|
1
|
Ramesh J, Gopalakrishnan RM, Nguyen THA, Lai SK, Li HY, Kim PS, Kutzner A, Inoue N, Heese K. Deciphering the molecular landscape of the FAM72 gene family: Implications for stem cell biology and cancer. Neurochem Int 2024; 180:105853. [PMID: 39236808 DOI: 10.1016/j.neuint.2024.105853] [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: 06/27/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
Family with sequence similarity 72 (FAM72) is a protein-coding gene family located on chromosome 1 in humans, uniquely featuring four paralogs: FAM72A, FAM72B, FAM72C, and FAM72D. While FAM72's presence as a gene pair with the SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2) is intriguing, its functional roles, particularly in neural stem cells, remain incompletely understood. This review explores the distinct characteristics of FAM72, shedding light on its expression patterns, potential roles in cell cycle regulation, stem cell renewal and implications in neurogenesis and tumorigenesis.
Collapse
Affiliation(s)
- Janani Ramesh
- Department of Medical Biochemistry, Dr ALM Postgraduate Institute of Biomedical Sciences, University of Madras, Chennai, Tamil Nadu, 600-113, India.
| | - Raja Mohan Gopalakrishnan
- Centre for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600-025, India.
| | - Tuan Hoang Anh Nguyen
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
| | - Soak-Kuan Lai
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637-551, Singapore.
| | - Hoi-Yeung Li
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637-551, Singapore.
| | - Pok-Son Kim
- Department of Information Security, Cryptology, and Mathematics, Kookmin University, Seoul, 136-702, Republic of Korea.
| | - Arne Kutzner
- Department of Information Systems, College of Computer Science, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
| | - Noriko Inoue
- Osaka University Institute for Sports and Global Health, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
| |
Collapse
|
|
2
|
Zhao Y, Zhang Q, Zhang B, Dai Y, Gao Y, Li C, Yu Y, Li C. Epstein-Barr Viruses: Their Immune Evasion Strategies and Implications for Autoimmune Diseases. Int J Mol Sci 2024; 25:8160. [PMID: 39125729 PMCID: PMC11311853 DOI: 10.3390/ijms25158160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most prevalent and persistent human viruses, infecting up to 90% of the adult population globally. EBV's life cycle includes primary infection, latency, and lytic reactivation, with the virus primarily infecting B cells and epithelial cells. This virus has evolved sophisticated strategies to evade both innate and adaptive immune responses, thereby maintaining a lifelong presence within the host. This persistence is facilitated by the expression of latent genes such as EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which play crucial roles in viral latency and oncogenesis. In addition to their well-known roles in several types of cancer, including nasopharyngeal carcinoma and B-cell lymphomas, recent studies have identified the pathogenic roles of EBV in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review highlights the intricate interactions between EBV and the host immune system, underscoring the need for further research to develop effective therapeutic and preventive strategies against EBV-associated diseases.
Collapse
Affiliation(s)
- Yuehong Zhao
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Qi Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Botian Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yihao Dai
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yifei Gao
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Chenzhong Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Yijing Yu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
| | - Conglei Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (Y.Z.); (Q.Z.); (B.Z.); (Y.D.); (Y.G.); (C.L.)
- Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| |
Collapse
|
|
3
|
Gou H, Chen P, Wu W. FAM72 family proteins as poor prognostic markers in clear cell renal carcinoma. Biochem Biophys Rep 2023; 35:101506. [PMID: 37457361 PMCID: PMC10344709 DOI: 10.1016/j.bbrep.2023.101506] [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: 04/22/2023] [Revised: 06/08/2023] [Accepted: 06/24/2023] [Indexed: 07/18/2023] Open
Abstract
Purpose This study aimed to investigate the prognostic significance of the Family with Sequence Similarity 72 member (FAM72) gene family in clear cell renal carcinoma (ccRCC) using a bioinformatic approach. Patients and methods To investigate the association between FAM72 and ccRCC, we utilized various databases and analysis tools, including TCGA, GEPIA, Metscape, cBioPortal, and MethSurv. We conducted an analysis of FAM72 expression levels in ccRCC tissues compared to normal kidney tissues and performed univariate and multivariate Cox analysis to determine the relationship between FAM72 expression and patient prognosis. Furthermore, we carried out Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) to identify enriched biological processes associated with FAM72 expression. Additionally, we analyzed immune cell infiltration and the level of methylation in ccRCC patients. Our bioinformatic analysis revealed that FAM72 expression levels were significantly higher in ccRCC tissues than in normal kidney tissues. High expression of FAM72 was associated with poor prognosis in ccRCC patients and was found to be an independent prognostic factor for ccRCC. GO and GSEA analyses indicated that FAM72 was enriched in biological processes related to mitosis, cell cycle, and DNA metabolism. Moreover, we found a significant correlation between FAM72 and immune cell infiltration and the level of methylation in ccRCC patients. Conclusion Our findings suggest that FAM72 could serve as an unfavorable prognostic molecular marker for ccRCC. A comprehensive understanding of FAM72 could provide crucial insights into tumor progression and prognosis.
