|
1
|
Wang H, Qiao S, Huang L, Zhang Z, Wang J, Tian W. PTPN9 promotes melanoma progression by regulating the ferroptosis pathway. FASEB J 2025; 39:e70394. [PMID: 39937573 DOI: 10.1096/fj.202402285r] [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: 09/24/2024] [Revised: 01/21/2025] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
In recent years, there has been a gradual increase in the incidence and mortality rates of melanoma, posing a significant threat to human health and life. Protein tyrosine phosphatases (PTPNs) have been implicated in the progression of various human cancers, including breast, lung, and cervical cancer. To investigate PTPN9 expression in melanoma, impacting the disease's survival and prognosis. Our study, which involved an analysis of The Cancer Genome Atlas database and immunohistochemical staining of pathological sections, identified an upregulation of PTPN9 expression in melanoma, impacting the disease's survival and prognosis. At the cellular level, we investigated the effects of PTPN9 on the proliferation, invasion, and metastasis of A375 and SK-MEL-28 cells. Through various experimental techniques such as Western blot protein detection, electron microscopy, and oil red O staining, we observed that PTPN9 potentially contributes to the development of skin cutaneous melanoma (SKCM) by regulating ferroptosis-related proteins ACSL4, FTH1, and P53, thereby influencing lipid metabolism. The results of this study highlight the unique role of PTPN9 in SKCM and suggest its potential as a biomarker for the disease.
Collapse
Affiliation(s)
- Hongmei Wang
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
- Center of Translational Medicine, Zibo Central Hospital, Zibo, China
| | - Sen Qiao
- Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Lingyan Huang
- Pathological Department, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Zhengping Zhang
- Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Jiao Wang
- Clinical Laboratory, Zibo Central Hospital, Zibo, China
| | - Wenxiu Tian
- Center of Translational Medicine, Zibo Central Hospital, Zibo, China
| |
Collapse
|
|
2
|
Chaudhary N, Kiranmayee B. Non-receptor Type PTPases and their Role in Controlling Pathways Related to Diabetes and Liver Cancer Signalling. Curr Pharm Biotechnol 2025; 26:654-664. [PMID: 38424416 DOI: 10.2174/0113892010288624240213072415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/22/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
The role of non-receptor type Protein Tyrosine Phosphatase (PTPases) in controlling pathways related to diabetes and Hepatocellular Carcinoma (HCC) is significant. The insulin signal transduction pathway is regulated by the steady-state phosphorylation of tyrosyl residues of the insulin receptor and post-receptor substrates. PTPase has been shown to have a physiological role in the regulation of reversible tyrosine phosphorylation. There are several non-receptor type PTPases. PTPase containing the SH-2 domain (SHP-2) and the non-receptor type PTPase (PTP1B; encoded by the PTPN1 gene) are involved in negative regulation of the insulin signaling pathway, thereby indicating that the pathway can be made more efficient by the reduction in the activity of specific PTPases. Reduction in insulin resistance may be achieved by drugs targeting these specific enzymes. The modifications in the receptor and post-receptor events of insulin signal transduction give rise to insulin resistance, and a link between insulin-resistant states and HCC has been established. The cancer cells thrive on higher levels of energy and their growth gets encouraged since insulin-resistant states lead to greater glucose levels. Cancer, hyperglycemia, and hypoglycemia are highly linked through various pathways hence, clarifying the molecular mechanisms through which non-receptor type PTPase regulates the insulin signal transduction is necessary to find an effective target for cancer. Targeting the pathways related to PTPases; both receptor and non-receptor types, may lead to an effective candidate to fight against diabetes and HCC.
