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Han J, Ding R, Xiong X. Expression of NUF2 and CD52 and Their Correlation With Chemotherapy Resistance and Prognosis in Patients With Non-Small Cell Lung Cancer. J Biochem Mol Toxicol 2025; 39:e70308. [PMID: 40421783 DOI: 10.1002/jbt.70308] [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: 03/27/2025] [Revised: 03/27/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025]
Abstract
Lung cancer is one of the most common malignant tumors. This study aim to investigate the expression of cell division related gene cell division cycle related protein 2 (NUF2) and immune-related gene CD52 in patients with non-small cell lung cancer (NSCLC) and their correlation with chemotherapy resistance and clinical prognosis. The cancer tissues and adjacent tissues of 72 patients with NSCLC were collected. According to the staining results, the patients were divided into NUF2 positive and negative expression groups, and CD52 positive and negative expression groups. The relationship of NUF2 and CD52 with clinicopathological features and chemoresistance was analyzed. The patients were followed up for 5 years, and Kaplan-Meier survival curve was used to analyze the relationship. COX regression analysis was used to analyze the risk factors. The positive expression rate of NUF2 in NSCLC tissues was 66.67% (48/72), which was significantly higher than 38.89% (28/72) in adjacent tissues (p < 0.05). The positive expression rate of CD52 in NSCLC tissues was also higher than the adjacent tissues (p < 0.05). NUF2 expression was related to the degree of differentiation, TNM stage, lymph node metastasis and pleural invasion in NSCLC patients (p < 0.05). The expression of CD52 was related to TNM stage, lymph node metastasis, vascular tumor thrombus and pleural invasion (p < 0.05). The median survival time of patients with positive CD52 and NUF2 expression was lower than patients with negative expression (p < 0.05). Platinum-resistance, lymph node metastasis, pleural invasion, NUF2 and CD52 positive expression were independent risk factors for poor prognosis of NSCLC (p < 0.05). In conclusion, NUF2 and CD52 are independent risk factors for poor prognosis of patients with NSCLC. They may be used as one of the indicators to evaluate drug resistance and prognosis of patients.
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Affiliation(s)
- Jun Han
- Department of Respiratory and Critical Care Medicine, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Rui Ding
- Department of Radiotherapy, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Xue Xiong
- Department of Respiratory and Critical Care Medicine, Shanxi Provincial People's Hospital, Taiyuan, China
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Lv B, Zhang F, Zhang X, Wang Z, Hao S, Ye N, He N. PBK as a novel biomarker performed excellent diagnostic and prognostic value in HCC associated with immune infiltration and methylation. J Mol Histol 2025; 56:129. [PMID: 40178670 PMCID: PMC11968539 DOI: 10.1007/s10735-024-10324-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/27/2024] [Indexed: 04/05/2025]
Abstract
Diagnostic and prognosis of hepatocellular carcinoma (HCC) remain major challenge in clinic. This study aimed to explore a gene signature for diagnosis and prognosis prediction of HCC followed by mechanism investigation. Differentially expressed genes (DEGs) in HCC were screened using TCGA. With specific formula, clinic features of prognosis associated DEGs were calculated to obtained a specific model followed by Kaplan-Meier analysis. Protein-protein interaction (PPI) were predicted using STRING and associations between hub gene and clinic features were analyzed using R software. The hub gene was silenced in HCC cell lines followed by cell behaviors analyses. A prognosis associated 14-gene model was identified in this study which could significantly distinguish samples into high-risk and low-risk groups. PBK, BUB1, NUF2, and CDCA8 were the key nodes involved in the 14 gene-coded PPI with high diagnostic values, and only PBK was an independent risk factor of disease specific survival (DSS) of HCC. Moreover, higher PBK was positively correlated with pathological and histological grades, higher AFP, and infiltrations of Th2, T helper cells and aDC of HCC, but negatively correlated with the killer immune cells. Dysregulated methylation might contribute to the higher expression of PBK and silencing PBK significantly suppressed the proliferation, growth, migration, and invasion of HCC cells. PBK, BUB1, NUF2, and CDCA8 played crucial role in prognosis associated 14-gene model with high diagnostic values. Methylation dysregulation-induced PBK accumulation might promote the development of HCC via modulating immune surveillance.
