Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Chengzhong You
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Fengshu Zhao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China
| | - Di Wu
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Mei Guo
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China
| | - Hui Xu
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China
| | - Fangfang Shi
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Danfeng Zheng
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China
| | - Jun Dou
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China.
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26
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He H, Wu Z, Li S, Chen K, Wang D, Zou H, Chen H, Li Y, Liu Z, Qu C. TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression. Cancer Lett 2020; 469:380-389. [PMID: 31730901 DOI: 10.1016/j.canlet.2019.11.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 01/01/2023]
Abstract
The tumor necrosis factor receptor-associated factor 7 (TRAF7) is a component of the tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB) pathway and is a putative E3-ubiquitin ligase. Based on importance of chronic inflammation in hepatocellular carcinoma (HCC), we investigated the biological effects and the molecular mechanisms of deregulated TRAF7 signaling in HCC. Our results showed that high TRAF7 expression in HCC samples was inversely associated with Krüppel-like factor 4 (KLF4) expression and the prognosis of HCC patients. TRAF7 could degrade KLF4 protein through ubiquitin by interacting with its N-terminus. The up-regulation of TRAF7 promoted HCC cell migration and invasion in vivo and in vitro, and TRAF7 knockdown had the opposite effects. Restoration of KLF4 abrogated the motility promotion induced by TRAF7. TRAF7 promotes HCC cell motility through inducing KLF4 protein turnover.
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Affiliation(s)
- Huan He
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhiyuan Wu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Sheng Li
- Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Kun Chen
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Dongmei Wang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haojing Zou
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hongyan Chen
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yi Li
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhihua Liu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Chunfeng Qu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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27
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Nakano T, Chen IH, Wang CC, Chen PJ, Tseng HP, Huang KT, Hu TH, Li LC, Goto S, Cheng YF, Lin CC, Chen CL. Circulating exosomal miR-92b: Its role for cancer immunoediting and clinical value for prediction of posttransplant hepatocellular carcinoma recurrence. Am J Transplant 2019; 19:3250-3262. [PMID: 31162867 DOI: 10.1111/ajt.15490] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/08/2019] [Accepted: 05/11/2019] [Indexed: 01/25/2023]
Abstract
A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence.
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Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - I-Hsuan Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Po-Jung Chen
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hui-Peng Tseng
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuang-Tzu Huang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Liver Transplantation Center and Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Lung-Chih Li
- Liver Transplantation Center and Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shigeru Goto
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka, Miyazaki, Japan.,Faculty of Nursing, Department of Nursing, Josai International University, Togane, Chiba, Japan
| | - Yu-Fan Cheng
- Liver Transplantation Center and Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Zhang W, Duan W, Mo Z, Wang J, Yang W, Wu W, Li X, Lin S, Tan Y, Wei W. Upregulation of SNHG14 suppresses cell proliferation and metastasis of colorectal cancer by targeting miR‐92b‐3p. J Cell Biochem 2019; 121:1998-2008. [PMID: 31692034 DOI: 10.1002/jcb.29434] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 10/10/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Wei Zhang
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Wenfei Duan
- Department of General Surgery The First Affiliated Hospital of Henan University Kaifeng China
| | - Zhifeng Mo
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Jianen Wang
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Wenbin Yang
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Wenrong Wu
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Xian Li
- Department of Obstetrics and Gynaecology The University of Hong Kong‐Shenzhen Hospital Shenzhen China
| | - Shuihua Lin
- Department of Medical Imaging The University of Hong Kong‐Shenzhen Hospital Shenzhen China
| | - Yuanfei Tan
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
| | - Wei Wei
- Emergency and Disaster Medical Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen China
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29
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Yao J, Zhang Z, Li S, Li B, Wang XH. Melittin inhibits proliferation, migration and invasion of bladder cancer cells by regulating key genes based on bioinformatics and experimental assays. J Cell Mol Med 2019; 24:655-670. [PMID: 31691530 PMCID: PMC6933335 DOI: 10.1111/jcmm.14775] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 09/05/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
The antitumour effect of melittin (MEL) has recently attracted considerable attention. Nonetheless, information regarding the functional role of MEL in bladder cancer (BC) is currently limited. Herein, we investigated the effect of MEL on critical module genes identified in BC. In total, 2015 and 4679 differentially expressed genes (DEGs) associated with BC were identified from the GSE31189 set and The Cancer Genome Atlas database, respectively. GSE‐identified DEGs were mapped and analysed using Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses to determine BC‐involved crucial genes and signal pathways. Coupled with protein–protein interaction network and Molecular Complex Detection analyses, Modules 2 and 4 were highlighted in the progression of BC. In in‐vitro experiments, MEL inhibited the proliferation, migration, and invasion of UM‐UC‐3 and 5637 cells. The expression of NRAS, PAK2, EGFR and PAK1 in Module 4—enriched in the MAPK signalling pathway—was significantly reduced after treatment with MEL at concentrations of 4 or 6 μg/mL. Finally, quantitative reverse transcription‐polymerase chain reaction and Western blotting analyses revealed MEL inhibited the expression of genes at the mRNA (ERK1/2, ERK5, JNK and MEK5), protein (ERK5, MEK5, JNK and ERK1/2) and phosphorylation (p‐ERK1/2, p‐JNK, and p‐38) levels. This novel evidence indicates MEL exerts effects on the ERK5‐MAK pathway—a branch of MAPK signalling pathway. Collectively, these findings provide a theoretical basis for MEL application in BC treatment.