Collapse
Affiliation(s)
- Nidhee Chaudhary
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
| | - Bellam Kiranmayee
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
| |
Collapse
|
|
3
|
Desouky EM, Khaliefa AK, Hozayen WG, Shaaban SM, Hasona NA. Signature of miR-21 and MEG-2 and their correlation with TGF-β signaling in breast cancer. Hum Exp Toxicol 2023; 42:9603271231159799. [PMID: 36825546 DOI: 10.1177/09603271231159799] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Breast cancer is highly prevalent and considered the main challenge to public health among females in Egypt as in other countries. MicroRNA-21 (miR-21) and MEG-2 are noncoding RNA attributed to their aberrant expression in several diseases, including breast cancer. This study aimed to assess the reliability of serum expression levels of miR-21 and MEG-2 in discriminating stages of breast cancer and scrutinize their correlations with the targeted transforming growth factor-beta (TGF-β) expression. One hundred and 30 participants whose ages ranged from 28 to 62 years were included in this study, divided into one hundred breast cancer patients and 30 healthy participants. miR-21 and TGF-β expression levels showed upregulation in patients with BC and elevated miR-21/TGF-β levels consistent with the BC stage. In addition, LncRNA (MEG-2) showed down-regulation in patients with BC. MEG-2 expression levels revealed a gradual decrease consistent with the BC stage. In addition, a negative relationship between the MEG-2 and the miR-21 and TGF-β differential expression was also noticed. This study suggested that miR-21 and MEG-2 can be used as prospective diagnostic biomarkers and emphasized the crucible role of TGF-β as therapeutic targets for BC.
Collapse
Affiliation(s)
- E M Desouky
- Department of Biochemistry, Faculty of Science, 158406Beni-Suef University, Beni-Suef, Egypt
| | - A K Khaliefa
- Department of Biochemistry, Faculty of Science, 158406Beni-Suef University, Beni-Suef, Egypt
| | - W G Hozayen
- Department of Biochemistry, Faculty of Science, 158406Beni-Suef University, Beni-Suef, Egypt
| | - S M Shaaban
- Department of Oncology, Faculty of Medicine, 158411Beni-Suef University, Beni-Suef, Egypt
| | - N A Hasona
- Department of Biochemistry, Faculty of Science, 158406Beni-Suef University, Beni-Suef, Egypt
| |
Collapse
|
|
4
|
Xiong J, Niu Y, Liu W, Zeng F, Cheng JF, Chen SQ, Zeng XZ. Effect of L3MBTL3/PTPN9 polymorphisms on risk to alcohol-induced ONFH in Chinese Han population. Neurol Sci 2022; 43:2823-2830. [PMID: 34373992 DOI: 10.1007/s10072-021-05486-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/16/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE Alcohol-induced osteonecrosis femoral head necrosis (ONFH) is a disease that seriously affects human health. Abnormal expression of L3MBTL3/PTPN9 gene can cause a variety of human diseases. The purpose of this study is to investigate the effect of L3MBTL3/PTPN9 gene polymorphism on the susceptibility of alcohol-induced ONFH in Chinese Han population. METHODS A total of 308 alcohol-induced ONFH patients and 425 healthy controls were enrolled in this case-control study. Alleles, genotypes, genetic models, haplotypes, and multifactor dimensionality reduction analyses (MDR) based on age-corrected by using odds ratio (OR) and 95% confidence interval (CI) were performed. RESULTS Our result revealed rs2068957 in the L3MBTL3 gene increased the risk of alcohol ONFH under the recessive model after correction. Besides, we also found that rs75393192 in the PTPN9 gene was a protective site in stratification over 40 years of age and stage. In stratified analysis of necrotic sites, we only found that rs2068957 was associated with increased susceptibility of alcohol-induced ONFH under the co-dominant model and recessive model. Haplotype "GC" in the block (rs76107647|rs10851882 in PTPN9 gene) significantly decreased the susceptibility of alcoholic ONFH. CONCLUSIONS Our results provide evidence that L3MBTL3/PTPN9 polymorphisms are associated with alcohol-induced ONFH risk in Chinese Han population.
