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1
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Patel A, Mahapatra S, Bishoyi AK, Sharma A, Makwana A, Swarnkar T, Gupta A, Sahoo PK, Shah S. Harnessing machine learning technique to authenticate differentially expressed genes in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2025; 139:211-219. [PMID: 39505585 DOI: 10.1016/j.oooo.2024.10.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/02/2024] [Accepted: 10/02/2024] [Indexed: 11/08/2024]
Abstract
OBJECTIVE Advancements in early detection of the disease, prognosis and the development of therapeutic strategies necessitate tumor-specific biomarkers. Despite continuous efforts, no molecular marker has been proven to be an effective therapeutic tool for the early detection of cancer. The study aims to determine diagnostic and prognostic signature genes that may be involved in cancer pathology and hence, may serve as molecular markers. STUDY DESIGN Eight candidate genes were selected based on our prior study of transcriptomic sequencing and validated in 100 matched pair samples of oral squamous cell carcinoma (OSCC). We further utilized machine learning approaches and examined the diagnostic presentation and predictive ability of the OSCC genes retrieved from publicly available The Cancer Genome Atlas (TCGA) database and compared with our results. RESULTS We conducted qPCR analysis to validate the expression of each gene and observed that each gene was present in the majority of OSCC samples. The predictive ability of selected genes was stable (with an average accuracy of 84%) across different classifiers. However, on validation with our dataset, it showed 75% accuracy, which might be because of the demographic variation of the samples. CONCLUSIONS The present research outlines cancer-associated molecular biomarkers that might eventually contribute to an enhanced prognosis of cancer patient by identifying novel therapeutic targets.
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Affiliation(s)
- Amisha Patel
- Department of Microbiology, School of Science, RK University, Rajkot, Gujarat 360020, India
| | - Saswati Mahapatra
- Department of Computer Application, Faculty of Technology, Siksha 'O' Anusandhan University, Bhubaneshwar, Odisha 751030, India
| | - Ashok Kumar Bishoyi
- Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat 360003, India
| | - Abhishek Sharma
- Department of Biotechnology and Bioengineering, Institute of Advanced Research, Gandhinagar, Gujarat 382426, India
| | - Abhijit Makwana
- Shree Nathalal Parekh Cancer Institute, Rajkot Cancer Society, Rajkot, Gujarat 360003, India
| | - Tripti Swarnkar
- Department of Computer Application, National Institute of Technology, Raipur CG (NITRR), Chhattisgarh 492010, India
| | - Anubha Gupta
- SBILab, Department of ECE, and Centre of Excellence in Healthcare, IIIT, Delhi, 110020, India
| | - Prasan Kumar Sahoo
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan City, 33302, Taiwan
| | - Sejal Shah
- Department of Bioinformatics, Faculty of Engineering and Technology, Marwadi University, Rajkot, Gujarat, 360003, India.
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2
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Vu T, Wang Y, Fowler A, Simieou A, McCarty N. TRIM44, a Novel Prognostic Marker, Supports the Survival of Proteasome-Resistant Multiple Myeloma Cells. Cells 2024; 13:1431. [PMID: 39273003 PMCID: PMC11394402 DOI: 10.3390/cells13171431] [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: 07/02/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) cytogenetic abnormalities. This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress. Collectively, our discoveries highlight TRIM44's significant role in MM progression and resistance to therapy, suggesting its potential value as a therapeutic target.
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Affiliation(s)
- Trung Vu
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
| | - Yuqin Wang
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
| | - Annaliese Fowler
- The Department of Biomedical Engineering, Texas A&M University, Houston, TX 77030, USA;
| | - Anton Simieou
- The Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA;
| | - Nami McCarty
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, TX 77021, USA; (T.V.); (Y.W.)
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3
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Price K, Yang WH, Cardoso L, Wang CM, Yang RH, Yang WH. Jun Dimerization Protein 2 (JDP2) Increases p53 Transactivation by Decreasing MDM2. Cancers (Basel) 2024; 16:1000. [PMID: 38473360 DOI: 10.3390/cancers16051000] [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: 02/05/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target genes. JDP2 has also demonstrates important roles in cell-cycle regulation, cancer development and progression, inhibition of adipocyte differentiation, and the regulation of antibacterial immunity and bone homeostasis. JDP2 and ATF3 exhibit significant similarity in their C-terminal domains, sharing 60-65% identities. Previous studies have demonstrated that ATF3 is able to influence both the transcriptional activity and p53 stability via a p53-ATF3 interaction. While some studies have shown that JDP2 suppresses p53 transcriptional activity and in turn, p53 represses JDP2 promoter activity, the direct interaction between JDP2 and p53 and the regulatory role of JDP2 in p53 transactivation have not been explored. In the current study, we provide evidence, for the first time, that JDP2 interacts with p53 and regulates p53 transactivation. First, we demonstrated that JDP2 binds to p53 and the C-terminal domain of JDP2 is crucial for the interaction. Second, in p53-null H1299 cells, JDP2 shows a robust increase of p53 transactivation in the presence of p53 using p53 (14X)RE-Luc. Furthermore, JDP2 and ATF3 together additively enhance p53 transactivation in the presence of p53. While JDP2 can increase p53 transactivation in the presence of WT p53, JDP2 fails to enhance transactivation of hotspot mutant p53. Moreover, in CHX chase experiments, we showed that JDP2 slightly enhances p53 stability. Finally, our findings indicate that JDP2 has the ability to reverse MDM2-induced p53 repression, likely due to decreased levels of MDM2 by JDP2. In summary, our results provide evidence that JDP2 directly interacts with p53 and decreases MDM2 levels to enhance p53 transactivation, suggesting that JDP2 is a novel regulator of p53 and MDM2.
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Affiliation(s)
- Kasey Price
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
| | - William H Yang
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
| | - Leticia Cardoso
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
| | - Chiung-Min Wang
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
| | - Richard H Yang
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
| | - Wei-Hsiung Yang
- Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA 31404, USA
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4
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Abbas H, Derkaoui DK, Jeammet L, Adicéam E, Tiollier J, Sicard H, Braun T, Poyet JL. Apoptosis Inhibitor 5: A Multifaceted Regulator of Cell Fate. Biomolecules 2024; 14:136. [PMID: 38275765 PMCID: PMC10813780 DOI: 10.3390/biom14010136] [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: 12/19/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Apoptosis, or programmed cell death, is a fundamental process that maintains tissue homeostasis, eliminates damaged or infected cells, and plays a crucial role in various biological phenomena. The deregulation of apoptosis is involved in many human diseases, including cancer. One of the emerging players in the intricate regulatory network of apoptosis is apoptosis inhibitor 5 (API5), also called AAC-11 (anti-apoptosis clone 11) or FIF (fibroblast growth factor-2 interacting factor). While it may not have yet the same level of notoriety as some other cancer-associated proteins, API5 has garnered increasing attention in the cancer field in recent years, as elevated API5 levels are often associated with aggressive tumor behavior, resistance to therapy, and poor patient prognosis. This review aims to shed light on the multifaceted functions and regulatory mechanisms of API5 in cell fate decisions as well as its interest as therapeutic target in cancer.