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Affiliation(s)
- Jie Yao
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhan Zhang
- Department of Rehabilitation Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Sheng Li
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bai Li
- Department of Rehabilitation Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xing-Huan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
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30
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Li C, Huo B, Wang Y, Cheng C. Downregulation of microRNA‐92b‐3p suppresses proliferation, migration, and invasion of gastric cancer SGC‐7901 cells by targeting Homeobox D10. J Cell Biochem 2019; 120:17405-17412. [PMID: 31106881 DOI: 10.1002/jcb.29005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/29/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Cheng Li
- Department of Surgical Oncology Shannxi Provincial People's Hospital Xi'an Shaanxi China
| | - Binliang Huo
- Department of Surgical Oncology Shannxi Provincial People's Hospital Xi'an Shaanxi China
| | - Yongheng Wang
- Department of Surgical Oncology Shannxi Provincial People's Hospital Xi'an Shaanxi China
| | - Chong Cheng
- Department of Surgical Oncology Shannxi Provincial People's Hospital Xi'an Shaanxi China
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31
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Reichenbach ZW, Murray MG, Saxena R, Farkas D, Karassik EG, Klochkova A, Patel K, Tice C, Hall TM, Gang J, Parkman HP, Ward SJ, Tétreault MP, Whelan KA. Clinical and translational advances in esophageal squamous cell carcinoma. Adv Cancer Res 2019; 144:95-135. [PMID: 31349905 DOI: 10.1016/bs.acr.2019.05.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is among the most deadly forms of human malignancy characterized by late stage diagnosis, metastasis, therapy resistance and frequent recurrence. Clinical management of ESCC remains challenging and the disease presently lacks approved targeted therapeutics. However, emerging data from recent clinical and translational investigations hold great promise for future progress toward improving patient outcomes in this deadly disease. Here, we review current clinical perspectives in ESCC epidemiology, pathophysiology, and clinical care, highlighting recent advances with potential to impact ESCC prevention, diagnosis and management. We further provide an overview of recent translational investigations contributing to our understanding of the molecular mechanisms underlying ESCC development, progression and therapy response, including insights gained from genetic studies and various murine model systems. Finally, we discuss future perspectives in the clinical and translational realms, along with remaining hurdles that must be overcome to eradicate ESCC.
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Affiliation(s)
- Zachary Wilmer Reichenbach
- Department of Medicine, Gastroenterology Section, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Mary Grace Murray
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Reshu Saxena
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Daniel Farkas
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Erika G Karassik
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Alena Klochkova
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Kishan Patel
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Caitlin Tice
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Timothy M Hall
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Julie Gang
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Henry P Parkman
- Department of Medicine, Gastroenterology Section, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Sarah J Ward
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
| | - Kelly A Whelan
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States; Department of Pathology & Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.
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32
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Prognostic Value of MicroRNAs in Esophageal Carcinoma: A Meta-Analysis. Clin Transl Gastroenterol 2018; 9:203. [PMID: 30420592 PMCID: PMC6232177 DOI: 10.1038/s41424-018-0070-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 09/26/2018] [Accepted: 10/08/2018] [Indexed: 12/18/2022] Open
Abstract
Background Numerous articles have reported that abnormal expression levels of microRNAs (miRNAs) are related to the survival times of esophageal carcinoma (EC) patients, which contains esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Nevertheless, there has not been a comprehensive meta-analysis to assess the accurate prognostic value of miRNAs in EC. Methods Studies published in English up to April 12, 2018 that evaluated the correlation of the expression levels of miRNAs with overall survival (OS) in EC were identified by online searches in PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews performed by two independent authors. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the correlation between OS and miRNA expression. HR ≥ 2 was considered cutoff for considering the miRNA as prognostic candidate. Results Forty-four pertinent articles with 22 miRNAs and 4310 EC patients were ultimately included. EC patients with tissue expression levels of high miR-21 or low miR-133a (HR = 2.48, 95% CI = 1.50–4.12), miR-133b (HR = 2.15, 95% CI = 1.27–3.62), miR-138 (HR = 2.27, 95% CI = 1.68–3.08), miR-203 (HR = 2.83, 95% CI = 1.35–5.95), miR-375 and miR-655 (HR = 2.66, 95% CI = 1.16–6.12) had significantly poorer OS (P < 0.05). In addition, EC patients with blood expression levels of high miR-21 (HR = 2.19, 95% CI = 1.31–3.68) and miR-223 had significantly shorter OS (P < 0.05). Conclusions In conclusion, tissue expression levels of miR-21, miR-133a, miR-133b, miR-138, miR-203, miR-375, and miR-655 and blood expression levels of miR-21 and miR-223 demonstrate significant prognostic value. Among them, the expression levels of miR-133a, miR-133b, miR-138, miR-203, and miR-655 in tissue and the expression level of miR-21 in blood are potential prognostic candidates for predicting OS in EC.