Collapse
Affiliation(s)
- Hui Gou
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Ping Chen
- Department of Pharmacy, Suining Central Hospital, Suining, 629000, China
| | - Wenbing Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| |
Collapse
|
|
4
|
Chi H, Gao X, Xia Z, Yu W, Yin X, Pan Y, Peng G, Mao X, Teichmann AT, Zhang J, Tran LJ, Jiang T, Liu Y, Yang G, Wang Q. FAM family gene prediction model reveals heterogeneity, stemness and immune microenvironment of UCEC. Front Mol Biosci 2023; 10:1200335. [PMID: 37275958 PMCID: PMC10235772 DOI: 10.3389/fmolb.2023.1200335] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/09/2023] [Indexed: 06/07/2023] Open
Abstract
Background: Endometrial cancer (UCEC) is a highly heterogeneous gynecologic malignancy that exhibits variable prognostic outcomes and responses to immunotherapy. The Familial sequence similarity (FAM) gene family is known to contribute to the pathogenesis of various malignancies, but the extent of their involvement in UCEC has not been systematically studied. This investigation aimed to develop a robust risk profile based on FAM family genes (FFGs) to predict the prognosis and suitability for immunotherapy in UCEC patients. Methods: Using the TCGA-UCEC cohort from The Cancer Genome Atlas (TCGA) database, we obtained expression profiles of FFGs from 552 UCEC and 35 normal samples, and analyzed the expression patterns and prognostic relevance of 363 FAM family genes. The UCEC samples were randomly divided into training and test sets (1:1), and univariate Cox regression analysis and Lasso Cox regression analysis were conducted to identify the differentially expressed genes (FAM13C, FAM110B, and FAM72A) that were significantly associated with prognosis. A prognostic risk scoring system was constructed based on these three gene characteristics using multivariate Cox proportional risk regression. The clinical potential and immune status of FFGs were analyzed using CiberSort, SSGSEA, and tumor immune dysfunction and rejection (TIDE) algorithms. qRT-PCR and IHC for detecting the expression levels of 3-FFGs. Results: Three FFGs, namely, FAM13C, FAM110B, and FAM72A, were identified as strongly associated with the prognosis of UCEC and effective predictors of UCEC prognosis. Multivariate analysis demonstrated that the developed model was an independent predictor of UCEC, and that patients in the low-risk group had better overall survival than those in the high-risk group. The nomogram constructed from clinical characteristics and risk scores exhibited good prognostic power. Patients in the low-risk group exhibited a higher tumor mutational load (TMB) and were more likely to benefit from immunotherapy. Conclusion: This study successfully developed and validated novel biomarkers based on FFGs for predicting the prognosis and immune status of UCEC patients. The identified FFGs can accurately assess the prognosis of UCEC patients and facilitate the identification of specific subgroups of patients who may benefit from personalized treatment with immunotherapy and chemotherapy.