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Affiliation(s)
- Beibei Lv
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China
| | - Fenna Zhang
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China
| | - Xinyi Zhang
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China
- Office of Graduate Student Affairs, Xi'an Medical University, Han Guang North Road 74#, Beilin District, Xi'an, China
| | - Ziyi Wang
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China
- Office of Graduate Student Affairs, Xi'an Medical University, Han Guang North Road 74#, Beilin District, Xi'an, China
| | - Shuai Hao
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China
- Office of Graduate Student Affairs, Xi'an Medical University, Han Guang North Road 74#, Beilin District, Xi'an, China
| | - Na Ye
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China.
| | - Na He
- The First Affiliated Hospital of Xi'an Medical University, Fenggao Western Road 48#, Lianhu District, Xi'an, China.
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Lv M, Chen X, Yang Q, Huang C, Lv Y, Zhang T, Cai J. Berberine restrains non-small cell lung cancer cell growth, invasion and glycolysis via inactivating the SPC25/NUF2 pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03729-w. [PMID: 39755832 DOI: 10.1007/s00210-024-03729-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/11/2024] [Indexed: 01/06/2025]
Abstract
Berberine (BBR) has been proved to inhibit the malignant progression of non-small cell lung cancer (NSCLC), but the underlying molecular mechanism still needs to be further revealed. NSCLC cells (A549 and H1299) were treated with BBR. CCK8 assay, colony formation assay, flow cytometry, TUNEL staining and transwell assay were used to examine cell proliferation, apoptosis and invasion. The levels of spindle pole body component 25 (SPC25) and NDC80 kinetochore complex component (NUF2) were detected by qRT-PCR or western blot. The interaction between SPC25 and NUF2 was confirmed by Co-IP assay and FISH assay. Xenograft tumors were constructed to assess the anti-tumor role of BBR in vivo. BBR inhibited NSCLC cell growth, invasion and glycolysis. SPC25 was upregulated in NSCLC tissues, and BBR could reduce SPC25 expression in NSCLC cells. SPC25 knockdown repressed NSCLC cell growth, invasion and glycolysis, and its overexpression also reversed the anti-tumor effect of BBR. SPC25 could interact with NUF2, and NUF2 overexpression abolished the inhibitory effect of SPC25 knockdown or BBR on NSCLC cell behaviors. In animal experiments, BBR could suppress NSCLC tumor growth by inhibiting SPC25/NUF2 axis in vivo. BBR mainly played an anti-NSCLC role by targeting SPC25/NUF2 axis, which provided a new idea for NSCLC treatment.
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Affiliation(s)
- Meng Lv
- Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, China
| | - Xiangrui Chen
- Department of Hematology and Oncology, Third People's Hospital of Zigong, Zigong, Sichuan, China
| | - Qiting Yang
- Department of Cardiopulmonary Rehabilitation and Sleep Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chushuan Huang
- Pneumology Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongbiao Lv
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tian Zhang
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junxiang Cai
- Department of Respiratory and Critical Care Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, No. 111, Dade Road, Guangzhou, 510120, China.
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Long B, Zhou H, Xiao L, Jiang X, Li J, Ma Z, He N, Xin W, Zhang B, Zhu X, Yu Z, Jiao Z. Targeting NUF2 suppresses gastric cancer progression through G2/M phase arrest and apoptosis induction. Chin Med J (Engl) 2024; 137:2437-2451. [PMID: 39193700 PMCID: PMC11479523 DOI: 10.1097/cm9.0000000000003006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2 , a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression. METHODS Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021. Cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2 -associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC. RESULTS NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro . NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models. CONCLUSIONS Collectively, NUF2 -mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.
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Affiliation(s)
- Bo Long
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Huinian Zhou
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Lixia Xiao
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xiangyan Jiang
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jian Li
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Zhijian Ma
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Na He
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Wei Xin
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Boya Zhang
- The Second Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xiaoqin Zhu
- The Second Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Zeyuan Yu
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Zuoyi Jiao
- The First Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730000, China
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Bao L, Gong Y, Che Y, Li Y, Xu T, Chen J, Wang S, Tan Z, Huang P, Pan Z, Ge M. Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression. Cell Death Dis 2024; 15:656. [PMID: 39242581 PMCID: PMC11379715 DOI: 10.1038/s41419-024-07041-6] [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: 01/29/2024] [Revised: 08/15/2024] [Accepted: 08/29/2024] [Indexed: 09/09/2024]
Abstract
Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.
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Affiliation(s)
- Lisha Bao
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yingying Gong
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yulu Che
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Ying Li
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Tong Xu
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Jinming Chen
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Shanshan Wang
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Zhuo Tan
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, China
| | - Ping Huang
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China.