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Liu F, Sang M, Meng L, Gu L, Liu S, Li J, Geng C. miR‑92b promotes autophagy and suppresses viability and invasion in breast cancer by targeting EZH2. Int J Oncol 2018; 53:1505-1515. [PMID: 30066891 PMCID: PMC6086627 DOI: 10.3892/ijo.2018.4486] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 05/30/2018] [Indexed: 01/02/2023] Open
Abstract
MicroRNAs (miRs) are a small non-coding RNA family with a length of 18–22 nucleotides. They are able to regulate gene expression by either triggering target messenger RNA degradation or by inhibiting mRNA translation. Enhancer of zeste homolog 2 (EZH2) is the core enzymatic subunit of polycomb repressor complex 2 and is responsible for the trimethylation of histone 3 on lysine 27 (H3K27me3); it is also able to silence a bundle of tumor suppressor genes through promoter binding. However, little is known regarding the effect of miR-92b on cell autophagy, viability and invasion as well as how it interacts with EZH2. The present study investigated the major role of miR-92b in the autophagy, viability and invasion of breast cancer. It was revealed that in MCF-7 and MDA-MB-453 cells, the expression of miR-92b promoted autophagy induced by starvation and rapamycin treatment. The results of in vitro experiments results demonstrated that miR-92b inhibited breast cancer cell viability, invasion and migration. To further elucidate the regulatory mechanisms of miR-92b in autophagy, a dual luciferase reporter assay was performed to determine whether miR-92b targeted the EZH2 gene. The expression of miR-92b was negatively correlated to EZH2 mRNA expression in breast cancer. Depletion of EZH2 induced phenocopied effects on miR-92b overexpression, thereby demonstrating its importance in autophagy. These results indicated that miR-92b may serve an important role in breast cancer in controlling autophagy, viability and invasion. The present study indicated that miR-92b and EZH2 may serve as potential biomarkers for cancer detection and highlighted their possible therapeutic implications.
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Affiliation(s)
- Fei Liu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Meixiang Sang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Lingjiao Meng
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Lina Gu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Shina Liu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Juan Li
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Cuizhi Geng
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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Naser R, Aldehaiman A, Díaz-Galicia E, Arold ST. Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development. Cancers (Basel) 2018; 10:E196. [PMID: 29891810 PMCID: PMC6025627 DOI: 10.3390/cancers10060196] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 05/31/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023] Open
Abstract
Focal adhesion kinase (FAK) and its close paralogue, proline-rich tyrosine kinase 2 (PYK2), are key regulators of aggressive spreading and metastasis of cancer cells. While targeted small-molecule inhibitors of FAK and PYK2 have been found to have promising antitumor activity, their clinical long-term efficacy may be undermined by the strong capacity of cancer cells to evade anti-kinase drugs. In healthy cells, the expression and/or function of FAK and PYK2 is tightly controlled via modulation of gene expression, competing alternatively spliced forms, non-coding RNAs, and proteins that directly or indirectly affect kinase activation or protein stability. The molecular factors involved in this control are frequently deregulated in cancer cells. Here, we review the endogenous mechanisms controlling FAK and PYK2, and with particular focus on how these mechanisms could inspire or improve anticancer therapies.
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Affiliation(s)
- Rayan Naser
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
| | - Abdullah Aldehaiman
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
| | - Escarlet Díaz-Galicia
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
| | - Stefan T Arold
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia.
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Zheng S, Zhang X, Wang X, Li J. Downregulation of miR-138 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Biomark 2018; 20:49-54. [PMID: 28759955 DOI: 10.3233/cbm-170079] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) have been proven to be critical players in many different types of tumors including esophageal squamous cell carcinoma (ESCC). OBJECTIVE This study aimed at investigating the correlation of miR-138 expression and clinical outcome of patients with ESCC. METHODS A total of 168 serum samples and 128 fresh cancer tissues as well as their corresponding adjacent non-cancerous tissues were collected. Real-time PCR was performed to evaluate the clinical value of miR-138 in ESCC. RESULTS Our results showed that tissue and serum miR-138 levels were both significantly reduced in ESCC compared to their respective controls. Tissue miR-138 levels were highly correlated with serum miR-138 levels. Serum miR-138 differentiated patients with ESCC from healthy controls with high accuracy. In addition, reduced tissue/serum miR-138 levels were correlated with unfavorable clinicopathological parameters including T stage, lymph node metastasis and TNM stage. ESCC patients with lower tissue/serum miR-138 levels had shorter five year overall survival compared with those with higher tissue/serum miR-138 levels. Finally, downregulation of miR-138 was demonstrated to be an independent prognostic risk factor for ESCC. CONCLUSIONS In conclusion, both tissue and serum miR-138 levels are reduced in ESCC, and might be promising prognostic biomarkers for ESCC.