Collapse
Affiliation(s)
- Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xinrui Gao
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Zhijia Xia
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Wanying Yu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xisheng Yin
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Yifan Pan
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Gaoge Peng
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xinrui Mao
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Alexander Tobias Teichmann
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jing Zhang
- Division of Basic Biomedical Sciences, The University of South Dakota Sanford School of Medicine, Vermillion, SD, United States
| | - Lisa Jia Tran
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Tianxiao Jiang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Yunfei Liu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
| | - Qin Wang
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
|
5
|
Liu H, Huang Y, Chen Y, Tang Z, Huang M, Ming Y, Wang M, Chen W, Huang Z, Qing L, Wang Q, Jia B. Family with Sequence Similarity 72 (FAM72) - A prospective biomarker for poor prognosis in patients with oral squamous cell carcinoma. Arch Oral Biol 2023; 151:105695. [PMID: 37086493 DOI: 10.1016/j.archoralbio.2023.105695] [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: 02/19/2023] [Revised: 03/20/2023] [Accepted: 04/06/2023] [Indexed: 04/24/2023]
Abstract
OBJECTIVE To study the effect of FAM72 on the prognosis of patients with oral squamous cell carcinoma (OSCC) and to explore the relationship between FAM72 and OSCC. DESIGN We used a vast array of databases and analytical vehicles to assess the relation between FAM72 and OSCC, including The Cancer Genome Atlas (TCGA), Metascape, and MethSurv. We made a preliminary verification of OSCC lines and tissues by real time quantitative polymerase chain reaction (RT-qPCR). RESULTS FAM72 was higher in OSCC than in normal tissues. Analysis of univariate COX data indicated that elevated expression of FAM72A, FAM72B, and FAM72C in OSCC was related to poor overall survival. Moreover, FAM72B and FAM72C were independent of overall survival in multiple COX regression. FAM72A-D and its coexpressed genes in Metascape were analyzed by Gene Ontology (GO), they were enriched in cellular cycle, mitotic and DNA metabolism. Gene set enrichment analysis (GSEA) demonstrated an enrichment in pathways related to cell metabolism. Additionally, high FAM72 expression related to a worse prognosis in OSCC patients. FAM72A-D linked to the infiltration of tumor immune cell in OSCC patients. We found that methylation levels are likely linked to prognosis in OSCC patients. We used RT-qPCR to ascertain the differential FAM72B and FAM72C expression levels in cancer and paracancerous tissues of OSCC, human normal oral keratinocytes (HOK), and human tongue squamous cell carcinoma (Cal-33). CONCLUSION Our findings indicate that FAM72B and FAM72C are potential molecular markers of poor prognosis in OSCC and may act as novel targets for OSCC treatment strategies.
Collapse
Affiliation(s)
- Hongyu Liu
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yisheng Huang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yuanxin Chen
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Zhengming Tang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Mingshu Huang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yue Ming
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Min Wang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Weixing Chen
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Zhijie Huang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Ling Qing
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Qin Wang
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Bo Jia
- Department of Oral Surgery, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
6
|
Fu Y, Jia X, Yuan J, Yang Y, Zhang T, Yu Q, Zhou J, Wang T. Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates. Dev Cell 2023; 58:398-415.e7. [PMID: 36868233 DOI: 10.1016/j.devcel.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/28/2022] [Accepted: 02/09/2023] [Indexed: 03/05/2023]
Abstract
The cell cycle is key to life. After decades of research, it is unclear whether any parts of this process have yet to be identified. Fam72a is a poorly characterized gene and is evolutionarily conserved across multicellular organisms. Here, we have found that Fam72a is a cell-cycle-regulated gene that is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C, respectively. Functionally, Fam72a directly binds to tubulin and both the Aα and B56 subunits of PP2A-B56 to modulate tubulin and Mcl1 phosphorylation, which in turn affects the progression of the cell cycle and signaling of apoptosis. Moreover, Fam72a is involved in early responses to chemotherapy, and it efficiently antagonizes various anticancer compounds such as CDK and Bcl2 inhibitors. Thus, Fam72a switches the tumor-suppressive PP2A to be oncogenic by reprogramming its substrates. These findings identify a regulatory axis of PP2A and a protein member in the cell cycle and tumorigenesis regulatory network in human cells.
Collapse
Affiliation(s)
- Yuan Fu
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Thoracic Oncology, Tianjin Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University, Tianjin 300070, China.
| | - Xiaofan Jia
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jinwei Yuan
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yuting Yang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Teng Zhang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Qiujing Yu
- Department of Immunology and Key Laboratory of Immune Microenvironment and Disease, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jun Zhou
- Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Ting Wang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Thoracic Oncology, Tianjin Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University, Tianjin 300070, China.
| |
Collapse
|
|
7
|
Prognostic and Immunological Implications of FAM72A in Pan-Cancer and Functional Validations. Int J Mol Sci 2022; 24:ijms24010375. [PMID: 36613817 PMCID: PMC9820597 DOI: 10.3390/ijms24010375] [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: 11/18/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022] Open
Abstract
The family with sequence similarity 72 Member A (FAM72A) is overexpressed in several types of cancer. However, its contributions to tumorigenesis remain largely unknown. Based on The Cancer Genome Atlas (TCGA) database, FAM72A was upregulated across 33 types of cancer. Accordingly, high levels of FAM72A predicted inferior outcomes in half of the cancer types using survival analysis (the Kaplan-Meier curve and univariate Cox regression model). Receiver operating characteristic (ROC) analysis demonstrated that FAM72A showed high accuracy in distinguishing cancerous tissues from normal ones. FAM72A was correlated with immune and stromal scores and immune cell infiltrations in various tumors. Moreover, FAM72A was also associated with tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint genes. Immunophenoscore (IPS) further validated that the FAM72Alow tumor showed high immunogenicity and tended to respond to anti-PD1/PDL1/PDL2, anti-CTLA4 treatment, and combined immunotherapies. We also investigated the functional role of FAM72A in lung adenocarcinoma (LUAD). In vitro studies demonstrated that the ectopic expression of FAM72A accelerated the proliferation and migration of NSCLC cells, whereas silencing FAM72A showed the opposite effects on them. In short, FAM72A had prognostic potential and correlated with tumor immunogenicity in various tumors. Functional analysis indicated that FAM72A is an oncogene in LUAD.