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Affiliation(s)
- Hafsia Abbas
- Université Oran 1, Ahmed Ben Bella, Oran 31000, Algeria; (H.A.); (D.K.D.)
| | | | - Louise Jeammet
- Jalon Therapeutics, 75010 Paris, France; (L.J.); (J.T.); (H.S.)
| | - Emilie Adicéam
- Jalon Therapeutics, 75010 Paris, France; (L.J.); (J.T.); (H.S.)
| | - Jérôme Tiollier
- Jalon Therapeutics, 75010 Paris, France; (L.J.); (J.T.); (H.S.)
| | - Hélène Sicard
- Jalon Therapeutics, 75010 Paris, France; (L.J.); (J.T.); (H.S.)
| | - Thorsten Braun
- Laboratoire de Transfert des Leucémies, EA3518, Institut de Recherche Saint Louis, Hôpital Saint Louis, Université de Paris, 75010 Paris, France;
- AP-HP, Service d’Hématologie Clinique, Hôpital Avicenne, Université Paris XIII, 93000 Bobigny, France
- OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Hôpital Saint-Louis, 75010 Paris, France
| | - Jean-Luc Poyet
- INSERM UMRS976, Institut de Recherche Saint Louis, Hôpital Saint Louis, 75010 Paris, France
- Université Paris Cité, 75015 Paris, France
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5
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Qin H, Hu LL, Wang WJ, Yu ZZ, Chen Y, Zhao YB, Liao YH, Zhang WL, Yang RQ. MiR-20b-5p involves in vascular aging induced by hyperhomocysteinemia. Exp Gerontol 2023; 184:112330. [PMID: 37967592 DOI: 10.1016/j.exger.2023.112330] [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: 10/18/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/17/2023]
Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis (AS). Some reports have shown that homocysteine (Hcy) could accelerate the development of AS by promoting endothelial cell senescence. miRNAs were widely involved in the pathophysiology of HHcy. However, few studies have focused on the changes of miRNA-mRNA networks in the artery of HHcy patients. For this reason, RNA-sequencing was adopted to investigate the expression of miRNA and mRNA in HHcy model mouse arteries. We found that the expression of 216 mRNAs and 48 miRNAs were significantly changed. Using TargetScan and miRDB web tools, 29 miRNA-mRNA pairs were predicted. Notably, miR-20b-5p and FJX1 shared the highest predicted score in TargetScan, and further study indicated that the miR-20b-5p inhibitor significantly upregulated the FJX1 expression in HHcy human umbilical vein endothelial cells (HUVECs) model. PPI analysis revealed an important sub-network which was centered on CDK1. Gene ontology (GO) enrichment analysis showed that HHcy had a significant effect on cell cycle. Further experiments found that Hcy management increased reactive oxygen species (ROS) generation, the activity of senescence associated β-galactosidase (SA-β-gal) and the protein expression of p16 and p21 in HUVECs, which were rescued by miR-20b-5p inhibitor. In general, our research indicated the important role of miR-20b-5p in HHcy-related endothelial cell senescence.
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Affiliation(s)
- Hao Qin
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Long-Long Hu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Wen-Jun Wang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Zuo-Zhong Yu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Yang Chen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Yuan-Bin Zhao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Yan-Hui Liao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Wei-Lin Zhang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China
| | - Ren-Qiang Yang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People's Republic of China.
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6
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Clements CM, Henen MA, Vögeli B, Shellman YG. The Structural Dynamics, Complexity of Interactions, and Functions in Cancer of Multi-SAM Containing Proteins. Cancers (Basel) 2023; 15:3019. [PMID: 37296980 PMCID: PMC10252437 DOI: 10.3390/cancers15113019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
SAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the structural dynamics, regulation, and functions of SAM domains in proteins containing more than one SAM (multi-SAM containing proteins, MSCPs). The topics here include how intrinsic disorder of some SAMs and an additional SAM domain in MSCPs increase the complexity of their interactions and oligomerization arrangements. Many similarities exist among these MSCPs, including their effects on cancer cell adhesion, migration, and metastasis. In addition, they are all involved in some types of receptor-mediated signaling and neurology-related functions or diseases, although the specific receptors and functions vary. This review also provides a simple outline of methods for studying protein domains, which may help non-structural biologists to reach out and build new collaborations to study their favorite protein domains/regions. Overall, this review aims to provide representative examples of various scenarios that may provide clues to better understand the roles of SAM domains and MSCPs in cancer in general.
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Affiliation(s)
- Christopher M. Clements
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Morkos A. Henen
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (M.A.H.); (B.V.)
| | - Beat Vögeli
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (M.A.H.); (B.V.)
| | - Yiqun G. Shellman
- Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
- Charles C. Gates Regenerative Medicine and Stem Cell Biology Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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7
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Huang M, Guo T, Meng Y, Zhou R, Xiong M, Ding J, Zhang Y, Liu S, Zhuang K. Comprehensive analysis of the prognosis and immune effect of the oncogenic protein Four Jointed Box 1. Front Oncol 2023; 13:1170482. [PMID: 37324001 PMCID: PMC10266275 DOI: 10.3389/fonc.2023.1170482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/02/2023] [Indexed: 06/17/2023] Open
Abstract
Background The Four Jointed Box 1 (FJX1) gene has been implicated in the upregulation of various cancers, highlighting its crucial role in oncology and immunity. In order to better understand the biological function of FJX1 and identify new immunotherapy targets for cancer, we conducted a comprehensive analysis of this gene. Methods We analyzed the expression profiles and prognostic value of FJX1 using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). Copy number alterations (CNAs), mutations, and DNA methylation were analyzed through cBioPortal. The Immune Cell Abundance Identifier (ImmuCellAI) was used to examine the correlation between FJX1 expression and immune cell infiltration. The relationship between FJX1 expression and immune-related genes and immunosuppressive pathway-related genes was analyzed using The Tumor Immune Estimation Resource version 2 (TIMER2). Tumor mutational burden (TMB) and microsatellite instability (MSI) were obtained from TCGA pan-cancer data. The effect of immunotherapy and the IC50 were assessed using IMvigor210CoreBiologies and Genomics For Drug Sensitivity in Cancer (GDSC). Finally, we evaluated the impact of FJX1 on colon cancer cell proliferation and migration through in vitro functional experiments. Results Our study indicated that FJX1 expression was high in most cancers and was significantly associated with poor prognosis. High FJX1 expression was also linked to significant alterations in CNA, DNA methylation, TMB, and MSI. Positive correlations were found between FJX1 expression and tumor-associated macrophages (TAMs) and with immune-related genes such as TGFB1 and IL-10 and immunosuppressive pathway-related genes such as TGFB1 and WNT1. On the other hand, FJX1 expression showed a negative relationship with CD8+ T cells. Furthermore, high FJX1 expression led to reduced effectiveness of immunotherapy and drug resistance. In colon cancer cells, FJX1 knockdown was found to decrease cell proliferation and migration. Conclusion Our research findings demonstrate that FJX1 is a new prognostic factor with a significant role in tumor immunity. Our results highlight the importance of further exploring the potential of targeting FJX1 as a therapeutic strategy in cancer.
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Affiliation(s)
- Mei Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tian Guo
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Meng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ruling Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Man Xiong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Ding
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yali Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Pazhou Lab, Guangzhou, Guangdong, China
- Department of Gastroenterology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, Guangdong, China
| | - Kangmin Zhuang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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8
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Jiang XY, Guan FF, Ma JX, Dong W, Qi XL, Zhang X, Chen W, Gao S, Gao X, Pan S, Wang JZ, Ma YW, Zhang LF, Lu D. Cardiac-specific Trim44 knockout in rat attenuates isoproterenol-induced cardiac remodeling via inhibition of AKT/mTOR pathway. Dis Model Mech 2023; 16:276033. [PMID: 35855640 PMCID: PMC9441189 DOI: 10.1242/dmm.049444] [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: 01/03/2022] [Accepted: 07/07/2022] [Indexed: 11/20/2022] Open
Abstract
When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3β/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF. Summary: This is the first study to demonstrate the function of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy.