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Identification of molecular targets for esophageal carcinoma diagnosis using miRNA-seq and RNA-seq data from The Cancer Genome Atlas: a study of 187 cases. Oncotarget 2018; 8:35681-35699. [PMID: 28415685 PMCID: PMC5482608 DOI: 10.18632/oncotarget.16051] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/28/2017] [Indexed: 12/14/2022] Open
Abstract
Esophageal carcinoma (ESCA) is one of the most common malignancies worldwide, and its pathogenesis is complex. In this study, we identified differentially expressed miRNAs (DEMs) and genes (DEGs) of ESCA from The Cancer Genome Atlas (TCGA) database. The diagnostic values of DEMs were determined by receiver operating characteristic (ROC) analyses and validated based on data from Gene Expression Omnibus (GEO). The top five DEMs with the best diagnostic values were selected, and their potential targets were predicted by various in silico methods. These target genes were then identified among the DEGs from TCGA. Furthermore, the overlapping genes were subjected to protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The miRNA-transcription factor (TF) regulatory relations were determined using CircuitsDB and TransmiR. Finally, the regulatory networks of miRNA-TF and miRNA-gene were constructed and analyzed. A total of 136 DEMs and 3541 DEGs were identified in ESCA. The top five DEMs with the highest area under the receiver operating characteristic curve (AUC) values were miRNA-93 (0.953), miRNA-21 (0.928), miRNA-4746 (0.915), miRNA-196a-1 (0.906) and miRNA-196a-2 (0.906). The combined AUC of these five DEMs was 0.985. The KEGG analysis with 349 overlapping genes showed that the calcium signaling pathway and the neuroactive ligand-receptor interaction were the most relevant pathways. The regulatory networks of miRNA-TF and miRNA-gene, including 38 miRNA-TF and 560 miRNA-gene pairs, were successfully established. Our findings may provide new insights into the molecular mechanisms of ESCA pathogenesis. Future research will aim to explore the role of novel miRNAs in the pathogenesis and improve the early diagnosis of ESCA.
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Ma G, Jing C, Huang F, Li X, Cao X, Liu Z. Integrin α6 promotes esophageal cancer metastasis and is targeted by miR-92b. Oncotarget 2018; 8:6681-6690. [PMID: 28036265 PMCID: PMC5351662 DOI: 10.18632/oncotarget.14259] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 12/12/2016] [Indexed: 01/05/2023] Open
Abstract
Tumor invasion and metastasis is responsible for the poor prognosis of esophageal squamous cell carcinoma (ESCC); therefore, exploring the mechanisms by which malignant cells disseminate, spread and flourish in secondary sites, as well as translating the bench results to clinical practice are in urgent need. Previous reports showed that integrin α6 increases in ESCC specimens and its dysregulated spatial localization correlates positively with the unfavorable outcome of ESCC patients. Here, we clarify that integrin α6 promotes invasion and metastasis of ESCC cells In vitro and in vivo. Mechanistically, decreased integrin α6 attenuates motility of malignant cells partially through deactivating Akt pathway, which is essential for ESCC cells motility. Moreover, integrin α6 serves as a genuine target of miR-92b in suppressing ESCC motility. Our results for the first time describe that miR-92b/integrin α6/Akt axis controls the motility of ESCC, thereby providing a promising diagnosis or therapeutic option.