Collapse
|
|
8
|
Zhou Q, Chen L, Yang L, Zhou H, Chen Y, Guo Y. Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma. Front Oncol 2022; 12:1046473. [DOI: 10.3389/fonc.2022.1046473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
BackgroundThe family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown.MethodsData from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays.ResultsFirst, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy.ConclusionsFAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.
Collapse
|
|
9
|
Stewart JA, Bhagwat AS. A redox-sensitive iron-sulfur cluster in murine FAM72A controls its ability to degrade the nuclear form of uracil-DNA glycosylase. DNA Repair (Amst) 2022; 118:103381. [PMID: 35908367 PMCID: PMC10996437 DOI: 10.1016/j.dnarep.2022.103381] [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: 06/03/2022] [Revised: 07/19/2022] [Accepted: 07/25/2022] [Indexed: 11/20/2022]
Abstract
Murine FAM72A, mFAM72A, binds the nuclear form of uracil-DNA glycosylase, mUNG2, inhibits its activity and causes its degradation. In immunoprecipitation assays the human paralog, hFAM72A, binds hUNG2 and is a potential anti-cancer drug target because of its high expression in many cancers. Using purified mFAM72A, and mUNG2 proteins we show that mFAM72A binds mUNG2, and the N-terminal 25 amino acids of mUNG2 bind mFAM72A at a nanomolar dissociation constant. We also show that mFAM72A is present throughout the cells, and mUNG2 helps localize it to nuclei. Based on in silico models of mFAM72A-mUNG2 interactions, we constructed several mutants of mFAM72A and found that while they have reduced ability to deplete mUNG2, the mutations also destabilized the former protein. We confirmed that Withaferin A, a predicted lead molecule for the design of FAM72A inhibitors, binds mFAM72A with micromolar affinity but has little affinity to mUNG2. We identified two potential metal-binding sites in mFAM72A and show that one of the sites contains an Fe-S cluster. This redox-sensitive cluster is involved in the mFAM72A-mUNG2 interaction and modulates mFAM72A activity. Hydrogen peroxide treatment of cells increases mUNG2 depletion in a FAM72A-dependent fashion suggesting that mFAM72A activity is redox-sensitive.
Collapse
Affiliation(s)
- Jessica A Stewart
- Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
| | - Ashok S Bhagwat
- Department of Chemistry, Wayne State University, Detroit, MI 48202, USA; Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| |
Collapse
|
|
10
|
Liu L, Qu J, Dai Y, Qi T, Teng X, Li G, Qu Q. An interactive nomogram based on clinical and molecular signatures to predict prognosis in multiple myeloma patients. Aging (Albany NY) 2021; 13:18442-18463. [PMID: 34260414 PMCID: PMC8351694 DOI: 10.18632/aging.203294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 06/23/2021] [Indexed: 12/29/2022]
Abstract
Although novel drugs and treatments have been developed and improved, multiple myeloma (MM) is still recurrent and difficult to cure. In the present study, the magenta module containing 400 hub genes was determined from the training dataset of GSE24080 through weighted gene co-expression network analysis (WGCNA). Then, using the least absolute shrinkage and selection operator (Lasso) analysis, a fifteen-gene signature was firstly selected and the predictive performance for overall survival (OS) was favorable, which was identified by Receiver Operating Characteristic (ROC) curves. The risk score model was constructed based on survival-associated fifteen genes from the Lasso model, which classified MM patients into high-risk and low-risk groups. Areas under the curve (AUC) of ROC curve and log-rank test showed that the high-risk group was correlated to the dismal survival outcome of MM patients, which was also identified in testing dataset of GSE9782. The calibration plot, the AUC value of the ROC curve and Concordance-index showed that the interactive nomogram with risk score could favorably predict the probability of multi-year OS of MM patients. Therefore, it may help clinicians make a precise therapeutic decision based on the easy-to-use tool of the nomogram.