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Affiliation(s)
- Xiao-Yu Jiang
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Fei-Fei Guan
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Jia-Xin Ma
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Wei Dong
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Xiao-Long Qi
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Xu Zhang
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Wei Chen
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Shan Gao
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Xiang Gao
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Shuo Pan
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Ji-Zheng Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Yuan-Wu Ma
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Lian-Feng Zhang
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
| | - Dan Lu
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China.,National Human Diseases Animal Model Resource Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Peking Union Medicine College, Beijing 100021, China
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Association of Inherited Copy Number Variation in ADAM3A and ADAM5 Pseudogenes with Oropharynx Cancer Risk and Outcome. Genes (Basel) 2022; 13:genes13122408. [PMID: 36553675 PMCID: PMC9778539 DOI: 10.3390/genes13122408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/01/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction. Individuals with three or more copies of ADAM3A and ADAM5 pseudogenes (8p11.22 chromosome region) were under 6.49-fold increased risk of OPSCC. ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p. Individuals carrying more than three copies of ADAM3A and ADAM5 presented higher ADAM9 expression levels. Moreover, patients with total deletion or one copy of pseudogenes and with higher expression of miR-122b-5p presented worse prognoses. Our data suggest, for the first time, that ADAM3A and ADAM5 pseudogene-inherited CNV could modulate OPSCC occurrence and prognosis, possibly through the interaction of ADAM5 pseudogene transcript, miR-122b-5p, and ADAM9.
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Wang N, Li R, Jia H, Xie H, Liu C, Jiang S, Zhang K, Lin P, Yu X. Apaf-1 interacting protein, a new target of microRNA-146a-3p, promotes prostate cancer cell development via the ERK1/2 pathway. Cell Biol Int 2022; 46:1156-1168. [PMID: 35293661 DOI: 10.1002/cbin.11796] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/25/2022] [Accepted: 03/13/2022] [Indexed: 11/06/2022]
Abstract
The Apaf-1 interacting protein APIP, a ubiquitously expressed anti-apoptotic molecule, is aberrantly expressed and of great significance in various cancers. However, little is known regarding the potential value and underlying mechanisms of APIP in prostate cancer. Here, we demonstrated that APIP expression is significantly upregulated in prostate cancer cell lines. APIP overexpression promoted tumor cell proliferation and migration and induced ERK1/2 activation. Pharmacological inhibition of ERK1/2 signaling reversed APIP-induced increase in cell proliferation and migration induced by APIP overexpression. Expression of APIP was hampered by miR-146a-3p. A dual luciferase reporter gene assay identified the regulatory relationship between APIP and miR-146a-3p in prostate cancer, suggesting that APIP is a direct target of miR-146a-3p. miR-146a-3p reduced cell proliferation and migration in prostate cancer. Furthermore, miR-146a-3p inhibited ERK1/2 activation. Application of an ERK1/2 inhibitor reversed the increase in cell proliferation and migration induced by miR-146a-3p inhibition. In summary, this study focused on the role of APIP in regulating cell growth and migration, and proposes a theoretical basis for APIP as a promising biomarker in prostate cancer development. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Nan Wang
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Rou Li
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Huizhen Jia
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Hui Xie
- Teaching Experiment Center of Biotechnology, Harbin Medical University, Harbin, Heilongjiang, 150001, P.R. China
| | - Chi Liu
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Shan Jiang
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Ke Zhang
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Ping Lin
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
| | - Xiaoguang Yu
- Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150086, P.R. China
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11
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Galetzka D, Böck J, Wagner L, Dittrich M, Sinizyn O, Ludwig M, Rossmann H, Spix C, Radsak M, Scholz-Kreisel P, Mirsch J, Linke M, Brenner W, Marron M, Poplawski A, Haaf T, Schmidberger H, Prawitt D. Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation. EXCLI JOURNAL 2022; 21:117-143. [PMID: 35221838 PMCID: PMC8859646 DOI: 10.17179/excli2021-4482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/15/2021] [Indexed: 12/18/2022]
Abstract
Most childhood cancers occur sporadically and cannot be explained by an inherited mutation or an unhealthy lifestyle. However, risk factors might trigger the oncogenic transformation of cells. Among other regulatory signals, hypermethylation of RAD9A intron 2 is responsible for the increased expression of RAD9A protein, which may play a role in oncogenic transformation. Here, we analyzed the RAD9A intron 2 methylation in primary fibroblasts of 20 patients with primary cancer in childhood and second primary cancer (2N) later in life, 20 matched patients with only one primary cancer in childhood (1N) and 20 matched cancer-free controls (0N), using bisulfite pyrosequencing and deep bisulfite sequencing (DBS). Four 1N patients and one 2N patient displayed elevated mean methylation levels (≥ 10 %) of RAD9A. DBS revealed ≥ 2 % hypermethylated alleles of RAD9A, indicative for constitutive mosaic epimutations. Bone marrow samples of NHL and AML tumor patients (n=74), EBV (Epstein Barr Virus) lymphoblasts (n=6), tumor cell lines (n=5) and FaDu subclones (n=13) were analyzed to substantiate our findings. We find a broad spectrum of tumor entities with an aberrant methylation of RAD9A. We detected a significant difference in mean methylation of RAD9A for NHL versus AML patients (p ≤0.025). Molecular karyotyping of AML samples during therapy with hypermethylated RAD9A showed an evolving duplication of 1.8 kb on Chr16p13.3 including the PKD1 gene. Radiation, colony formation assays, cell proliferation, PCR and molecular karyotyping SNP-array experiments using generated FaDu subclones suggest that hypermethylation of RAD9A intron 2 is associated with genomic imbalances in regions with tumor-relevant genes and survival of the cells. In conclusion, this is the very first study of RAD9A intron 2 methylation in childhood cancer and Leukemia. RAD9A epimutations may have an impact on leukemia and tumorigenesis and can potentially serve as a biomarker.
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Affiliation(s)
- Danuta Galetzka
- Department of Radiation Oncology and Radiation Therapy, University Medical Centre, Mainz, Germany
| | - Julia Böck
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.,Institute of Pathology, Julius Maximilians University, Würzburg, Germany
| | - Lukas Wagner
- Center for Pediatrics and Adolescent Medicine, University Medical Centre, Mainz, Germany
| | - Marcus Dittrich
- Bioinformatics Department, Julius Maximilians University, Würzburg, Germany
| | - Olesja Sinizyn
- Department of Radiation Oncology and Radiation Therapy, University Medical Centre, Mainz, Germany
| | | | - Heidi Rossmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre, Mainz, Germany
| | - Claudia Spix
- Division of Childhood Cancer Epidemiology, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Mainz, Germany
| | - Markus Radsak
- Department of Hematology, University Medical Centre, Mainz, Germany
| | | | - Johanna Mirsch
- Radiation Biology and DNA Repair, Technical University of Darmstadt, Germany
| | - Matthias Linke
- Institute of Human Genetics, University Medical Centre, Mainz, Germany
| | - Walburgis Brenner
- Department of Obstetrics and Women's Health, University Medical Centre, Mainz, Germany
| | - Manuela Marron
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - Alicia Poplawski
- Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Mainz, Germany
| | - Thomas Haaf
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
| | - Heinz Schmidberger
- Department of Radiation Oncology and Radiation Therapy, University Medical Centre, Mainz, Germany
| | - Dirk Prawitt
- Center for Pediatrics and Adolescent Medicine, University Medical Centre, Mainz, Germany
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12
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Cheng T, Zhu X, Lu J, Teng X. MiR-532-3p suppresses cell proliferation, migration and invasion of colon adenocarcinoma via targeting FJX1. Pathol Res Pract 2022; 232:153835. [DOI: 10.1016/j.prp.2022.153835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 02/14/2022] [Accepted: 03/05/2022] [Indexed: 12/19/2022]
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13
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Liprins in oncogenic signaling and cancer cell adhesion. Oncogene 2021; 40:6406-6416. [PMID: 34654889 PMCID: PMC8602034 DOI: 10.1038/s41388-021-02048-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 12/30/2022]
Abstract
Liprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.