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, China.
| | - Zongfu Pan
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China.
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, China.
| | - Minghua Ge
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, China.
- Zhejiang Provincial Clinical Research Center for malignant tumor, Hangzhou, China.
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Liu Y, Wang Y, Wang J, Jiang W, Chen Y, Shan J, Li X, Wu X. NUF2 regulated the progression of hepatocellular carcinoma through modulating the PI3K/AKT pathway via stabilizing ERBB3. Transl Oncol 2024; 44:101933. [PMID: 38507923 PMCID: PMC10966282 DOI: 10.1016/j.tranon.2024.101933] [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: 10/16/2023] [Revised: 02/08/2024] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The NDC80 kinetochore complex component NUF2 has been previously identified as up-regulating in HCC and associated with patient prognosis. However, the pathophysiological effects and molecular mechanisms of NUF2 in tumorigenesis remain unclear. In this study, we confirmed a significant increase in NUF2 expression in HCC tissues and established a correlation between high NUF2 expression and adverse outcomes in HCC patients. Through in vitro and in vivo experiments, we demonstrated that genetic inhibition of NUF2 suppressed the proliferation of HCC cells and disrupted the cell cycle. Further investigation into the molecular mechanisms revealed that NUF2 interacted with ERBB3, inhibiting its ubiquitination degradation, thus activating the PI3K/AKT signaling pathway and influencing cell cycle regulation. Overall, this study revealed the crucial role of NUF2 in promoting the malignant progression of HCC, suggesting its potential as both a prognostic biomarker and a therapeutic target for HCC.
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Affiliation(s)
- Yiwei Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China.
| | - Yuming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Jifei Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Wangjie Jiang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Yananlan Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Jijun Shan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China
| | - Xiao Li
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Xiaofeng Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China; Jiangsu Provincial Medical Innovation Center; Jiangsu Provincial Medical Key Laboratory, Nanjing, China.
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Aimaier R, Chung MH, Gu Y, Yu Q, Wei C, Li H, Guo Z, Long M, Li Y, Wang W, Li Q, Wang Z. FOXM1 promotes neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor progression in a NUF2-dependent manner. Cancer Gene Ther 2023; 30:1390-1402. [PMID: 37488294 DOI: 10.1038/s41417-023-00645-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 06/23/2023] [Accepted: 07/04/2023] [Indexed: 07/26/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas characterized by poor prognosis and low drug response rates. Traditional chemo/radiotherapies show only mild benefits for patients with MPNSTs, and no targeted therapy is available in the clinic. A better understanding of the molecular background of MPNSTs is critical for the development of effective targeted therapies. Forkhead box M1 (FOXM1) has been implicated in the progression of many human malignancies, though its role in MPNSTs is unclear. In this study, using four Gene Expression Omnibus (GEO) datasets and a tissue microarray, we demonstrated that FOXM1 upregulation was associated with poor prognosis in patients with MPNSTs. FOXM1 overexpression and knockdown regulated the proliferation and colony formation of MPNST cells. Using bioinformatics analysis and luciferase reporter assays, we identified NUF2 as a direct downstream target of FOXM1. Both in vitro and in vivo experiments demonstrated that the induction of MPNST cell proliferation by FOXM1 was dependent on elevated NUF2 expression, as NUF2 knockdown abolished the FOXM1-induced proliferation of MPNST cells. Our study showed that the FOXM1-NUF2 axis mediates human MPNST progression and could be a potential therapeutic target.