Collapse
Affiliation(s)
- Jun Xiong
- Department of Orthopedic Trauma, the Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xiuhua Road, Haikou, 570311, Hainan Province, China
| | - Yi Niu
- Department of Emergency and Critical Care Medicine, the Haikou Orthopedic and Diabetes Hospital of Shanghai Sixth People's Hospital, No. 3, Changxiu Road, Haikou, 570300, Hainan Province, China
| | - Wei Liu
- Department of Orthopedic Trauma, the Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xiuhua Road, Haikou, 570311, Hainan Province, China
| | - Fan Zeng
- Department of Orthopedic Trauma, the Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xiuhua Road, Haikou, 570311, Hainan Province, China
| | - Jian-Fei Cheng
- Department of Orthopedic Trauma, the Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xiuhua Road, Haikou, 570311, Hainan Province, China
| | - Shi-Qiang Chen
- Department of Orthopedic Trauma, the Hainan Affiliated Hospital of Hainan Medical University, No. 19, Xiuhua Road, Haikou, 570311, Hainan Province, China
| | - Xiang-Zhou Zeng
- Department of Pharmacology, School of Basic Medicine and Life Science, the Hainan Medical University, No. 3, Xueyuan Road, Haikou, 571199, Hainan Province, China.
| |
Collapse
|
|
5
|
Zhu L, Guo T, Chen W, Lin Z, Ye M, Pan X. CircMMD_007 promotes oncogenic effects in the progression of lung adenocarcinoma through microRNA-197-3p/protein tyrosine phosphatase non-receptor type 9 axis. Bioengineered 2022; 13:4991-5004. [PMID: 35156900 PMCID: PMC8974229 DOI: 10.1080/21655979.2022.2037956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Circular RNAs play important roles in cancer biology. In this research, we explored the underlying function and mechanism of cirMMD_007 in lung adenocarcinoma (LC). Clinical lung adenocarcinoma samples were obtained from surgery. Bioinformatic databases were used to predict miRNAs that can potentially target circRNAs and miRNA target genes. hsa_circMMD_007, miR-197-3p, and PTPN9 mRNA expressions were investigated by qRT-PCR. Protein expressions were examined using Western blot. The proliferation abilities were assessed by Cell Counting Kit-8 assays. Wound healing cell migration assay was applied to evaluate cell migration ability. Luciferase reporter assay and rescue experiments were then performed to elucidate the underlying mechanism. We found that the expression of circMMD_007 was abnormally increased in LC. The expression of circMMD_007 was higher in advanced stages. Knockout of circMMD_007 hindered the tumorigenesis of LC in vivo and in vitro. circMMD_007 could negatively regulate the expression of miR-197-3p. PTPN9 behaved to be a molecular target of miR-197-3p. In summary, this research demonstrated that circular RNA circMMD_007 could promote the oncogenic effects in the progression of LC through miR-197-3p/PTPN9 axis.
Collapse
Affiliation(s)
- Lihuan Zhu
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Tianxing Guo
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Wenshu Chen
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zhaoxian Lin
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Mingfan Ye
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xiaojie Pan
- Department of Thoracic Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| |
Collapse
|
|
6
|
Yang Y, Li D, He C, Peng L, Xing S, Bai M, Rong H, Yuan D, He Y, He X, Wang L, Jin T. Fc receptor-like 1, 3, and 6 variants are associated with rheumatoid arthritis risk in the Chinese Han population. Genes Environ 2021; 43:42. [PMID: 34620245 PMCID: PMC8499487 DOI: 10.1186/s41021-021-00213-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/04/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is the most common autoimmune system diseases in our world. More studies in recent years have shown that FCRL gene polymorphisms is closely related to autoimmune diseases. It is suggested that genetic factors play a crucial role in the pathogenesis of this disease. In this study, we aimed to investigate the relationship between FCRL1 rs2050568, FCRL3 rs2317230 and FCRL6 rs58240276 polymorphisms and RA risk in the Chinese Han population. 506 with RA patients and 509 healthy controls were recruited in this study, and the single nucleotide polymorphisms (SNPs) was successfully genotyped using the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for age and gender were conducted to assess these SNPs polymorphisms and RA risk. The multifactor dimensionality reduction (MDR) method was conducted to analyze SNP-SNP interaction. RESULTS Our results revealed that there no significant association was observed between the allele and genotype frequencies among these SNPs and RA risk (all p > 0.05). Straified analysis by age and gender, the results confirmed that FCRL1 rs2050568 T/T genotype enhanced the risk of RA in females (p = 0.014). The G/T - T/T genotype of FCRL3 rs2317230 was correlated with a decreased RA risk in males (p = 0.021). We also observed that the C/T-T/T genotype of FCRL6 rs58240276 was increased the risk of RA in the group at age > 54 years (p = 0.016). In addition, FCRL1 rs2050568-TT, FCRL6 rs58240276-TT and FCRL1 rs2050568-TT, FCRL3 rs2317230-TT, FCRL6 rs58240276-TT are the best models for multi-site MDR analysis (p < 0.05), and the two best models mentioned above and classes RA have the most significant correlation. CONCLUSIONS Our study demonstrated that FCRL1 rs2050568, FCRL3 rs2317230, and FCRL6 rs58240276 polymorphisms were correlated with RA susceptibility in the Chinese Han population.