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14
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Lyu L, Lin TC, McCarty N. TRIM44 mediated p62 deubiquitination enhances DNA damage repair by increasing nuclear FLNA and 53BP1 expression. Oncogene 2021; 40:5116-5130. [PMID: 34211088 PMCID: PMC9744239 DOI: 10.1038/s41388-021-01890-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 05/20/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022]
Abstract
Cancer cells show increases in protein degradation pathways, including autophagy, during progression to meet the increased protein degradation demand and support cell survival. On the other hand, reduced autophagy activity during aging is associated with a reduced DNA damage response and increased genomic instability. Therefore, it is a puzzling how DNA repair can be increased in cancer cells that are resistant to chemotherapies or during progression when autophagy activity is intact or increased. We discovered that tripartite motif containing 44 (TRIM44) is a pivotal element regulating the DNA damage response in cancer cells with intact autophagy. TRIM44 deubiquitinates p62, an autophagy substrate, which leads to its oligomerization. This prevents p62 localization to the nucleus upon irradiation. Increased cytoplasmic retention of p62 by TRIM44 prevents the degradation of FLNA and 53BP1, which increases DNA damage repair. Together, our data support TRIM44 a potential therapeutic target for therapy-resistant tumor cells with intact autophagy.
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Affiliation(s)
- Lin Lyu
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA
| | - Tsung-Chin Lin
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA
| | - Nami McCarty
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA.,Correspondence: Nami McCarty, Ph.D., University of Texas-Health Science Center at Houston, 1825 Pressler St., IMM-630A, Houston, TX 77030, USA, , Tel: 713-500-2495, Fax: 713-500-2424
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15
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Hagiwara S, Sasaki E, Hasegawa Y, Suzuki H, Nishikawa D, Beppu S, Terada H, Sawabe M, Takahashi M, Hanai N. Serum CD109 levels reflect the node metastasis status in head and neck squamous cell carcinoma. Cancer Med 2021; 10:1335-1346. [PMID: 33565282 PMCID: PMC7926025 DOI: 10.1002/cam4.3737] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/12/2020] [Accepted: 12/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background Various biomarkers are being developed for the early diagnosis of cancer and for predicting its prognosis. The aim of this study is to evaluate the diagnostic significance of serum CD109 in head and neck squamous cell carcinoma (HNSCC). Methods The serum CD109 levels in a total of 112 serum samples collected before and after surgery from 56 HNSCC patients were analyzed with an enzyme‐linked immunosorbent assay (ELISA). The clinical factor that showed a statistically significant association with both the preoperative serum CD109 level, and the CD109 index: which was defined as the ratio of the preoperative serum CD109 level to the postoperative serum CD109 level, were assessed. The correlations between the serum CD109 levels and lymph node density (LND), pathological features such as lymphatic invasion, and serum SCC antigen levels were also assessed. Results The ELISA measurement revealed that preoperative serum CD109 levels were elevated in patients with node metastasis‐positive and stage IV disease, in comparison to those with node metastasis‐negative and Stage I+II+III disease, respectively. A multiple regression analysis indicated that serum CD109 level was significantly associated with the node metastasis status. A Spearman's rank correlation analysis also revealed a positive correlation between the preoperative serum CD109 level and LND. Furthermore, the probabilities of the overall and relapse‐free survival were significantly lower in patients with a preoperative serum CD109 level of ≥38.0 ng/ml and a CD109 index of ≥1.6, respectively, than in others. There was no significant correlation between the serum CD109 and SCC antigen levels. Conclusions The serum CD109 levels were elevated in patients with advanced stage disease, reflecting the node metastasis status. CD109 in sera could be a novel prognostic marker for HNSCC involving lymph node metastasis.
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Affiliation(s)
- Sumitaka Hagiwara
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yasuhisa Hasegawa
- Department of Head and Neck Surgery - Otolaryngology, Asahi University Hospital, Gifu, Japan
| | - Hidenori Suzuki
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Daisuke Nishikawa
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Shintaro Beppu
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hoshino Terada
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Michi Sawabe
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Masahide Takahashi
- International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Nobuhiro Hanai
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan
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16
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Xiao G, Yang Q, Bao Z, Mao H, Zhang Y, Lin S. Expression of tripartite motif-containing 44 and its prognostic and clinicopathological value in human malignancies:a meta-analysis. BMC Cancer 2020; 20:525. [PMID: 32503466 PMCID: PMC7275359 DOI: 10.1186/s12885-020-07014-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/28/2020] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Previous researches have reported that tripartite motif-containing 44 (TRIM44) is related to the prognosis of multiple human tumors. This study was designed to systematically assess the prognostic value of TRIM44 in human malignancies and summarize its possible tumor-related mechanisms. METHODS The available databases were searched for eligible studies that evaluated the clinicopathological and prognostic roles of TRIM44 in patients with malignancies. The hazard ratios (HR) and odds ratios (OR) were combined to assess the predictive role of TRIM44 using Stata/SE 14.1 software. RESULTS A total of 1740 patients from thirteen original studies were finally included in this study. The results of the combined analysis showed that over-expression of TRIM44 protein was significantly correlated with shorter overall survival (OS) (HR = 1.94, 95% CI: 1.60-2.35) and worse disease-free survival (DFS) (HR = 2.13, 95% CI: 1.24-3.65) in cancer patients. Additionally, the combined ORs indicated that elevated expression level of TRIM44 protein was significantly associated with lymph node metastasis (OR = 2.69, 95% CI: 1.71-4.24), distant metastasis (OR = 10.35, 95% CI: 1.01-106.24), poor tumor differentiation (OR = 1.78, 95% CI: 1.03-3.09), increased depth of tumor invasion (OR = 2.72, 95% CI: 1.73-4.30), advanced clinical stage (OR = 2.75, 95% CI: 2.04-3.71), and recurrence (OR = 2.30, 95% CI: 1.34-3.95). Furthermore, analysis results using Gene Expression Profiling Interactive Analysis (GEPIA) showed that the expression level of TRIM44 mRNA was higher in most tumor tissues than in the corresponding normal tissues, and the relationship between TRIM44 mRNA level and prognosis in various malignant tumors also explored in GEPIA and OS analysis webservers. CONCLUSIONS TRIM44 may serve as a valuable prognostic biomarker and a potential therapeutic target for patients with malignancies.
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Affiliation(s)
- Guoliang Xiao
- Department of General Surgery, the First People's Hospital of Neijiang, Neijiang, 641000, Sichuan Province, PR China
| | - Qiuxi Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, PR China
| | - Ziwei Bao
- Department of medicine, Southwest Medical University, Luzhou, 646000, Sichuan Province, PR China
| | - Haixia Mao
- Department of medicine, Southwest Medical University, Luzhou, 646000, Sichuan Province, PR China
| | - Yi Zhang
- Department of General Surgery, the First People's Hospital of Neijiang, Neijiang, 641000, Sichuan Province, PR China.
| | - Shibu Lin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, PR China
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17
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Elgart K, Faden DL. Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus. CURRENT OTORHINOLARYNGOLOGY REPORTS 2020; 8:111-119. [PMID: 32582473 PMCID: PMC7314379 DOI: 10.1007/s40136-020-00279-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Sinonasal squamous cell carcinoma (SNSCC) is a rare disease with considerable histologic diversity. Currently, there is a poor understanding of the etiology and pathogenesis of SNSCC. Here, we review recent literature to summarize what is known regarding (1) the etiology of SNSCC, (2) the role of Human Papilloma Virus (HPV) in SNSCC, and (2) the molecular underpinnings of SNSCC. RECENT FINDINGS 1. High risk HPVappears to play a role in the pathogenesis of a subset of SNSCCs. SNSCCs with high risk HPV have improved survival compared with those without HPV and occur in patients who are younger, similar to HPV mediated oropharyngeal cancer. 2. A subset of inverted papillomas have transcriptionally active low-risk HPV and have a higher risk of transformation, while low risk HPV negative inverted papillomas frequently have EGFR mutations. SUMMARY SNSCC is a diverse disease with likely multiple etiologies including carcinogen, irritant exposure, and HPV. While not definitively proven, evidence supports a role for high-risk HPV in a subset of SNSCC, and low-risk HPV in a subset of inverted papillomas which transform to SNSCC. In-depth molecular and genomic studies are needed in SNSCC to better understand the genomic underpinnings and oncogenic drivers.