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Affiliation(s)
- Gang Ma
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing, China
| | - Chao Jing
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing, China
| | - Furong Huang
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing, China
| | - Xukun Li
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing, China
| | - Xiufeng Cao
- Department of Oncological Surgery, The Affiliated Nanjing 1st Hospital, Nanjing Medical University, Nanjing, China
| | - Zhihua Liu
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing, China
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MicroRNA-182 drives colonization and macroscopic metastasis via targeting its suppressor SNAI1 in breast cancer. Oncotarget 2018; 8:4629-4641. [PMID: 27894095 PMCID: PMC5354860 DOI: 10.18632/oncotarget.13542] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 11/07/2016] [Indexed: 12/12/2022] Open
Abstract
Metastasis is a multi-step process. Tumor cells occur epithelial-mesenchymal transition (EMT) to start metastasis, then, they need to undergo a reverse progression of EMT, mesenchymal-epithelial transition (MET), to colonize and form macrometastases at distant organs to complete the whole process of metastasis. Although microRNAs (miRNAs) functions in EMT process are well established, their influence on colonization and macrometastases formation remains unclear. Here, we established an EMT model in MCF-10A cells with SNAI1 overexpression, and characterized some EMT-related microRNAs. We identified that miR-182, which was directly suppressed by SNAI1, could enable an epithelial-like state in breast cancer cells in vitro, and enhance colonization and macrometastases in vivo. Subsequent studies showed that miR-182 exerted its function through targeting its suppressor SNAI1. Moreover, higher expression level of miR-182 was detected in metastatic lymph nodes, compared with paired primary tumor tissues. In addition, the expression level of miR-182 was negatively correlated with that of SNAI1 in these clinical specimens. Taking together, our findings describe the role of miR-182 in colonization and macrometastases in breast cancer for the first time, and provide a promise for diagnosis or therapy of breast cancer metastasis.
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Qian J, Ji F, Ye X, Cheng H, Ma R, Chang X, Shou C, Cui H. IGHG1 promotes motility likely through epithelial-mesenchymal transition in ovarian cancer. Chin J Cancer Res 2018; 30:282-290. [PMID: 29861613 DOI: 10.21147/j.issn.1000-9604.2018.02.11] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Objective Ovarian cancer (OC) is one of the leading causes of death for female cancer patients. COC166-9 is an OC-specific monoclonal antibody and we have identified immunoglobulin γ-1 heavy chain constant region (IGHG1) as its antigen. We explore the function of IGHG1 in proliferation, apoptosis and motility of OC cells further in this research. Methods IGHG1 expression in OC specimens was detected through immunohistochemistry. Real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting assay was used to test IGHG1 expression in OC cells. Viability of OC cells was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry or western blotting assay was used to detect cell cycle and apoptosis. Cellular motility was analyzed by using transwell assay and the markers of epithelial-mesenchymal transition (EMT) were tested through immunoblots. Results Although it exerts negligible effect on the viability and apoptosis of OC cells, IGHG1 could promote migration and invasion of malignant cells in vitro. Mechanistically, IGHG1 increases the expression of N-cadherin and Vimentin while decreases E-cadherin expression. Additionally, IGHG1 expression in OC specimens is higher relative to the paired normal counterparts. Further analysis demonstrates that the increased IGHG1 expression correlates positively with the lymph node metastasis of OC. Conclusions IGHG1 promotes the motility of OC cells likely through executing the EMT program. Increased IGHG1 expression in OC specimens is associated with the lymph node metastasis.
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Affiliation(s)
- Jingfeng Qian
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Fangxing Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xue Ye
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Hongyan Cheng
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Ruiqiong Ma
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Xiaohong Chang
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Heng Cui
- Center of Gynecological Oncology, Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
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Luo J, Wang Z, Huang J, Yao Y, Sun Q, Wang J, Shen Y, Xu L, Ren B. HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3. Cancer Sci 2017; 109:317-329. [PMID: 29168599 PMCID: PMC5797812 DOI: 10.1111/cas.13453] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/15/2017] [Accepted: 11/17/2017] [Indexed: 12/20/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC), the dominant subtype of esophageal cancer, is one of the most common digestive tumors worldwide. In this study, we confirmed that HOXC13, a member of the homeobox HOXC gene family, was significantly upregulated in ESCC and its overexpression was associated with poorer clinical characteristics and worse prognosis. Moreover, knockdown of HOXC13 inhibited proliferation and induced apoptosis of ESCC through upregulating CASP3. ChIP analysis revealed that HOXC13 repressed transcription of CASP3 through directly targeting the promotor region of CASP3. We also found that miR‐503 downregulated HOXC13, by directly targeting its 3′UTR, and inhibited proliferation of ESCC. In conclusion, our study demonstrates that HOXC13, which is directly targeted by miR‐503, promotes proliferation and inhibits apoptosis of ESCC through repressing transcription of CASP3.
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Affiliation(s)
- Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China
| | - Zhongqiu Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, Institute Affiliated to Nanjing Medical University, Nanjing, China
| | - Jianfeng Huang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, Institute Affiliated to Nanjing Medical University, Nanjing, China
| | - Yu Yao
- Department of Respiratory Medicine, Nanjing Chest Hospital, Medical School of Southeast University, Nanjing, China
| | - Qi Sun
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China
| | - Jie Wang
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China
| | - Yi Shen
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lin Xu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, Institute Affiliated to Nanjing Medical University, Nanjing, China
| | - Binhui Ren
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, China.,Department of Thoracic Surgery, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, Institute Affiliated to Nanjing Medical University, Nanjing, China
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41
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Fang YF, Geng Q. Research progress and prospects of esophageal cancer in era of precision medicine. Shijie Huaren Xiaohua Zazhi 2017; 25:2829-2837. [DOI: 10.11569/wcjd.v25.i32.2829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) is a common digestive system carcinoma, and China has the highest incidence of EC in the world. The prognosis of EC is poor; the five-year survival rate of EC in developing countries is extremely low because the clinical symptoms are often found too late, which makes the patients cannot be cured. In the era of precision medicine, new concepts and technologies are applied to the screening, diagnosis, and treatment of EC. Therefore, it becomes possible to formulate a personalized and accurate disease prevention and treatment program for each patient, so as to achieve maximum therapeutic effect, minimize side effects, and ultimately achieve the goal of improving the prognosis of EC. This article reviews the recent research progress and prospects of EC in the era of precision medicine with regard to disease screening, diagnosis, and treatment.