Collapse
Affiliation(s)
- Linxin Liu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Jian Qu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yuxin Dai
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, China
| | - Tingting Qi
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Xinqi Teng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Guohua Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Qiang Qu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
11
|
Zhang T, Nie Y, Gu J, Cai K, Chen X, Li H, Wang J. Identification of Mitochondrial-Related Prognostic Biomarkers Associated With Primary Bile Acid Biosynthesis and Tumor Microenvironment of Hepatocellular Carcinoma. Front Oncol 2021; 11:587479. [PMID: 33868990 PMCID: PMC8047479 DOI: 10.3389/fonc.2021.587479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 03/15/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-associated deaths worldwide. Despite great progress in early diagnosis and multidisciplinary tumor management, the long-term prognosis of HCC remains poor. Currently, metabolic reprogramming during tumor development is widely observed to support rapid growth and proliferation of cancer cells, and several metabolic targets that could be used as cancer biomarkers have been identified. The liver and mitochondria are the two centers of human metabolism at the whole organism and cellular levels, respectively. Thus, identification of prognostic biomarkers based on mitochondrial-related genes (Mito-RGs)-the coding-genes of proteins located in the mitochondria-that reflect metabolic changes associated with HCC could lead to better interventions for HCC patients. In the present study, we used HCC data from The Cancer Genome Atlas (TCGA) database to construct a classifier containing 10 Mito-RGs (ACOT7, ADPRHL2, ATAD3A, BSG, FAM72A, PDK3, PDSS1, RAD51C, TOMM34, and TRMU) for predicting the prognosis of HCC by using 10-fold Least Absolute Shrinkage and Selection Operation (LASSO) cross-validation Cox regression. Based on the risk score calculated by the classifier, the samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), t-distributed stochastic neighbor embedding (t-SNE), and consensus clusterPlus algorithms were used to identify metabolic pathways that were significantly different between the high- and low-risk groups. We further investigated the relationship between metabolic status and infiltration of immune cells into HCC tumor samples by using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm combined with the Tumor Immune Estimation Resource (TIMER) database. Our results showed that the classifier based on Mito-RGs could act as an independent biomarker for predicting survival of HCC patients. Repression of primary bile acid biosynthesis plays a vital role in the development and poor prognosis of HCC, which provides a potential approach to treatment. Our study revealed cross-talk between bile acid and infiltration of tumors by immune cells, which may provide novel insight into immunotherapy of HCC. Furthermore, our research may provide a novel method for HCC metabolic therapy based on modulation of mitochondrial function.
Collapse
Affiliation(s)
- Tao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingli Nie
- Department of Dermatology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Gu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huili Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiliang Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
12
|
Chatonnet F, Pignarre A, Sérandour AA, Caron G, Avner S, Robert N, Kassambara A, Laurent A, Bizot M, Agirre X, Prosper F, Martin-Subero JI, Moreaux J, Fest T, Salbert G. The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation. Haematologica 2020; 105:774-783. [PMID: 31221779 PMCID: PMC7049362 DOI: 10.3324/haematol.2019.222133] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 06/19/2019] [Indexed: 01/16/2023] Open
Abstract
Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and pathological conditions. Although genetic alterations are well documented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the definition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 transcription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases.
Collapse
Affiliation(s)
- Fabrice Chatonnet
- Université Rennes 1, Établissement Français du Sang de Bretaggne, Inserm, MICMAC -UMR_S 1236, Rennes, France
- Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
| | - Amandine Pignarre
- Université Rennes 1, Établissement Français du Sang de Bretaggne, Inserm, MICMAC -UMR_S 1236, Rennes, France
- Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
| | - Aurélien A Sérandour
- CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France
- Ecole Centrale de Nantes, Nantes, France
- Institut de Cancérologie de l'Ouest, Site René-Gauducheau, Saint-Herblain, France
| | - Gersende Caron
- Université Rennes 1, Établissement Français du Sang de Bretaggne, Inserm, MICMAC -UMR_S 1236, Rennes, France
- Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
| | - Stéphane Avner
- SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France
| | - Nicolas Robert
- Department of Biological Hematology, CHU Montpellier, Montpellier, France
| | | | - Audrey Laurent
- SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France
| | - Maud Bizot
- SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France
| | - Xabier Agirre
- Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Felipe Prosper
- Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | | | - Jérôme Moreaux
- Department of Biological Hematology, CHU Montpellier, Montpellier, France
- IGH, CNRS, Univ Montpellier, France
| | - Thierry Fest
- Université Rennes 1, Établissement Français du Sang de Bretaggne, Inserm, MICMAC -UMR_S 1236, Rennes, France
- Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
| | - Gilles Salbert
- SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France
| |
Collapse
|
|
13
|