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Affiliation(s)
- Katya Elgart
- Massachusetts Eye and Ear, Boston, MA 02114, USA
| | - Daniel L. Faden
- Massachusetts Eye and Ear, Boston, MA 02114, USA
- Harvard Medical School, 243 Charles St, Boston, MA 02114, USA
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18
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Pang X, Lin X, Du J, Zeng D. LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy. Acta Physiol (Oxf) 2020; 228:e13377. [PMID: 31512380 DOI: 10.1111/apha.13377] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/19/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022]
Abstract
AIM Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodelling in a rat model of DCM, with the involvement of NF-κB signalling pathway. METHODS The rat model of DCM was treated with si-LTBP2 and/or activator of NF-κB signalling pathway to examine the haemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodelling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF-κB signalling pathway in DCM. RESULTS LTBP2 was up-regulated in DCM rats. After LTBP2 was knocked down, haemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), tumour necrosis factor beta 1 (TGF-β1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col-I, Col-III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF-κB signalling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments. CONCLUSIONS LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in DCM rats by down-regulating the NF-κB signalling pathway.
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Affiliation(s)
- Xue‐Feng Pang
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
| | - Xue Lin
- Department of Cardiovascular Peking Union Medical College Hospital Beijing China
| | - Jian‐Jun Du
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
| | - Ding‐Yin Zeng
- Department of Cardiovascular The First Hospital of China Medical University Shenyang China
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Kato K, Miyazawa H, Kobayashi H, Noguchi N, Lambert D, Kawashiri S. Caveolin-1 Expression at Metastatic Lymph Nodes Predicts Unfavorable Outcome in Patients with Oral Squamous Cell Carcinoma. Pathol Oncol Res 2020; 26:2105-2113. [PMID: 31907776 DOI: 10.1007/s12253-019-00791-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 12/30/2019] [Indexed: 12/17/2022]
Abstract
We evaluated the clinical and prognostic value of the protein expression of caveolin-1 (CAV1) and p16 at the primary site and metastatic lymph nodes of oral squamous cell carcinoma (OSCC). Primary site specimens from 80 OSCC cases were randomly selected and lymph node specimens from 15 preserved metastatic lymph nodes from among those patients were selected for examination. We evaluated the CAV1 and p16 expression at both the primary site and metastatic lymph nodes, and analyzed the patients' clinicopathological data in relation to CAV1 and p16 expression. Our analysis revealed significant positive correlations between CAV1 expression at the primary site and pathological metastasis, cell differentiation, and mode of invasion (p = 0.019, p = 0.002, p = 0.015, respectively), but p16 expression was not associated with any clinicopathological factors. Patients with high CAV1 expression at the primary sites showed significantly worse prognoses than those with low or negative CAV1 expression (p = 0.002), and multivariate analysis showed that the T classification and CAV1 expression were independent OSCC prognostic factors. CAV1 expression was also present in the metastatic lymph nodes of the OSCC cases with particularly poor differentiation and high invasive grade, and patients with CAV1-positive metastatic lymph nodes showed significantly worse prognoses than those with CAV1-negative metastatic lymph nodes (p = 0.018). CAV1 may activate metastaticity and the invasive capacity of OSCC cells. CAV1 expression, particularly at metastatic lymph nodes, predicts a worse outcome for OSCC, suggesting that CAV1 could be used as a prognostic marker for OSCC.
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Affiliation(s)
- Koroku Kato
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
| | - Hiroki Miyazawa
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Hisano Kobayashi
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Natsuyo Noguchi
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Daniel Lambert
- Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Shuichi Kawashiri
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
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20
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de Vicente JC, Donate-Pérez Del Molino P, Rodrigo JP, Allonca E, Hermida-Prado F, Granda-Díaz R, Rodríguez Santamarta T, García-Pedrero JM. SOX2 Expression Is an Independent Predictor of Oral Cancer Progression. J Clin Med 2019; 8:jcm8101744. [PMID: 31640140 PMCID: PMC6832966 DOI: 10.3390/jcm8101744] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/14/2019] [Accepted: 10/16/2019] [Indexed: 12/11/2022] Open
Abstract
Potentially malignant oral lesions, mainly leukoplakia, are common. Malignant transformation varies widely, even in the absence of histological features such as dysplasia. Hence, there is a need for novel biomarker-based systems to more accurately predict the risk of cancer progression. The pluripotency transcription factor SOX2 is frequently overexpressed in cancers, including oral squamous cell carcinoma (OSCC), thereby providing a link between malignancy and stemness. This study investigates the clinical relevance of SOX2 protein expression in early stages of oral carcinogenesis as a cancer risk biomarker, and also its impact on prognosis and disease outcome at late stages of OSCC progression. SOX2 expression was evaluated by immunohistochemistry in 55 patients with oral epithelial dysplasia, and in 125 patients with OSCC, and correlated with clinicopathological data and outcomes. Nuclear SOX2 expression was detected in four (7%) cases of oral epithelial dysplasia, using a cut-off of 10% stained nuclei, and in 16 (29%) cases when any positive nuclei was evaluated. Univariate analysis showed that SOX2 expression and histopathological grading were significantly associated with oral cancer risk; and both were found to be significant independent predictors in the multivariate analysis. Nuclear SOX2 expression was also found in 49 (39%) OSCC cases, was more frequent in early tumor stages and N0 cases, and was associated with a better survival. In conclusion, SOX2 expression emerges as an independent predictor of oral cancer risk in patients with oral leukoplakia. These findings underscore the relevant role of SOX2 in early oral tumorigenesis rather than in tumor progression.
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Affiliation(s)
- Juan C de Vicente
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA). C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Department of Surgery, University of Oviedo. Avda. Julián Clavería, s/n, 33006 Oviedo, Asturias, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
| | - Paula Donate-Pérez Del Molino
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA). C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Department of Surgery, University of Oviedo. Avda. Julián Clavería, s/n, 33006 Oviedo, Asturias, Spain.
| | - Juan P Rodrigo
- Department of Surgery, University of Oviedo. Avda. Julián Clavería, s/n, 33006 Oviedo, Asturias, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA). C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Ciber de Cáncer (CIBERONC), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain.
| | - Eva Allonca
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Ciber de Cáncer (CIBERONC), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain.
| | - Francisco Hermida-Prado
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Ciber de Cáncer (CIBERONC), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain.
| | - Rocío Granda-Díaz
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Ciber de Cáncer (CIBERONC), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain.
| | - Tania Rodríguez Santamarta
- Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA). C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Department of Surgery, University of Oviedo. Avda. Julián Clavería, s/n, 33006 Oviedo, Asturias, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
| | - Juana M García-Pedrero
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo. C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Department of Otolaryngology, Hospital Universitario Central de Asturias (HUCA). C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
- Ciber de Cáncer (CIBERONC), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. 28029 Madrid, Spain.