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Affiliation(s)
- Rehanguli Aimaier
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Man-Hon Chung
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yihui Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingxiong Yu
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Chengjiang Wei
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haibo Li
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zizhen Guo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Manmei Long
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuehua Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhichao Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Shan J, Jiang W, Chang J, Zhou T, Chen Y, Zhang Y, Wang J, Wang Y, Wang Y, Xu X, Liu S, Shi X, Fan S, Chen R, Li C, Li X. NUF2 Drives Cholangiocarcinoma Progression and Migration via Inhibiting Autophagic Degradation of TFR1. Int J Biol Sci 2023; 19:1336-1351. [PMID: 37056930 PMCID: PMC10086752 DOI: 10.7150/ijbs.80737] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/27/2023] [Indexed: 03/13/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy and associated with poor prognosis. Lack of therapeutic methods for CCA and insensitivity of targeted therapy and immunotherapy make its treatment challenging. NUF2, a component of Ndc80 kinetochore complex, is implicated in the initiation and development of multiple cancers. However, the role and mechanism of NUF2 in CCA is still unclear. In this research, we investigated the biological processes and underlying mechanisms of NUF2 in CCA. We discovered that the expression of NUF2 was upregulated in CCA and negatively correlated with prognosis. Changes in NUF2 levels had an impact on cell proliferation and migration. Moreover, NUF2 functioned as an oncogene to promote the progression of CCA through p38/MAPK signaling by inhibiting p62 binding of TFR1 and affecting its autophagic degradation. In addition, TFR1 promoted CCA progression and Kaplan-Meier analyses uncovered patients with high expression of TFR1 was associated with the poor survival. In conclusion, our study demonstrated that NUF2 promoted CCA progression by regulating TFR1 protein degradation, and the NUF2/TFR1/MAPK axis could be an excellent therapeutic target for CCA.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Changxian Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University
| | - Xiangcheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University
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9
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Ren M, Zhao H, Gao Y, Chen Q, Zhao X, Yue W. NUF2 promotes tumorigenesis by interacting with HNRNPA2B1 via PI3K/AKT/mTOR pathway in ovarian cancer. J Ovarian Res 2023; 16:17. [PMID: 36670423 PMCID: PMC9862784 DOI: 10.1186/s13048-023-01101-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/11/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Ovarian cancer (OC) is one of the commonest and deadliest diseases that threaten the health of women worldwide. It is essential to find out its pathogenic mechanisms and therapeutic targets for OC patients. Although NUF2 (Ndc80 kinetochore complex component) has been suggested to play an important role in the development of many cancers, but little is known about its function and the roles of proteins that regulate NUF2 in OC. This study aimed to investigate the effect of NUF2 on the tumorigenicity of OC and the activities of proteins that interact with NUF2. METHODS Oncomine database and immunohistochemical (IHC) staining were used to evaluate the expression of NUF2 in OC tissues and normal tissues respectively. Normal ovarian epithelial cell lines (HOSEpiC) and OC cell lines (OVCAR3、HEY、SKOV3) were cultured. Western blot was applied to analyze the expression of NUF2 in these cell lines. Small interfering RNA (siRNA) was used to silence the expression of NUF2 in OC cell lines, SKOV3 and HEY. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), the CCK-8 method, colony formation assay and flow cytometry were conducted to analyze the biological functions of NUF2 in vitro. OC subcutaneous xenograft tumor models were used for in vivo tests. Immunoprecipitation and mass spectrometry (IP/MS) were performed to verify the molecular mechanisms of NUF2 in OC. IP, immunofluorescence, IHC staining, and Gene Expression Profiling Interactive Analysis platform (GEPIA) were used to analyze the relationship between HNRNPA2B1 and NUF2 in OC cells. SiRNA was used to silence the expression of HNRNPA2B1 in SKOV3 cells, reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay and western blot were used to detect the effect of HNRNPA2B1 on NUF2. GEPIA, The Cancer Genome Atlas (TCGA) database, GSEA and western blot were used to detect the potential signaling pathways related to the roles of HNRNPA2B1 and NUF2 in OC cells. RESULTS Our results showed high NUF2 expression in OC tissues and OC cell lines, which was associated with shorter overall survival and progression-free survival in patients. NUF2 depletion by siRNA suppressed the proliferation abilities and induced cell apoptosis of OC cells in vitro, and impeded OC growth in vivo. Mechanistically, NUF2 interacted with HNRNPA2B1 and activated the PI3K/AKT/mTOR signaling pathway in OC cells. CONCLUSION NUF2 could serve as a prognostic biomarker, and regulated the carcinogenesis and progression of OC. Moreover, NUF2 may interact with HNRNPA2B1 by activating the PI3K/AKT/mTOR signaling pathway to promote the development of OC cells. Our present study supported the key role of NUF2 in OC and suggested its potential as a novel therapeutic target.