Rahane CS, Kutzner A, Heese K. A cancer tissue-specific FAM72 expression profile defines a novel glioblastoma multiform (GBM) gene-mutation signature. J Neurooncol 2018; 141:57-70. [PMID: 30414097 DOI: 10.1007/s11060-018-03029-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/09/2018] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Glioblastoma multiform (GBM) is a neural stem cell (NSC)-derived malignant brain tumor with complex genetic alterations challenging clinical treatments. FAM72 is a NSC-specific protein comprised of four paralogous genes (FAM72 A-D) in the human genome, but its functional tumorigenic significance is unclear. METHODS We conducted an in-depth expression and somatic mutation data analysis of FAM72 (A-D) in GBM using the comprehensive human clinical cancer study database cBioPortal [including The Cancer Genome Atlas (TCGA)]. RESULTS We established a FAM72 transcription profile across TCGA correlated with the expression of the proliferative marker MKI67 and a tissue-specific gene-mutation signature represented by pivotal genes involved in driving the cell cycle. FAM72 paralogs are overexpressed in cancer cells, specifically correlating with the mitotic cell cycle genes ASPM, KIF14, KIF23, CENPE, CENPE, CEP55, SGO1, and BUB1, thereby contributing to centrosome and mitotic spindle formation. FAM72 expression correlation identifies a novel GBM-specific gene set (SCN9A, MXRA5, ADAM29, KDR, LRP1B, and PIK3C2G) in the de novo pathway of primary GBM predestined as viable targets for therapeutics. CONCLUSION Our newly identified primary GBM-specific gene-mutation signature, along with FAM72, could thus provide a new basis for prognostic biomarkers for diagnostics of GBM and could serve as potential therapeutic targets.
Collapse
Affiliation(s)
- Chinmay Satish Rahane
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea
| | - Arne Kutzner
- Department of Information Systems, College of Engineering, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
| |
Collapse
|
|
14
|
Wang SN, Wang LT, Sun DP, Chai CY, Hsi E, Kuo HT, Yokoyama KK, Hsu SH. Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC. Oncotarget 2018; 7:36924-36939. [PMID: 27175585 PMCID: PMC5095049 DOI: 10.18632/oncotarget.9228] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 04/16/2016] [Indexed: 01/29/2023] Open
Abstract
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is involved in cell proliferation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms linking gene expression and tumor formation remain unclear. In this study, we found that ISX transcriptionally activated E2F transcription factor 1 (E2F1) and associated oncogenic activity by directly binding to the E2 site of its promoter. Forced expression of ISX increased the expression of and phosphorylated the serine residue at position 332 of E2F1, which may be translocated into the nucleus to form the E2F1–DP-1 complex, suggesting that the promotion of oncogenic activities of the ISX–E2F1 axis plays a critical role in hepatoma cells. Coexpression of ISX and E2F1 significantly promoted p53 and RB-mediated cell proliferation and anti-apoptosis, and repressed apoptosis and autophagy. In contrast, short hairpin RNAi-mediated attenuation of ISX and E2F1 decreased cell proliferation and malignant transformation, respectively, in hepatoma cells in vitro and in vivo. The mRNA expression of E2F1 and ISX in 238 paired specimens from human HCC patients, and the adjacent, normal tissues exhibited a tumor-specific expression pattern which was highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. Therefore, our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression.
Collapse
Affiliation(s)
- Shen-Nien Wang
- Division of Hepatobiliary Surgery, Department of Surgery, Faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Li-Ting Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ding-Ping Sun
- Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan.,Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung, Taiwan
| | - Edward Hsi
- Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsing-Tao Kuo
- Department of Internal Medicine, Division of Hepatogastroenterology, Chi-Mei Medical Center, Tainan, Taiwan.,Department of Senior Citizen Service Management, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Research Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, Japan.,Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| |
Collapse
|
|
15
|
Chang PY, Huang Y, Hung TY, Chong KY, Chang YS, Chao CCK, Chow KPN. Spontaneous metastases in immunocompetent mice harboring a primary tumor driven by oncogene latent membrane protein 1 from Epstein-Barr virus. Biomed J 2016; 39:261-271. [PMID: 27793268 PMCID: PMC6139811 DOI: 10.1016/j.bj.2015.12.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 12/09/2015] [Indexed: 02/07/2023] Open
Abstract
Background In vitro and clinical studies suggest that the oncogene LMP1 (latent membrane protein 1) encoded by Epstein–Barr virus (EBV) plays a role in the development of nasopharyngeal carcinoma (NPC) and the formation of metastases in immunocompetent individuals. However, whether LMP1 itself is sufficient to drive these events in immunocompetent hosts remains elusive due to the lack of appropriate experimental models. The aim of this study was to study LMP1-dependent tumorigenesis and metastasis in BALB/c mice inoculated with BALB/c-3T3 cells expressing N-LMP1 (a Taiwanese NPC variant). Methods Following cancer cell inoculation, metastasis formation was monitored over time using PCR analysis of LMP1 as tumor marker. We also used a luciferase (Luc)-containing N-LMP1 and bioluminescent imaging (BLI) to monitor metastasis formation in a non-invasive manner. Results N-LMP1 appeared early in draining lymph nodes and in various distant organs before the rapid growth of the primary tumor. Lung metastasis was observed by BLI and further confirmed by histological examination. Furthermore, we detected luciferase signals in the lungs, even before the animals were sacrificed. Conclusions Our results demonstrate the high metastatic character of N-LMP1 in immunocompetent hosts. Systemic tumor dissemination occurs even before aggressive tumor growth at the primary site, suggesting that early treatment of primary LMP1-associated tumors and distant micro-metastases is critical to achieve positive results.