Collapse
Affiliation(s)
- Yonghui Yang
- Clinical Laboratory, Xi'an 630 Hospital, Yanliang, Xi'an, Shaanxi, China
| | - Dandan Li
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Chunjuan He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Linna Peng
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Shishi Xing
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Mei Bai
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Hao Rong
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Dongya Yuan
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Yongjun He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Xue He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Li Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, #6 East Wenhui Road, Xianyang, 712082, Shaanxi, China.
| |
Collapse
|
|
7
|
Gong SN, Zhu JP, Ma YJ, Zhao DQ. Proteomics of the mediodorsal thalamic nucleus of rats with stress-induced gastric ulcer. World J Gastroenterol 2019; 25:2911-2923. [PMID: 31249449 PMCID: PMC6589736 DOI: 10.3748/wjg.v25.i23.2911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 05/08/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stress-induced gastric ulcer (SGU) is one of the most common visceral complications after trauma. Restraint water-immersion stress (RWIS) can cause serious gastrointestinal dysfunction and has been widely used to study the pathogenesis of SGU to identify medications that can cure the disease. The mediodorsal thalamic nucleus (MD) is the centre integrating visceral and physical activity and contributes to SGU induced by RWIS. Hence, the role of the MD during RWIS needs to be studied.
AIM To screen for differentially expressed proteins in the MD of the RWIS rats to further elucidate molecular mechanisms of SGU.
METHODS Male Wistar rats were selected randomly and divided into two groups, namely, a control group and an RWIS group. Gastric mucosal lesions of the sacrificed rats were measured using the erosion index and the proteomic profiles of the MD were generated through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography and tandem mass spectrometry. Additionally, iTRAQ results were verified by Western blot analysis.
RESULTS A total of 2853 proteins were identified, and these included 65 dysregulated (31 upregulated and 34 downregulated) proteins (fold change ratio ≥ 1.2). Gene Ontology (GO) analysis showed that most of the upregulated proteins are primarily related to cell division, whereas most of the downregulated proteins are related to neuron morphogenesis and neurotransmitter regulation. Ingenuity Pathway Analysis revealed that the dysregulated proteins are mainly involved in the neurological disease signalling pathways. Furthermore, our results indicated that glycogen synthase kinase-3 beta might be related to the central mechanism through which RWIS gives rise to SGU.
CONCLUSION Quantitative proteomic analysis elucidated the molecular targets associated with the production of SGU and provides insights into the role of the MD. The underlying molecular mechanisms need to be further dissected.