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Affiliation(s)
- Yi-Fan Fang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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42
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Long M, Zhan M, Xu S, Yang R, Chen W, Zhang S, Shi Y, He Q, Mohan M, Liu Q, Wang J. miR-92b-3p acts as a tumor suppressor by targeting Gabra3 in pancreatic cancer. Mol Cancer 2017; 16:167. [PMID: 29078789 PMCID: PMC5659029 DOI: 10.1186/s12943-017-0723-7] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 09/15/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors by controlling cell proliferation, differentiation, metastasis and apoptosis, and miRNA dysregulation is involved in the development of pancreatic cancer (PC). Our previous study demonstrated that Gabra3 plays critical roles in cancer progression. However, whether Gabra3 is regulated by miRNAs in PC remains unknown. METHODS The expression levels of miR-92b-3p and Gabra3 were measured by quantitative PCR (qPCR), immunoblotting, in situ hybridization (ISH) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Wound-healing and transwell assays were used to examine the invasive abilities of PC cells. Dual-luciferase reporter assays were used to determine how miR-92b-3p regulates Gabra3. Xenograft mouse models were used to assess the role of miR-92b-3p in PC tumor formation in vivo. RESULTS Here, we provide evidence that miR-92b-3p acted as a tumor suppressor in PC by regulating Gabra3 expression. MiR-92b-3p expression levels were lower in PC tissues than corresponding noncancerous pancreatic (CNP) tissues and were associated with a poor prognosis in PC patients. MiR-92b-3p overexpression suppressed the proliferation and invasion of PC cells in both in vivo and in vitro models. Conversely, miR-92b-3p knockdown induced an aggressive phenotype in PC cells. Mechanistically, miR-92b-3p overexpression suppressed Gabra3 expression, which then led to the inactivation of important oncogenic pathways, including the AKT/mTOR and JNK pathways. CONCLUSION Our results suggest that miR-92b-3p acted as a tumor suppressor by targeting Gabra3-associated oncogenic pathways; these results provide novel insight into future treatments for PC patients.
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Affiliation(s)
- Manmei Long
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
- Department of Pathology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China
| | - Ming Zhan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Sunwang Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Ruimeng Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Wei Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Shilei Zhang
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yongheng Shi
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Qiao He
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Man Mohan
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Jian Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
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Wu Q, Zhou W, Feng Q, Liu X, Xiong Y, Li H. MicroRNA-92b promotes cell proliferation and invasion in osteosarcoma by directly targeting Dickkopf-related protein 3. Exp Ther Med 2017; 15:173-181. [PMID: 29250147 PMCID: PMC5729699 DOI: 10.3892/etm.2017.5356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 05/11/2017] [Indexed: 01/13/2023] Open
Abstract
Deregulation of microRNA-92b (miR-92b) has been implicated in osteosarcoma. However, the underlying regulatory mechanism of miR-92b in osteosarcoma growth and metastasis remains largely unclear. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were used to measure mRNA and protein expression. MTT and Transwell assays were conducted to determine cell proliferation and invasion, and a luciferase reporter assay was performed to confirm the association between miR-92b and Dickkopf3-related protein (DKK3). The results demonstrated that miR-92b was significantly upregulated in osteosarcoma tissues compared with matched adjacent non-tumor tissues. Additionally, high miR-92b levels were significantly associated with lung metastasis and advanced tumor, node, metastasis stage (P<0.05) but not with age, sex, tumor size, location, serum lactate dehydrogenase or serum alkaline phosphatase. miR-92b expression was also significantly upregulated in osteosarcoma cell lines compared with normal osteoblast cells. Knockdown of miR-92b significantly inhibited the proliferation and invasion of osteosarcoma U2OS cells (P<0.01). By contrast, overexpression of miR-92b significantly increased U2OS cell proliferation and invasion (P<0.01). DKK3 was identified as a target gene of miR-92b and it was demonstrated that DKK3 expression was negatively regulated by miR-92b in U2OS cells. Restoration of DKK3 expression abrogated the increased proliferation and invasion of U2OS cells induced by miR-92b overexpression. Notably, DKK3 was significantly downregulated in osteosarcoma tissues compared with adjacent non-tumor tissues and its expression was inversely correlated to miR-92b levels in osteosarcoma tissues. Taken together, these data indicate that miR-92b promotes cell proliferation and invasion in osteosarcoma by targeting DKK3. Therefore, miR-92b may become a potential therapeutic target for osteosarcoma.