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Affiliation(s)
- Meng Ren
- grid.24696.3f0000 0004 0369 153XCentral Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 People’s Republic of China
| | - Hongyu Zhao
- grid.429392.70000 0004 6010 5947Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110 USA
| | - Yan Gao
- grid.24696.3f0000 0004 0369 153XCentral Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 People’s Republic of China
| | - Qi Chen
- grid.24696.3f0000 0004 0369 153XCentral Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 People’s Republic of China
| | - Xiaoting Zhao
- grid.24696.3f0000 0004 0369 153XCentral Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 People’s Republic of China
| | - Wentao Yue
- grid.24696.3f0000 0004 0369 153XCentral Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 People’s Republic of China
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Leng R, Meng Y, Sun X, Zhao Y. NUF2 overexpression contributes to epithelial ovarian cancer progression via ERBB3-mediated PI3K-AKT and MAPK signaling axes. Front Oncol 2022; 12:1057198. [PMID: 36620547 PMCID: PMC9811817 DOI: 10.3389/fonc.2022.1057198] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction NDC80 kinetochore complex component (NUF2) is upregulated and plays an important role in various human cancers. However, the function and mechanism of NUF2 in epithelial ovarian cancer (EOC) remain unclear. Methods NUF2 expression was detected in EOC tissues and cell lines. The effects of NUF2 downregulation on cell proliferation, migration and invasion in EOC were analyzed by CCK-8 and Transwell assays. Meanwhile, the effect of NUF2 downregulation on tumor growth in vivo was determined by xenograft tumor models. The mechanisms by which NUF2 regulates EOC progression were detected by RNA sequencing and a series of in vitro assays. Results We showed that NUF2 was significantly upregulated in EOC tissues and cell lines, and high NUF2 expression was associated with FIGO stage, pathological grade and poor EOC prognosis. NUF2 downregulation decreased cell proliferation, migration, invasion and tumor growth in nude mice. RNA sequencing studies showed that NUF2 knockdown inhibited several genes enriched in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. Erb-B2 receptor tyrosine kinase 3 (ERBB3) was the key factor involved in both of the above pathways. We found that ERBB3 silencing could inhibit EOC progression and repress activation of the PI3K-AKT and MAPK signaling pathways. Furthermore, the exogenous overexpression of ERBB3 partially reversed the inhibitory effects on EOC progression induced by NUF2 downregulation, while LY294002 and PD98059 partially reversed the effects of ERBB3 upregulation. Conclusion These results showed that NUF2 promotes EOC progression through ERBB3-induced activation of the PI3K-AKT and MAPK signaling axes. These findings suggest that NUF2 might be a potential therapeutic target for EOC.
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Affiliation(s)
- Ruobing Leng
- Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China,*Correspondence: Ruobing Leng,
| | - Yunfang Meng
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiaomei Sun
- Department of Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yingzi Zhao
- Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Singharajkomron N, Yodsurang V, Seephan S, Kungsukool S, Petchjorm S, Maneeganjanasing N, Promboon W, Dangwilailuck W, Pongrakhananon V. Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer. Int J Mol Sci 2022; 23:ijms232314724. [PMID: 36499051 PMCID: PMC9738182 DOI: 10.3390/ijms232314724] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
Microtubule-associated proteins (MAPs) play essential roles in cancer development. This study aimed to identify transcriptomic biomarkers among MAP genes for the diagnosis and prognosis of lung cancer by analyzing differential gene expressions and correlations with tumor progression. Gene expression data of patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) from the Cancer Genome Atlas (TCGA) database were used to identify differentially expressed MAP genes (DEMGs). Their prognostic value was evaluated by Kaplan-Meier and Cox regression analysis. Moreover, the relationships between alterations in lung cancer hallmark genes and the expression levels of DEMGs were investigated. The candidate biomarker genes were validated using three independent datasets from the Gene Expression Omnibus (GEO) database and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on clinical samples. A total of 88 DEMGs were identified from TCGA data. The 20 that showed the highest differential expression were subjected to association analysis with hallmark genes. Genetic alterations in TP53, EGFR, PTEN, NTRK1, and PIK3CA correlated with the expression of most of these DEMGs. Of these, six candidates-NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2-were significantly differentially expressed and correlated with the overall survival (OS) of the patients. The mRNA expression profiles of these candidates were consistently verified using three GEO datasets and qRT-PCR on patient lung tissues. The expression levels of NUF2, KIF4A, KIF18B, DLGAP5, NEK2, and LRRK2 can serve as diagnostic biomarkers for LUAD and LUSC. Moreover, the first five can serve as prognostic biomarkers for LUAD, while LRRK2 can be a prognostic biomarker for LUSC. Our research describes the novel role and potential application of MAP-encoding genes in clinical practice.