Collapse
Affiliation(s)
- Sheng-Nan Gong
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Jian-Ping Zhu
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Ying-Jie Ma
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Dong-Qin Zhao
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| |
Collapse
|
|
8
|
Wang D, Cheng Z, Zhao M, Jiao C, Meng Q, Pan H, Xie Y, Li L, Zhu Y, Wang W, Qu C, Liang D. PTPN9 induces cell apoptosis by mitigating the activation of Stat3 and acts as a tumor suppressor in colorectal cancer. Cancer Manag Res 2019; 11:1309-1319. [PMID: 30804683 PMCID: PMC6371942 DOI: 10.2147/cmar.s187001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are involved in regulating the transduction of many signaling pathways and play important roles in modulating the progression of some cancers, but the functions of PTPs in cancers have not been well elucidated until now. Here, we aimed to identify the roles of protein tyrosine phosphatase nonreceptor type 9 (PTPN9), a cytoplasmic PTP, in the development of colorectal cancer and elucidate the regulatory mechanism involved. Materials and methods Cell viability assessment, colony formation assay, caspase-3 and caspase-9 activity assay, real-time PCR, and Western blot analysis were applied. Results Our results showed that PTPN9 expression was frequently downregulated in colorectal cancer tissues compared with adjacent normal tissues. Overexpression of PTPN9 mitigated cell growth and colony formation and induced cell apoptosis in colorectal cancer. Conversely, PTPN9 knockdown promoted cell growth and survival. Moreover, PTPN9 negatively regulated the activation of Stat3 and depressed its nuclear translocation in colorectal cancer. The effects of PTPN9 knockdown on cell apoptosis were attenuated by inhibition of the Stat3 pathway. Conclusion These results indicate that PTPN9 inhibits cell growth and survival by repressing the activation of Stat3 in colorectal cancer, which suggests an important underlying mechanism of regulating cell growth and provides a novel candidate therapeutic target for colorectal cancer.
Collapse
Affiliation(s)
- Dawei Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Zhuoxin Cheng
- Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, People's Republic of China.,Heilongjiang Provincial Key Laboratory of Metabolic Disease, Jiamusi 154002, People's Republic of China
| | - Ming Zhao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Chengbin Jiao
- Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, People's Republic of China
| | - Qinghui Meng
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Huayang Pan
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Yu Xie
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Long Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Yexing Zhu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Wei Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Chunlei Qu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| | - Deshen Liang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China,
| |
Collapse
|
|
9
|
Ying D, Ruan Y, Zhou X. MEG2 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting AKT pathway. Gene 2018; 687:1-8. [PMID: 30399427 DOI: 10.1016/j.gene.2018.11.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 10/22/2018] [Accepted: 11/01/2018] [Indexed: 11/19/2022]
Abstract
MEG2 was recently found to have important functions in human cancers. However, the expression status and biological functions of MEG2 in hepatocellular carcinoma (HCC) remain unknown. In this study, we demonstrated that MEG2 expression was reduced in HCC tissues and cell lines using qRT-PCR, western blot and immunohistochemical staining. Decreased MEG2 expression predicted unfavorable clinical features and decreased overall survival and disease-free survival of HCC patients. In vitro functional assays showed that overexpression of MEG2 inhibited the cell viability, migration and invasion of HCCLM3 cells while MEG2 knockdown promoted these biological functions of Hep3B cells. Subcutaneous injection model and tail vein injection model showed that forced expression of MEG2 in HCCLM3 decreased the growth and lung metastasis of HCCLM3 cells in nude mice. Mechanically, MEG2 inhibited the EMT and AKT phosphorylation of HCC cells. The promoting effects of MEG2 knockdown on EMT, cell viability, proliferation, migration and invasion of Hep3B cells was blocked by AKT phosphorylation inhibition. In all, this study demonstrates that MEG2 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting AKT pathway.