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Affiliation(s)
- Qing Wu
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wei Zhou
- Department of Vascular Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qiong Feng
- Nursing School, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xing Liu
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yanfei Xiong
- Department of Orthopedics, Jing An Hospital, Yichun, Jiangxi 330600, P.R. China
| | - Hui Li
- Department of Immunology and Microbiology, Medical School of Jishou University, Jishou, Hunan 416000, P.R. China
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44
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Zhao C, Zhao F, Feng H, Xu S, Qin G. MicroRNA-92b inhibits epithelial-mesenchymal transition-induced migration and invasion by targeting Smad3 in nasopharyngeal cancer. Oncotarget 2017; 8:91603-91613. [PMID: 29207670 PMCID: PMC5710950 DOI: 10.18632/oncotarget.21342] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/26/2017] [Indexed: 12/20/2022] Open
Abstract
Increasing studies reports that aberrant miRNAs contribute to nasopharyngeal carcinoma (NPC) development and progression. However, the role of miR-92b in NPC remains unclear. In present research, we found that a reduced miR-92b expression in NPC tissues and cell lines. The clinical data showed that the down-regulated miR-92b expression was obviously associated with adverse prognostic characteristic. Furthermore, we confirmed that miR-92b was a novel independent prognostic symbol for predicting 5-year survival of NPC patients. MiR-92b overexpression inhibited cell migration, invasion and EMT progress, while down-regulated miR-92b reversed the effect. Besides, miR-92b could modulate Smad3 by directly binding to its 3’-UTR. In clinical samples of NPC, miR-92b inversely correlated with Smad3. Alternation of Smad3 expression at least partially abrogated the migration, invasion and EMT progress of miR-92b on NPC cells. In summary, our results indicated that miR-92b functioned as a tumor suppressor gene in regulating the EMT and metastasis of NPC via targeting Smad3, and may represent a novel potential therapeutic target and prognostic marker for NPC.
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Affiliation(s)
- Chong Zhao
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Feipeng Zhao
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Huajun Feng
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Shengen Xu
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
| | - Gang Qin
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P.R. China
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45
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Ma J, Zhan Y, Xu Z, Li Y, Luo A, Ding F, Cao X, Chen H, Liu Z. ZEB1 induced miR-99b/let-7e/miR-125a cluster promotes invasion and metastasis in esophageal squamous cell carcinoma. Cancer Lett 2017; 398:37-45. [PMID: 28408353 DOI: 10.1016/j.canlet.2017.04.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/01/2017] [Accepted: 04/04/2017] [Indexed: 01/10/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors in Asia. Recent researches demonstrate that miRNAs are involved in the development of ESCC. In this study, we identified a miRNA cluster, termed miR-99b/let-7e/miR-125a as pro-metastasis oncomir. Overexpression of this miRNA cluster promoted ESCC cell migration and invasion in vitro and induced an experimental metastasis in vivo. ZEB1 was discovered to bind to the promoter region of miR-99b/let-7e/miR-125a cluster and regulate the expression of miRNAs at transcriptional level. Knockdown of ZEB1 resulted in a decrease of both mature and primary miRNAs. Further research revealed AT-rich interaction domain 3A (ARID3A) as a direct target of miR-99b/let-7e/miR-125a cluster. Reduced ARID3A phenocopied miR-99b/let-7e/miR-125a overexpression, and elevated ARID3A counteracted the pro-metastasis effect of miR-99b/let-7e/miR-125a. Moreover, ARID3A was downregulated by ZEB1 in a miR-99b/let-7e/miR-125a dependent manner. Collectively, our study sheds light on the essential role of miR-99b/let-7e/miR-125a cluster in tumor metastasis.