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Affiliation(s)
- Natsaranyatron Singharajkomron
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Varalee Yodsurang
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Preclinical Toxicity and Efficacy, Assessment of Medicines and Chemicals Research Unit, Chulalongkorn University, Bangkok 10330, Thailand
| | - Suthasinee Seephan
- Pharmaceutical Sciences and Technology Graduate Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sakkarin Kungsukool
- Respiratory Medicine Department, Central Chest Institute of Thailand, Muang District, Nonthaburi 11000, Thailand
| | - Supinda Petchjorm
- Division of Anatomical Pathology, Central Chest Institute of Thailand, Muang District, Nonthaburi 11000, Thailand
| | - Nara Maneeganjanasing
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Warunyu Promboon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Wadsana Dangwilailuck
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Preclinical Toxicity and Efficacy, Assessment of Medicines and Chemicals Research Unit, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence: ; Tel.: +662-218-8325; Fax: +662-218-8340
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Guo L, Wu Z. FOXM1-mediated NUF2 expression confers temozolomide resistance to human glioma cells by regulating autophagy via the PI3K/AKT/mTOR signaling pathway. Neuropathology 2022; 42:430-446. [PMID: 35701983 DOI: 10.1111/neup.12824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022]
Abstract
Glioma is the most common malignant tumor in the central nervous system and has a high mortality rate. Temozolomide (TMZ) is a widely used chemotherapeutic drug for glioma. NDC80 kinetochore complex (NUF2) is suggested to play a regulatory role in different cancers, but its specific function and mechanism in glioblastoma TMZ resistance remain unknown. NUF2, assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), was highly expressed in glioma cell lines. TMZ was used to treat cells to establish a TMZ-resistant cell line. The potential functions of NUF2 in glioma were assessed using cell counting kit-8 (CCK-8) assays, colony formation assays, 5-Ethynyl-2'-deoxyuridine (EdU) assays, flow cytometry, Western blotting, and a tumor xenograft model. The results showed that NUF2 knockdown attenuated malignant phenotypes of TMZ-resistant cells and prevented tumor growth. Mechanistically, as luciferase reporter assays and chromatin immunoprecipitation (ChIP) as showed, Fox transcription factor M1 (FOXM1) had binding sites on the NUF2 promoter. Rescue assays demonstrated that FOXM1 upregulation counteracted the inhibitory effects of NUF2 depletion on the malignancies of TMZ-resistant cells. This study demonstrates that FOXM1-activated NUF2 promotes TMZ to human glioma cells by regulating proliferation, apoptosis, and autophagy.
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Affiliation(s)
- Liang Guo
- Department of Neurosurgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Zhangyi Wu
- Department of Neurosurgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Li Z, Ma Z, Xue H, Shen R, Qin K, Zhang Y, Zheng X, Zhang G. Chromatin Separation Regulators Predict the Prognosis and Immune Microenvironment Estimation in Lung Adenocarcinoma. Front Genet 2022; 13:917150. [PMID: 35873497 PMCID: PMC9305311 DOI: 10.3389/fgene.2022.917150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Abnormal chromosome segregation is identified to be a common hallmark of cancer. However, the specific predictive value of it in lung adenocarcinoma (LUAD) is unclear. Method: The RNA sequencing and the clinical data of LUAD were acquired from The Cancer Genome Atlas (TACG) database, and the prognosis-related genes were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were carried out for functional enrichment analysis of the prognosis genes. The independent prognosis signature was determined to construct the nomogram Cox model. Unsupervised clustering analysis was performed to identify the distinguishing clusters in LUAD-samples based on the expression of chromosome segregation regulators (CSRs). The differentially expressed genes (DEGs) and the enriched biological processes and pathways between different clusters were identified. The immune environment estimation, including immune cell infiltration, HLA family genes, immune checkpoint genes, and tumor immune dysfunction and exclusion (TIDE), was assessed between the clusters. The potential small-molecular chemotherapeutics for the individual treatments were predicted via the connectivity map (CMap) database. Results: A total of 2,416 genes were determined as the prognosis-related genes in LUAD. Chromosome segregation is found to be the main bioprocess enriched by the prognostic genes. A total of 48 CSRs were found to be differentially expressed in LUAD samples and were correlated with the poor outcome in LUAD. Nine CSRs were identified as the independent prognostic signatures to construct the nomogram Cox model. The LUAD-samples were divided into two distinct clusters according to the expression of the 48 CSRs. Cell cycle and chromosome segregation regulated genes were enriched in cluster 1, while metabolism regulated genes were enriched in cluster 2. Patients in cluster 2 had a higher score of immune, stroma, and HLA family components, while those in cluster 1 had higher scores of TIDES and immune checkpoint genes. According to the hub genes highly expressed in cluster 1, 74 small-molecular chemotherapeutics were predicted to be effective for the patients at high risk. Conclusion: Our results indicate that the CSRs were correlated with the poor prognosis and the possible immunotherapy resistance in LUAD.