Collapse
MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Movement
- Cell Proliferation
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/secondary
- Lymphatic Metastasis
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Neoplasm Invasiveness
- Prognosis
- Protein Tyrosine Phosphatases, Non-Receptor/genetics
- Protein Tyrosine Phosphatases, Non-Receptor/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Survival Rate
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- Dongjian Ying
- Department of Minimal Invasive Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo 315040, Zhejiang, China
| | - Yi Ruan
- Department of Minimal Invasive Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo 315040, Zhejiang, China
| | - Xinhua Zhou
- Department of Minimal Invasive Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo 315040, Zhejiang, China.
| |
Collapse
|
|
10
|
Huang Y, Zhang Y, Ge L, Lin Y, Kwok HF. The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma. Cancers (Basel) 2018; 10:cancers10030082. [PMID: 29558404 PMCID: PMC5876657 DOI: 10.3390/cancers10030082] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/12/2018] [Accepted: 03/15/2018] [Indexed: 02/08/2023] Open
Abstract
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies. Recent studies have unveiled both oncogenic and tumor suppressive functions of PTP in HCC. Here, we review the current knowledge on the involvement of PTP in HCC and further discuss the possibility of targeting PTP in HCC.
Collapse
Affiliation(s)
- Yide Huang
- Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau, China.
| | - Yafei Zhang
- Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
| | - Lilin Ge
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau, China.
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yao Lin
- Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
| | - Hang Fai Kwok
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau, China.
| |
Collapse
|
|
11
|
Ma X, Shi W, Peng L, Qin X, Hui Y. MiR-96 enhances cellular proliferation and tumorigenicity of human cervical carcinoma cells through PTPN9. Saudi J Biol Sci 2018; 25:863-867. [PMID: 30108433 PMCID: PMC6087804 DOI: 10.1016/j.sjbs.2017.10.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 10/11/2017] [Accepted: 10/11/2017] [Indexed: 01/05/2023] Open
Abstract
Up to date, the cervical cancer remains to be one of the leading gynecological malignancies worldwide. MicroRNAs (miRNAs) play critical roles in the process of tumor initiation and progression. However, miR-96 has rarely been investigated in human cervical carcinoma. We aimed to investigate the biological function and underlying molecular mechanism of miR-96 in human cervical carcinoma. MiR-96 levels were determined by qRT-PCR. Protein tyrosine phosphatase, non-receptor type 9 (PTPN9) mRNA and protein levels were investigated by qRT-PCR and western blotting. The cellular proliferation in cervical cells was monitored by CyQuant assay. Soft agar assay was employed to determine the tumorigenicity. 3' UTR luciferase assay was used to validate the target gene of miR-96. SPSS was used to analyze statistical significance in different treatment. MiR-96 was dramatically upregulated in human cervical tumor tissues. Overexpression of miR-96 was found to significantly promote the cellular proliferation and tumorigenicity of cervical cells. Furthermore, we showed that PTPN9 was a direct target gene of miR-96 and had opposite effect to those of miR-96 on cervical cells. MiR-96 may promote the cellular proliferation and tumorigenicity of cervical cells by silencing PTPN9. Our study highlights an importantly regulatory role of miR-96 and suggests that an appropriate manipulation of miR-96 may be a new treatment of human cervical carcinoma in the future.
Collapse
Affiliation(s)
- Xiaoping Ma
- Department of Gynecology and Obstetrics, The Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng 252000, Shandong Province, PR China
| | - Wentian Shi
- Department of Gynecology and Obstetrics, The Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng 252000, Shandong Province, PR China
| | - Lina Peng
- Department of Gynecology and Obstetrics, The Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng 252000, Shandong Province, PR China
| | - Xuying Qin
- Department of Gynecology and Obstetrics, The Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng 252000, Shandong Province, PR China
| | - Yuzuo Hui
- Department of Neurosurgery, The Affiliated Liaocheng People's Hospital of Shandong University, Liaocheng 252000, Shandong Province, PR China
| |
Collapse
|
|
12
|
Meeusen B, Janssens V. Tumor suppressive protein phosphatases in human cancer: Emerging targets for therapeutic intervention and tumor stratification. Int J Biochem Cell Biol 2017; 96:98-134. [PMID: 29031806 DOI: 10.1016/j.biocel.2017.10.002] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 10/04/2017] [Accepted: 10/05/2017] [Indexed: 02/06/2023]
Abstract
Aberrant protein phosphorylation is one of the hallmarks of cancer cells, and in many cases a prerequisite to sustain tumor development and progression. Like protein kinases, protein phosphatases are key regulators of cell signaling. However, their contribution to aberrant signaling in cancer cells is overall less well appreciated, and therefore, their clinical potential remains largely unexploited. In this review, we provide an overview of tumor suppressive protein phosphatases in human cancer. Along their mechanisms of inactivation in defined cancer contexts, we give an overview of their functional roles in diverse signaling pathways that contribute to their tumor suppressive abilities. Finally, we discuss their emerging roles as predictive or prognostic markers, their potential as synthetic lethality targets, and the current feasibility of their reactivation with pharmacologic compounds as promising new cancer therapies. We conclude that their inclusion in clinical practice has obvious potential to significantly improve therapeutic outcome in various ways, and should now definitely be pushed forward.