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An Oncogenic Role for Four-Jointed Box 1 (FJX1) in Nasopharyngeal Carcinoma. DISEASE MARKERS 2019; 2019:3857853. [PMID: 31236144 PMCID: PMC6545767 DOI: 10.1155/2019/3857853] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/07/2019] [Indexed: 12/24/2022]
Abstract
Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer prevalent in Southern China and Southeast Asia. The current knowledge on the molecular pathogenesis of NPC is still inadequate to improve disease management. Using gene expression microarrays, we have identified the four-jointed box 1 (FJX1) gene to be upregulated in primary NPC tissues relative to nonmalignant tissues. An orthologue of human FJX1, the four-jointed (fj) gene in Drosophila and Fjx1 in mouse, has reported to be associated with cancer progression pathways. However, the exact function of FJX1 in human is not well characterized. The overexpression of FJX1 mRNA was validated in primary NPC tissue samples, and the level of FJX1 protein was significantly higher in a subset of NPC tissues (42%) compared to the normal epithelium, where no expression of FJX1 was observed (p = 0.01). FJX1 is also found to be overexpressed in microarray datasets and TCGA datasets of other cancers including head and neck cancer, colorectal, and ovarian cancer. Both siRNA knockdown and overexpression experiments in NPC cell lines showed that FJX1 promotes cell proliferation, anchorage-dependent growth, and cellular invasion. Cyclin D1 and E1 mRNA levels were increased following FJX1 expression indicating that FJX1 enhances proliferation by regulating key proteins governing the cell cycle. Our data suggest that the overexpression of FJX1 contributes to a more aggressive phenotype of NPC cells and further investigations into FJX1 as a potential therapeutic target for NPC are warranted. The evaluation of FJX1 as an immunotherapy target for NPC and other cancers is currently ongoing.
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22
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Ramos‐García P, González‐Moles MÁ, Ayén Á, González‐Ruiz L, Ruiz‐Ávila I, Gil‐Montoya JA. Prognostic and clinicopathological significance of
CTTN
/cortactin alterations in head and neck squamous cell carcinoma: Systematic review and meta‐analysis. Head Neck 2018; 41:1963-1978. [DOI: 10.1002/hed.25632] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 11/29/2018] [Accepted: 12/13/2018] [Indexed: 12/18/2022] Open
Affiliation(s)
| | | | - Ángela Ayén
- School of MedicineUniversity of Granada Granada Spain
| | - Lucía González‐Ruiz
- Servicio de DermatologíaHospital General Universitario de Ciudad Real Ciudad Real Spain
| | - Isabel Ruiz‐Ávila
- Instituto de Investigación Biosanitaria Granada Spain
- Servicio de Anatomía PatológicaComplejo Hospitalario Universitario de Granada Granada Spain
| | - José Antonio Gil‐Montoya
- School of DentistryUniversity of Granada Granada Spain
- Instituto de Investigación Biosanitaria Granada Spain
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23
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Horn D, Gross M, Dyckhoff G, Fuchs J, Grabe N, Weichert W, Herpel E, Herold‐Mende C, Lichter P, Hoffmann J, Hess J, Freier K. Cortactin expression: Association with disease progression and survival in oral squamous cell carcinoma. Head Neck 2018; 40:2685-2694. [DOI: 10.1002/hed.25515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 08/21/2018] [Accepted: 10/06/2018] [Indexed: 01/01/2023] Open
Affiliation(s)
- Dominik Horn
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Madeleine Gross
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity Hospital Heidelberg Heidelberg Germany
- Division of Molecular GeneticsGerman Cancer Research Center (DKFZ) Heidelberg Germany
| | - Gerhard Dyckhoff
- Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital Heidelberg Heidelberg Germany
- Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Jennifer Fuchs
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Niels Grabe
- Hamamatsu Tissue Imaging and Analysis Center (TIGA)BIOQUANT, University of Heidelberg Heidelberg Germany
| | - Wilko Weichert
- Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
| | - Esther Herpel
- Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
- Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg Germany
| | - Christel Herold‐Mende
- Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Peter Lichter
- Division of Molecular GeneticsGerman Cancer Research Center (DKFZ) Heidelberg Germany
| | - Jürgen Hoffmann
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Hospital Heidelberg Heidelberg Germany
- Research Group Molecular Mechanisms of Head and Neck TumorsGerman Cancer Research Center (DKFZ) Heidelberg Germany
| | - Kolja Freier
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity Hospital Heidelberg Heidelberg Germany
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24
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TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization. Leukemia 2018; 33:469-486. [PMID: 30089913 PMCID: PMC6365383 DOI: 10.1038/s41375-018-0222-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 05/29/2018] [Accepted: 06/13/2018] [Indexed: 12/26/2022]
Abstract
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.
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25
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Ramos-García P, González-Moles MÁ, González-Ruiz L, Ayén Á, Ruiz-Ávila I, Navarro-Triviño FJ, Gil-Montoya JA. An update of knowledge on cortactin as a metastatic driver and potential therapeutic target in oral squamous cell carcinoma. Oral Dis 2018; 25:949-971. [PMID: 29878474 DOI: 10.1111/odi.12913] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/15/2018] [Accepted: 06/05/2018] [Indexed: 12/12/2022]
Abstract
Cortactin is a protein encoded by the CTTN gene, localized on chromosome band 11q13. As a result of the amplification of this band, an important event in oral carcinogenesis, CTTN is also usually amplified, promoting the frequent overexpression of cortactin. Cortactin enhances cell migration in oral cancer, playing a key role in the regulation of filamentous actin and of protrusive structures (invadopodia and lamellipodia) on the cell membrane that are necessary for the acquisition of a migratory phenotype. We also analyze a series of emerging functions that cortactin may exert in oral cancer (cell proliferation, angiogenesis, regulation of exosomes, and interactions with the tumor microenvironment). We review its molecular structure, its most important interactions (with Src, Arp2/3 complex, and SH3-binding partners), the regulation of its functions, and its specific oncogenic role in oral cancer. We explore the mechanisms of its overexpression in cancer, mainly related to genetic amplification. We analyze the prognostic implications of the oncogenic activation of cortactin in potentially malignant disorders and in head and neck cancer, where it appears to be relevant in the development of lymph node metastasis. Finally, we discuss its usefulness as a therapeutic target and suggest future research lines.
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Affiliation(s)
| | - Miguel Ángel González-Moles
- School of Dentistry, University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria, Granada, Spain
| | - Lucía González-Ruiz
- Servicio de Dermatología, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Ángela Ayén
- School of Medicine, University of Granada, Granada, Spain
| | - Isabel Ruiz-Ávila
- Instituto de Investigación Biosanitaria, Granada, Spain.,Servicio de Anatomía Patológica, Complejo Hospitalario Universitario de Granada, Granada, Spain
| | | | - José Antonio Gil-Montoya
- School of Dentistry, University of Granada, Granada, Spain.,Instituto de Investigación Biosanitaria, Granada, Spain
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26
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Peng R, Zhang P, Zhang C, Huang X, Ding Y, Deng B, Bai D, Xu Y. Elevated TRIM44 promotes intrahepatic cholangiocarcinoma progression by inducing cell EMT via MAPK signaling. Cancer Med 2018; 7:796-808. [PMID: 29446253 PMCID: PMC5852353 DOI: 10.1002/cam4.1313] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Revised: 10/17/2017] [Accepted: 11/27/2017] [Indexed: 02/05/2023] Open
Abstract
Surgical results for intrahepatic cholangiocarcinoma (ICC) remain unsatisfactory due to the high rate of recurrence. Here, we investigated that the expression and roles of tripartite motif-containing protein 44 (TRIM44) in human ICCs. Firstly, TRIM44 expression was analyzed in several kinds of cancers by referring to public Oncomine database, and the expressions of TRIM44 mRNA and protein were tested in ICC and corresponding paratumorous tissues. Secondly, functions and mechanisms of TRIM44 in ICC cells were further evaluated by TRIM44 interference and cDNA transfection. Finally, the prognostic role of TRIM44 was assessed by Kaplan-Meier and Cox regression. We found that TRIM44 expression was upregulated in ICC tissues compared with corresponding paratumorous tissues, which were consistent with the results from the public cancer database. Knockdown of TRIM44 repressed the invasion and migration of ICC cells, while increased the ICC cell apoptosis. Additionally, high level of TRIM44 was shown to induce ICC cell epithelial to mesenchymal transition (EMT). Mechanistically, a high level of TRIM44 was found to activate MAPK signaling, and a MEK inhibitor, AZD6244, reversed cell EMT and apoptosis endowed by TRIM44 overexpression. Clinically, TRIM44 expression was positively associated with large tumor size (P = 0.035), lymphatic metastasis (P = 0.008) and poor tumor differentiation (P = 0.036). Importantly, patients in TRIM44high group had shorter overall survival and higher cumulative rate of recurrence than patients in TRIM44low group. Our results suggest elevated TRIM44 promotes ICC development by inducing cell EMT and apoptosis resistance, and TRIM44 is a valuable prognostic biomarker and promising therapeutic target of ICC.