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Affiliation(s)
- Zhaoshui Li
- Qingdao Medical College, Qingdao University, Qingdao, China
- Cardiothoracic Surgery Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Zaiqi Ma
- Cardiothoracic Surgery Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Hong Xue
- Heart Center Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Ruxin Shen
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Kun Qin
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Zhang
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xin Zheng
- Cancer Center Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
- *Correspondence: Xin Zheng, ; Guodong Zhang,
| | - Guodong Zhang
- Thoracic Surgery Department, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Xin Zheng, ; Guodong Zhang,
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Jiang F, Huang X, Yang X, Zhou H, Wang Y. NUF2 Expression Promotes Lung Adenocarcinoma Progression and Is Associated With Poor Prognosis. Front Oncol 2022; 12:795971. [PMID: 35814368 PMCID: PMC9259841 DOI: 10.3389/fonc.2022.795971] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
Aberrant expression of the gene encoding the Ndc80 kinetochore complex component (NUF2) reportedly contributes to the progression of several human cancers. However, the functional roles of NUF2 and their underlying mechanisms in lung adenocarcinoma (LUAD) are largely unknown. The current study aimed to investigate the role of NUF2 in LUAD tumorigenesis. Here, TCGA, ONCOMINE, the Human Protein Atlas, UALCAN, and the results of our cohort were used to analyze the expression of NUF2 in LUAD. A Kaplan–Meier analysis and univariate and multivariate Cox regression analyses were performed to estimate the prognostic values of NUF2 expression in the Cancer Genome Atlas cohort. We studied the effects of NUF2 expression on proliferation, migration, invasion, and tumor growth using LUAD cell lines. Gene set enrichment analysis (GSEA) was used to analyze the pathways and biological function enrichment of NUF2 in LUAD. The ssGSEA database was used to analyze the relationship between NUF2 expression and immune cell infiltration in LUAD. Results revealed elevated expression of NUF2 in LUAD specimens. Patients overexpressing NUF2 had poor prognoses relative to those with low NUF2 expression. Knockdown of NUF2 suppressed the proliferation, migration, invasion, epithelial-mesenchymal transition, and colony formation of LUAD cells. Moreover, NUF2 knockdown induced cell cycle arrest at the G0/G1 phase. Gene Ontology and GSEA analyses suggested that NUF2 may be involved in immunity, proliferation, and apoptosis-related pathways. NUF2 overexpression was positively correlated with differential immune cell infiltration. In conclusion, NUF2 expression was associated with the clinical phenotype of LUAD and hence has potential implications in LUAD treatment.
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Affiliation(s)
- Feng Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, China
| | - Xiaolu Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, China
| | - Xiang Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, China
| | - Huixin Zhou
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, China
| | - Yumin Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, China
- *Correspondence: Yumin Wang,
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Construction of a Prognosis-Related Gene Signature by Weighted Gene Coexpression Network Analysis in Ewing Sarcoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8798624. [PMID: 35126643 PMCID: PMC8814720 DOI: 10.1155/2022/8798624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 12/16/2021] [Indexed: 11/18/2022]
Abstract
Background Ewing sarcoma (ES) is the second most common pediatric bone tumor with a high rate of metastasis, high recurrence, and low survival rate. Therefore, the identification of new biomarkers which can improve the prognosis of ES patients is urgently needed. Methods Here, GSE17679 dataset was downloaded from GEO databases. WGCNA method was used to identify one module associating with OVS (overall vital survival) and event. cytoHubba was used to screen out 50 hub genes from the module genes. Then, GSE17679 dataset was randomly divided into train cohort and test cohort. Next, univariate Cox analysis, LASSO regression analysis, and multivariate Cox analysis were conducted on 50 hub genes combined with train cohort data to select pivotal genes. Finally, an optimal 7-gene-based risk assessment model was established, which was verified by test cohort, entire GSE17679, and two independent datasets (GSE63157 and TCGA-SARC). Results The results of the functional enrichment analysis revealed that the OVS and event-associated module were mainly enriched in the protein transcription, cell proliferation, and cell-cycle control. And the train cohort was divided into high-risk and low-risk subgroups based on the median risk score; the results showed that the survival of the low-risk subgroup was significantly longer than high-risk. ROC analysis revealed that AUC values of 1, 3, and 5-year survival were 0.85, 0.94, and 0.88, and Kaplan-Meier analysis also revealed that P value < 0.0001, indicating that this model was accurate, which was also verified in the test, entire cohort, and two independent datasets (GSE63157 and TCGA-SARC). Then, we performed a comprehensive analysis (differential expression analysis, correlation analysis and survival analysis) of seven pivotal genes, and found that four genes (NCAPG, KIF4A, NUF2 and CDC20) plays a more crucial role in the prognosis of ES. Conclusion Taken together, this study established an optimal 7-gene-based risk assessment model and identified 4 potential therapeutic targets, to improve the prognosis of ES patients.