Collapse
Affiliation(s)
- Pu-Yuan Chang
- Tumor Biology Laboratory, Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yenlin Huang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tzu-Yuan Hung
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medical Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Chuck C-K Chao
- Tumor Biology Laboratory, Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Kai-Ping N Chow
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| |
Collapse
|
|
16
|
All-or-(N)One - an epistemological characterization of the human tumorigenic neuronal paralogous FAM72 gene loci. Genomics 2015. [PMID: 26206078 DOI: 10.1016/j.ygeno.2015.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumourigenic effects of FAM72. Our in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbour SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs.
Collapse
|
|
17
|
Chiou SS, Wang LT, Huang SB, Chai CY, Wang SN, Liao YM, Lin PC, Liu KY, Hsu SH. Wntless (GPR177) expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia via Wnt signaling. Carcinogenesis 2014; 35:2357-2364. [DOI: 10.1093/carcin/bgu166] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
|
|
18
|
Tang Y, Luo C, Cheng A, Lu S, Xu J, Fu T, Gan R. Expression of latent membrane proteins in Epstein‑Barr virus-transformed lymphocytes in vitro. Mol Med Rep 2014; 10:1117-21. [PMID: 24919846 DOI: 10.3892/mmr.2014.2313] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 04/07/2014] [Indexed: 11/05/2022] Open
Abstract
Infection with Epstein-Barr virus (EBV) induces activation and proliferation of B lymphocytes. Detection of latent membrane protein (LMP)-1 is used to identify the proliferative ability of B cells. However, changes in the expression levels of the three LMPs during EBV-induced B lymphocyte transformation, have not yet been reported. In the present study, the expression levels of LMP-1, LMP-2A and LMP-2B were compared between EBV-transformed B lymphocytes and paired normal lymphocytes. Seven lymphoblast cell lines were established by EBV infection of normal human lymphocytes in vitro. The expression levels of LMP genes and LMP-1 protein were determined using quantitative (q)PCR and western blotting in lymphoblasts and normal lymphocytes, respectively. The expression of LMP1, LMP-2A and LMP-2B genes was significantly upregulated in EBV-induced lymphoblasts compared with the normal lymphocytes. The LMP-1 protein level was also significantly increased in EBV-transformed B lymphocytes. Expression of LMP1, LMP-2A and LMP-2B genes was significantly upregulated in EBV-induced lymphoblasts, suggesting LMP genes are important in the transformation of human lymphocytes.
Collapse
Affiliation(s)
- Yunlian Tang
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Chunyan Luo
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ailan Cheng
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Suli Lu
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jinhua Xu
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ting Fu
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Runliang Gan
- Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China
| |
Collapse
|
|
19
|
The protein p17 signaling pathways in cancer. Tumour Biol 2013; 34:4081-7. [PMID: 23900679 DOI: 10.1007/s13277-013-0999-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 07/02/2013] [Indexed: 10/26/2022] Open
Abstract
P17 is a novel neuronal protein expressed under physiological conditions only at very low levels in other tissues. Accumulating data indicate its crucial involvement in tumorigenic effects. Using molecular, cellular, and biocomputational methods, the current study unraveled p17 mode of action. Data indicate that mitochondria-associated p17 interacts with the proteins TMEM115, YPEL3, ERP44, CDK5RAP, and NNAT. Moreover, p17 drives the cell cycle into the G0/G1 phase and enhances survival of proliferating cells. Interference with p17 activities thus might become a novel option to influence also the tumor suppressor protein p53 signaling pathways for the treatment of tumors.