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Affiliation(s)
- Rui Peng
- Department of GastroenterologyShanghai Tenth People's HospitalTongji University School of MedicineShanghai200032China
- Department of Hepatobiliary and Pancreatic SurgerySubei People's HospitalClinical Medical SchoolYangzhou University Affiliated HospitalYangzhouChina
- The Second Affiliated Hospital of Xiangya School of MedicineCentral South UniversityHunanChina
| | - Peng‐Fei Zhang
- Department of GastroenterologyShanghai Tenth People's HospitalTongji University School of MedicineShanghai200032China
- Department of OncologyShanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Chi Zhang
- Department of Hepatobiliary and Pancreatic SurgerySubei People's HospitalClinical Medical SchoolYangzhou University Affiliated HospitalYangzhouChina
| | - Xiao‐Yong Huang
- Liver Cancer InstituteMinistry of EducationZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Shanghai200032China
| | - Yan‐bing Ding
- Department of GastroenterologyYangzhou No. 1, People's HospitalThe Second Clinical School of Yangzhou UniversityYangzhouChina
| | - Bin Deng
- Department of GastroenterologyYangzhou No. 1, People's HospitalThe Second Clinical School of Yangzhou UniversityYangzhouChina
| | - Dou‐Sheng Bai
- Department of Hepatobiliary and Pancreatic SurgerySubei People's HospitalClinical Medical SchoolYangzhou University Affiliated HospitalYangzhouChina
| | - Ya‐Ping Xu
- Department of GastroenterologyShanghai Tenth People's HospitalTongji University School of MedicineShanghai200032China
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27
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Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA, Baras AS, Patel SS, Anders RA, Rimm DL, Cimino-Mathews A. Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 2018; 31:214-234. [PMID: 29192647 PMCID: PMC6132263 DOI: 10.1038/modpathol.2017.156] [Citation(s) in RCA: 264] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/06/2017] [Accepted: 09/24/2017] [Indexed: 02/06/2023]
Abstract
Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an 'Immunoscore', which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.
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Affiliation(s)
- Janis M Taube
- Department of Dermatology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche des Cordeliers, Paris, France
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Tricia R Cottrell
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Nicolas A Giraldo
- Department of Dermatology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Alexander S Baras
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - Sanjay S Patel
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Robert A Anders
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Ashley Cimino-Mathews
- Department of Pathology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins University SOM and Bloomberg-Kimmel Institute for Immunotherapy, Baltimore, MD, USA
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28
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Han L, Tang MM, Xu X, Jiang B, Huang J, Feng X, Qiang J. LTBP2 is a prognostic marker in head and neck squamous cell carcinoma. Oncotarget 2018; 7:45052-45059. [PMID: 27281608 PMCID: PMC5216705 DOI: 10.18632/oncotarget.8855] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 04/02/2016] [Indexed: 12/15/2022] Open
Abstract
Latent transforming growth factor (TGF)-beta binding protein 2 (LTBP2) belongs to the fibrillin/LTBP extracellular matrix glycoprotein superfamily. It plays vital roles in tumorigenesis through regulating TGFβ activity, elastogenesis and maintenance of the extracellular matrix (ECM) structure. In this study, we determined the expression levels of LTBP2 mRNA and protein in head and neck squamous cell carcinoma (HNSCC) tissues and adjacent normal tissues by quantitative reverse transcription PCR (qRT-PCR) and tissue microarray immunohistochemistry analysis (TMA-IHC) respectively. LTBP2 protein levels in cancer tissues were correlated with HNSCC patients' clinical characteristics and overall survival. Both LTBP2 mRNA and protein levels were significantly higher in HNSCC tissues than in adjacent normal tissues. High LTBP2 protein level was associated with lymph node metastasis and higher pTNM stages. High LTBP2 protein level is an independent prognostic marker in HNSCC. Our data suggest that LTBP2 acts as an oncogene in HNSCC development and progression. Detection of LTBP2 expression could be a useful prognosis marker and targeting LTBP2 may represent a novel strategy for cancer treatment through regulating activities of TGFβ.
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Affiliation(s)
- Liang Han
- Department of Head and Neck Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Ming Ming Tang
- Department of Head and Neck Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Xinjiang Xu
- Department of Head and Neck Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Bin Jiang
- Department of Head and Neck Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Jianfei Huang
- Department of Clinical Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jianfeng Qiang
- Department of Graduate, Medical School of Nantong University, Nantong, Jiangsu, China
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Xing Y, Meng Q, Chen X, Zhao Y, Liu W, Hu J, Xue F, Wang X, Cai L. TRIM44 promotes proliferation and metastasis in non‑small cell lung cancer via mTOR signaling pathway. Oncotarget 2017; 7:30479-91. [PMID: 27058415 PMCID: PMC5058694 DOI: 10.18632/oncotarget.8586] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Accepted: 03/04/2016] [Indexed: 11/25/2022] Open
Abstract
Tripartite motif-containing protein 44 (TRIM44) was recently identified as a potential therapeutic target in several types of malignancy, but its effect on the clinical course of malignancy and its underlying regulatory mechanism remain largely unknown. The present study shows that upregulation of TRIM44 is associated with poor differentiation, advanced pTNM stage, adenocarcinoma subtype, lymph node metastasis and, most importantly, unfavorable survival in patients with non-small cell lung cancer (NSCLC). TRIM44 knockdown inhibited the invasion and migration of human NSCLC cells, which was concurrent with downregulation of mesenchymal markers and upregulation of epithelial markers. Overexpression of TRIM44 induced the epithelial-to-mesenchymal transition (EMT) and increased the metastatic potential of lung cancer cells. Additionally, TRIM44 induced cell proliferation in vitro and tumor growth in vivo by accelerating G1/S transition via upregulation of cyclins and CDKs. TRIM44-induced mTOR signaling, EMT, and cyclin/CDK upregulation were reversed by treatment with a mammalian target of rapamycin (mTOR) inhibitor. These results provide a model for the relationship between TRIM44 expression and lung cancer progression, and open up new avenues for the prognosis and therapy of lung cancer.