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Affiliation(s)
- Jianlin Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yun Zhan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhipeng Xu
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210001, China
| | - Yi Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Aiping Luo
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fang Ding
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiufeng Cao
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210001, China
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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46
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Xu Z, Zou L, Ma G, Wu X, Huang F, Feng T, Li S, Lin Q, He X, Liu Z, Cao X. Integrin β1 is a critical effector in promoting metastasis and chemo-resistance of esophageal squamous cell carcinoma. Am J Cancer Res 2017; 7:531-542. [PMID: 28401009 PMCID: PMC5385641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 02/21/2017] [Indexed: 06/07/2023] Open
Abstract
Metastasis of esophageal squamous cell carcinoma (ESCC) remains a challenge in clinical practice. In this study, we clarified that integrin β1 (ITGB1) plays critical roles in the metastasis of ESCC. By analyzing the expression of integrin β1 in ESCC specimens, we found that the expression of this integrin was higher in malignant than in normal tissues and that this increase was associated with lymph node metastasis. Moreover, in vitro functional experiments demonstrated that deletion of integrin β1 impaired the motility of ESCC cells, and we also showed that integrin β1 deletion significantly inhibited metastases formation in the lungs and lymph nodes of two murine models. Mechanistically, integrin β1 promoted cellular motility by regulating the FAK-Rac1 signaling pathway. Finally, we found that blocking integrin β1 significantly impaired the resistance of ESCC cells to cisplatin (DDP) treatment based on in vitro and in vivo experiments. Overall, our data suggest that integrin β1 promotes metastasis and confers DDP resistance to ESCC, which provides experimental evidence for targeting this protein to treat ESCC in the future.
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Affiliation(s)
- Zhipeng Xu
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Li Zou
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Gang Ma
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and TherapyTianjin 300060, China
| | - Xiaowei Wu
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Furong Huang
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Tingting Feng
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Suqing Li
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Qingfeng Lin
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Xiaoting He
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Zhihua Liu
- The State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Xiufeng Cao
- Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
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47
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Cheng L, Yang F, Zhou B, Yang H, Yuan Y, Li X, Han S. RAB23, regulated by miR-92b, promotes the progression of esophageal squamous cell carcinoma. Gene 2016; 595:31-38. [PMID: 27659550 DOI: 10.1016/j.gene.2016.09.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 09/14/2016] [Accepted: 09/17/2016] [Indexed: 11/30/2022]
Abstract
RAB23, a member of Ras-related small GTPase family, has been reported to be up-regulated in several cancer types. However, its biological functions and the underlying molecular mechanisms for its oncogenic roles in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we have shown that the expression of RAB23 was elevated in ESCC tissues and ESCC cells. Overexpression of RAB23 promoted the growth and migration of the ESCC cells, while knocking down the expression RAB23 inhibited the growth, migration and metastasis of the ESCC cells. The molecular mechanism study showed that RAB23 activated beta-catenin/TCF signaling and regulated the expression of several target genes. In the further study, it was found that the expression of RAB23 was regulated by the miR-92b. Forced expression of MiR-92b decreased the mRNA and protein level of RAB23, and RAB23 rescued the biological functions of miR-92b. Taken together, this study revealed the oncogenic roles and the regulation of RAB23 in ESCC, suggesting RAB23 might be a therapeutic target.
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Affiliation(s)
- Lina Cheng
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
| | - Fan Yang
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
| | - Bingxi Zhou
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
| | - Hui Yang
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
| | - Yuan Yuan
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
| | - Xiuling Li
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China.
| | - Shuangyin Han
- Department of Gastroenterology, People's Hospital of Zhengzhou University (Henan Provincial People's Hospital), Henan Province, China
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48
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Jing C, Ma G, Li X, Wu X, Huang F, Liu K, Liu Z. MicroRNA-17/20a impedes migration and invasion via TGF-β/ITGB6 pathway in esophageal squamous cell carcinoma. Am J Cancer Res 2016; 6:1549-1562. [PMID: 27508097 PMCID: PMC4969404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 06/18/2016] [Indexed: 06/06/2023] Open
Abstract
Patients with esophageal squamous cell carcinoma (ESCC) have an overall poor prognosis due to invasion and metastasis. Although it has been studied extensively, the metastatic mechanisms of ESCC remains largely unclear. Here, we evaluated microRNA expression in ESCC cell sublines with distinct motility and found that microRNA-17 and microRNA-20a (miR-17/20a) dramatically impeded cell migration and invasion of ESCC in vitro and decreased pulmonary arrest in vivo. Furthermore, we identified that TGF-β receptor 2 (TGFBR2) and Smad anchor for receptor activation (SARA) served as genuine miR-17/20a targets, which are both implicated in TGF-β pathway. TGF-β treatment promoted the motility of ESCC cells, and miR-17/20a could attenuate the activation of TGF-β pathway by weakening the phosphorylation of Smad2/3 to reduce the expression of ITGB6, which was crucial in migration and invasion of ESCC cells. Moreover, evaluation of ESCC specimens revealed a close correlation between miR-17/20a, TGFBR2, SARA and lymph node metastasis. Together, our findings demonstrate that miR-17/20a suppresses cell migration and invasion of ESCC by modulating TGF-β/ITGB6 pathway, suggesting a promising strategy for diagnosis and therapy of ESCC invasion and metastasis.
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Affiliation(s)
- Chao Jing
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
| | - Gang Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
| | - Xukun Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
| | - Xiaowei Wu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
| | - Furong Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
| | - Kuangyu Liu
- Shenzhen Experimental SchoolShenzhen 518000, Guangdong Province, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer MedicineBeijing 100021, China
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