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Lin J, Chen X, Yu H, Min S, Chen Y, Li Z, Xie X. NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation. Int J Biol Sci 2022; 18:3621-3635. [PMID: 35813477 PMCID: PMC9254462 DOI: 10.7150/ijbs.70972] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 05/09/2022] [Indexed: 02/05/2023] Open
Abstract
The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the HMGA2 promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.
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Affiliation(s)
- Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong, China
| | - Xiangling Chen
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong, China
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong, China
| | - Hongjian Yu
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong, China
| | - Shasha Min
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong, China
| | - Yequn Chen
- Department of Community Surveillance, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong, China
- ✉ Corresponding authors: Xina Xie, E-mail: ; Zesong Li, E-mail:
| | - Xina Xie
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong, China
- ✉ Corresponding authors: Xina Xie, E-mail: ; Zesong Li, E-mail:
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Shan L, Zhu XL, Zhang Y, Gu GJ, Cheng X. Expression and clinical significance of NUF2 in kidney renal clear cell carcinoma. Transl Androl Urol 2021; 10:3628-3637. [PMID: 34733658 PMCID: PMC8511540 DOI: 10.21037/tau-21-620] [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: 06/25/2021] [Accepted: 08/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background To explore the expression and clinical significance of the cytokinesis-related gene NUF2 in kidney renal clear cell carcinoma (KIRC). Methods Gene expression profiles of KIRC patients were extracted from The Cancer Genome Atlas (TCGA) database. The differences in NUF2 mRNA expression between patients and controls, as well as the relationship between the clinical characteristics and overall survival of the patients, were analyzed. The expression of NUF2 protein in 83 cancer tissues and para-cancerous tissues was detected to analyze the relationship with clinical characteristics. Gene Set Enrichment Analysis (GSEA) was used to investigate the possible regulatory pathways of the NUF2 in the development of KIRC. Results NUF2 mRNA was significantly higher in patients with KIRC, and the prognosis of patients with high expression of NUF2 mRNA was significantly worse than those with low expression, and was related to the AJCC stage, T stage, lymph node metastases, and distant metastases. NUF2 mRNA was an independent prognostic risk factor for KIRC patients. The expression of NUF2 protein was significantly higher in KIRC patients than in paraneoplastic tissues and was markedly associated with the pathological grade. In addition, the high expression of NUF2 was associated with the upregulation of pathways such as homologous recombination and DNA replication. Conclusions NUF2 may act as an independent prognostic biomarker for predicting the survival of KIRC patients.
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Affiliation(s)
- Li Shan
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Xiao-Li Zhu
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Yuan Zhang
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Guo-Jian Gu
- Department of Pathology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Xu Cheng
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
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Jacobs NR, Norton PA. Role of chromosome 1q copy number variation in hepatocellular carcinoma. World J Hepatol 2021; 13:662-672. [PMID: 34239701 PMCID: PMC8239492 DOI: 10.4254/wjh.v13.i6.662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/13/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Chromosome 1q often has been observed to be amplified in hepatocellular carcinoma. This review summarizes literature reports of multiple genes that have been proposed as possible 1q amplification drivers. These largely fall within 1q21-1q23. In addition, publicly available copy number alteration data from The Cancer Genome Atlas project were used to identify additional candidate genes involved in carcinogenesis. The most frequent location for gene amplification was 1q22, consistent with the results of the literature search. The genes TPM3 and NUF2 were found to be candidates whose amplification and/or mRNA up-regulation was most highly associated with poorer hepatocellular carcinoma outcomes.
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Affiliation(s)
- Nathan R Jacobs
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
| | - Pamela A Norton
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
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