Collapse
|
|
20
|
Tseng CE, Shu TW, Lin CW, Liao KS. Synchronous adenocarcinoma and extranodal natural killer/T-cell lymphoma of the colon: A case report and literature review. World J Gastroenterol 2013; 19:1850-1854. [PMID: 23555176 PMCID: PMC3607764 DOI: 10.3748/wjg.v19.i11.1850] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 01/20/2013] [Accepted: 02/08/2013] [Indexed: 02/06/2023] Open
Abstract
Extranodal natural killer/T-cell lymphoma (ENKTL) is a distinct subtype of non-Hodgkin’s lymphoma and is rare in the colon. Synchronous adenocarcinoma and ENKTL of the colon has not been reported in the literature. In the present study, we report a 63-year-old male who suffered from intermittent bloody stools for 2 mo. He did not have fever, body weight loss or night sweat. Endoscopic and imaging studies revealed a 4.5-cm ulcerative mass in the ascending colon and a 3.0-cm polypoid, easy bleeding mass in the sigmoid colon, respectively. Thought to have double carcinoma of the colon, he received simultaneous right hemicolectomy and sigmoidectomy. The pathological diagnosis was a synchronous ENKTL (ascending colon) and adenocarcinoma (sigmoid colon). The literature on synchronous adenocarcinoma and malignant lymphoma of the colon was also reviewed.
Collapse
|
|
21
|
Hsu SH, Wang LT, Lee KT, Chen YL, Liu KY, Suen JL, Chai CY, Wang SN. Proinflammatory homeobox gene, ISX, regulates tumor growth and survival in hepatocellular carcinoma. Cancer Res 2012; 73:508-18. [PMID: 23221382 DOI: 10.1158/0008-5472.can-12-2795] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chronic inflammation drives initiation of hepatocellular carcinoma (HCC), but the underlying mechanisms linking inflammation and tumor formation remain obscure. In this study, we compared the expression of interleukin (IL)-6 and cyclin D1 (CCND1) with the IL-6-induced homeobox gene ISX (intestine-specific homeobox) in 119 paired specimens of HCCs and adjacent normal tissues and also in paired specimens from 11 patients with non-HCCs. In pathologic analysis, ISX exhibited a tumor-specific expression pattern and a high correlation to patient survival time, tumor size, tumor number, and progression stage. Enforced expression of ISX accelerated cell proliferation and tumorigenic activity in hepatoma cells through CCND1 induction. In contrast, short hairpin RNA-mediated attenuation of ISX in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. A high positive correlation existed in human hepatoma tumors between ISX and CCND1 expression. Together, our results highlight ISX as an important regulator in hepatoma progression with significant potential as a prognostic and therapeutic target in HCCs.
Collapse
Affiliation(s)
- Shih-Hsien Hsu
- Graduate Institute of Medicine, Kaohsiung Medical University, 807, Kaohsiung, Taiwan, ROC.
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Functional characterization of mammalian Wntless homolog in mammalian system. Kaohsiung J Med Sci 2012; 28:355-61. [DOI: 10.1016/j.kjms.2012.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 08/24/2011] [Indexed: 11/20/2022] Open
|
|
23
|
Epstein-Barr virus downregulates microRNA 203 through the oncoprotein latent membrane protein 1: a contribution to increased tumor incidence in epithelial cells. J Virol 2011; 86:3088-99. [PMID: 22205737 DOI: 10.1128/jvi.05901-11] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The Epstein-Barr virus (EBV) is highly associated with nasopharyngeal carcinoma (NPC), and it regulates some microRNAs (miRNAs) that are involved in the development of cancer. The role of EBV in the deregulation of cellular miRNAs and how this affects the progression of NPC remain to be investigated. An analysis of the miRNA profile in an EBV-infected cell line revealed that miRNA 203 (miR-203) was downregulated. miR-203 is expressed specifically in epithelial cells. This downregulation of miR-203 was further verified and functionally analyzed. miR-203 was downregulated substantially in epithelial cells and NPC tissues that were latently infected with EBV. Downregulation of miR-203 also occurred during the early stage of EBV infection. Furthermore, the viral oncoprotein, latent membrane protein 1 (LMP1), was responsible for downregulation of miR-203. Removal of the latent EBV genome or suppression of LMP1 resulted in restoration of miR-203 expression. EBV-LMP1 mediated the downregulation of miR-203 at the primary transcript level. E2F3 and CCNG1 were identified as target genes of miR-203. Ectopic expression of miR-203 inhibited EBV-induced S-phase entry and transformation in vivo. Overexpression of the targets overcame the effects of miR-203 mimics on the cell cycle, and the expression of target genes in tumor models was inhibited by miR-203. Inhibitors of Jun N-terminal protein kinase (JNK) and NF-κB blocked miR-203 downregulation. These results imply that EBV promotes malignancy by downregulating cellular miR-203, which contributes to the etiology of NPC.
Collapse
|