Collapse
Affiliation(s)
- Bob Meeusen
- Laboratory of Protein Phosphorylation & Proteomics, Dept. of Cellular & Molecular Medicine, Faculty of Medicine, KU Leuven & Leuven Cancer Institute (LKI), KU Leuven, Belgium
| | - Veerle Janssens
- Laboratory of Protein Phosphorylation & Proteomics, Dept. of Cellular & Molecular Medicine, Faculty of Medicine, KU Leuven & Leuven Cancer Institute (LKI), KU Leuven, Belgium.
| |
Collapse
|
|
13
|
Zhu J, Li H, Ma J, Huang H, Qin J, Li Y. PTPN9 promotes cell proliferation and invasion in Eca109 cells and is negatively regulated by microRNA-126. Oncol Lett 2017; 14:1419-1426. [PMID: 28789358 PMCID: PMC5529898 DOI: 10.3892/ol.2017.6315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 04/13/2017] [Indexed: 12/23/2022] Open
Abstract
Protein tyrosine phosphatase non-receptor type 9 (PTPN9), also named PTP-MEG2, is an important member of the protein tyrosine phosphatase family that is involved in variety of human diseases. However, the role of PTPN9 in esophageal squamous cell carcinoma (ESCC) remains to be established. The present evaluated the potential effect and underlying mechanism of action of PTPN9 in ESCC. Immunohistochemistry was performed to detect PTPN9 protein expression in 84 ESCC tumor specimens and 30 normal esophageal tissues. The association between positive expression of PTPN9 and clinicopathological features and prognosis was analyzed. The prognostic role of PTPN9 was further investigated using multivariate regression analysis. PTPN9-small interfering RNA and microRNA (miR-126)-mimics were transfected into Eca109 cells to construct PTPN9 silencing and an miR-126 ectopic expression cell model. Reverse transcription-quantitative polymerase chain reaction, western blot analysis, cell counting kit-8, Transwell assays and flow cytometry were used to investigate the role of PTPN9 in the process of ESCC progression and its potential downstream signaling pathway. Immunohistochemical analysis revealed that PTPN9 was upregulated in ESCC tumor specimens compared with normal esophageal tissues. The χ2 test indicated that positive expression of PTPN9 was correlated with tumor node metastasis stage, tumor classification and node classification. Patients with PTPN9 positive expression had shorter survival time, compared with those that were PTPN9 negative. Multivariate regression analysis with the Cox proportional hazards regression model revealed that PTPN9 expression was a prognostic factor of overall survival for patients with ESCC. Using RNA interference, the present study demonstrated that knockdown of PTPN9 significantly suppressed cell proliferation and invasion in Eca109. Additionally, it was hypothesized that miR-126, described as a tumor suppressor in ESCC, may act at least in part via its inhibition of PTPN9 at the post-transcriptional level. To the best of our knowledge, this is the first study to demonstrate that PTPN9 is overexpressed in ESCC and associated with poor survival, and may therefore be important in the pathogenesis of ESCC.
Collapse
Affiliation(s)
- Junwei Zhu
- Department of Thoracic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Haomiao Li
- Department of Thoracic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Jun Ma
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Haibo Huang
- Department of Thoracic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Jianjun Qin
- Department of Thoracic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Yin Li
- Department of Thoracic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| |
Collapse
|