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Affiliation(s)
- Ying Xing
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qingwei Meng
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xuesong Chen
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanbin Zhao
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei Liu
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jing Hu
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Feng Xue
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaoyuan Wang
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Li Cai
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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30
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Relevance of chromosomal band 11q13 in oral carcinogenesis: An update of current knowledge. Oral Oncol 2017; 72:7-16. [DOI: 10.1016/j.oraloncology.2017.04.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
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Kawaguchi T, Komatsu S, Ichikawa D, Hirajima S, Nishimura Y, Konishi H, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Otsuji E. Overexpression of TRIM44 is related to invasive potential and malignant outcomes in esophageal squamous cell carcinoma. Tumour Biol 2017; 39:1010428317700409. [PMID: 28618928 DOI: 10.1177/1010428317700409] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Recent studies have shown that some members of the tripartite motif-containing protein family function as important regulators for carcinogenesis. In this study, we investigated whether tripartite motif-containing protein 44 acts as a cancer-promoting gene through its overexpression in esophageal squamous cell carcinoma. We analyzed esophageal squamous cell carcinoma cell lines to evaluate malignant potential and also analyzed 68 primary tumors to evaluate clinical relevance of tripartite motif-containing protein 44 protein in esophageal squamous cell carcinoma patients. Expression of the tripartite motif-containing protein 44 protein was detected in esophageal squamous cell carcinoma cell lines (8/14 cell lines; 57%) and primary tumor samples of esophageal squamous cell carcinoma (39/68 cases; 57%). Knockdown of tripartite motif-containing protein 44 expression in esophageal squamous cell carcinoma cells using several specific small interfering RNAs inhibited cell migration and invasion, but not cell proliferation. Immunohistochemical analysis demonstrated that the overexpression of the tripartite motif-containing protein 44 protein in the tumor infiltrated region was associated with the status of lymph node metastasis ( p = 0.049), and the overall survival rates were significantly worse among patients with tripartite motif-containing protein 44-overexpressing tumors than those with non-expressing tumors ( p = 0.029). Moreover, multivariate Cox regression model identified that overexpression of the tripartite motif-containing protein 44 protein was an independent worse prognostic factor (hazard ratio = 2.815; p = 0.041), as well as lymphatic invasion (hazard ratio = 2.735; p = 0.037). These results suggest that tripartite motif-containing protein 44 protein could play a crucial role in tumor invasion through its overexpression and highlight its usefulness as a predictor and potential therapeutic target in esophageal squamous cell carcinoma.
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Affiliation(s)
- Tsutomu Kawaguchi
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shuhei Komatsu
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Daisuke Ichikawa
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shoji Hirajima
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yukihisa Nishimura
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hirotaka Konishi
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Shiozaki
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Fujiwara
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuma Okamoto
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Tsuda
- 2 Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.,3 Department of Basic Pathology, National Defense Medical College, Saitama, Japan
| | - Eigo Otsuji
- 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Chang HJ, Yoo JY, Kim TH, Fazleabas AT, Young SL, Lessey BA, Jeong JW. Overexpression of Four Joint Box-1 Protein (FJX1) in Eutopic Endometrium From Women With Endometriosis. Reprod Sci 2017; 25:207-213. [PMID: 28673206 DOI: 10.1177/1933719117716780] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The four jointed box 1 (FJX1) is a regulator of angiogenesis, and the levels of FJX1 are increased in several types of cancer. Angiogenesis plays a critical role in endometrial growth as well as in several gynecologic disorders including endometriosis. However, the function of FJX1 has not been studied in endometriosis. Therefore, we examined the levels of FJX1 in eutopic endometrium from women with or without endometriosis. The levels of FJX1 protein did not change in endometrial cells during the menstrual cycle in endometrium from women without endometriosis. However, its levels were significantly higher in the secretory phase of the eutopic endometrium from women with endometriosis when compared to women without endometriosis. Hypoxia-inducible factor-1α (HIF1α) is known as a key mediator of endometriosis by regulating genes essential to estrogen production, angiogenesis, proliferation, inflammation, and extracellular invasion. It has been reported that FJX1 induces an increase in HIF1α through posttranslational stabilization. The results of our Western blot analysis reveal a significant positive correlation between FJX1 and HIF1α proteins in endometrium of women with and without endometriosis. This overexpression of FJX1 was confirmed by sequential analysis of the eutopic endometrium during endometriosis progression, using an induced model of endometriosis in the baboon. Therefore, our results suggest that high levels of FJX1 proteins may play an important role in the pathogenesis of endometriosis.
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Affiliation(s)
- Hye Jin Chang
- 1 Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA.,2 Health Promotion Center, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jung-Yoon Yoo
- 1 Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Tae Hoon Kim
- 1 Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Asgerally T Fazleabas
- 1 Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Steven L Young
- 3 Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA
| | - Bruce A Lessey
- 4 Obstetrics and Gynecology, Greenville Health System, Greenville, SC, USA
| | - Jae-Wook Jeong
- 1 Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
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Wang CM, Wang RX, Liu R, Yang WH. Jun Dimerization Protein 2 Activates Mc2r Transcriptional Activity: Role of Phosphorylation and SUMOylation. Int J Mol Sci 2017; 18:ijms18020304. [PMID: 28146118 PMCID: PMC5343840 DOI: 10.3390/ijms18020304] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 01/26/2017] [Indexed: 12/11/2022] Open
Abstract
Jun dimerization protein 2 (JDP2), a basic leucine zipper transcription factor, is involved in numerous biological and cellular processes such as cancer development and regulation, cell-cycle regulation, skeletal muscle and osteoclast differentiation, progesterone receptor signaling, and antibacterial immunity. Though JDP2 is widely expressed in mammalian tissues, its function in gonads and adrenals (such as regulation of steroidogenesis and adrenal development) is largely unknown. Herein, we find that JDP2 mRNA and proteins are expressed in mouse adrenal gland tissues. Moreover, overexpression of JDP2 in Y1 mouse adrenocortical cancer cells increases the level of melanocortin 2 receptor (MC2R) protein. Notably, Mc2r promoter activity is activated by JDP2 in a dose-dependent manner. Next, by mapping the Mc2r promoter, we show that cAMP response elements (between −1320 and −720-bp) are mainly required for Mc2r activation by JDP2 and demonstrate that −830-bp is the major JDP2 binding site by real-time chromatin immunoprecipitation (ChIP) analysis. Mutations of cAMP response elements on Mc2r promoter disrupts JDP2 effect. Furthermore, we demonstrate that removal of phosphorylation of JDP2 results in attenuated transcriptional activity of Mc2r. Finally, we show that JDP2 is a candidate for SUMOylation and SUMOylation affects JDP2-mediated Mc2r transcriptional activity. Taken together, JDP2 acts as a novel transcriptional activator of the mouse Mc2r gene, suggesting that JDP2 may have physiological functions as a novel player in MC2R-mediated steroidogenesis as well as cell signaling in adrenal glands.
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Affiliation(s)
- Chiung-Min Wang
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Raymond X Wang
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Runhua Liu
- Department of Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Wei-Hsiung Yang
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
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34
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Yamada Y, Takayama KI, Fujimura T, Ashikari D, Obinata D, Takahashi S, Ikeda K, Kakutani S, Urano T, Fukuhara H, Homma Y, Inoue S. A novel prognostic factor TRIM44 promotes cell proliferation and migration, and inhibits apoptosis in testicular germ cell tumor. Cancer Sci 2016; 108:32-41. [PMID: 27754579 PMCID: PMC5276827 DOI: 10.1111/cas.13105] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/09/2016] [Accepted: 10/12/2016] [Indexed: 12/17/2022] Open
Abstract
Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto-protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer-specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer-specific mortality (P = 0.046). Gain-of-function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44-knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti-apoptosis in TGCT.
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Affiliation(s)
- Yuta Yamada
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ken-Ichi Takayama
- Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan
| | - Tetsuya Fujimura
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daisaku Ashikari
- Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Urology, Nihon University School of Medicine, Itabashi-ku, Japan
| | - Daisuke Obinata
- Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Urology, Nihon University School of Medicine, Itabashi-ku, Japan
| | - Satoru Takahashi
- Urology, Nihon University School of Medicine, Itabashi-ku, Japan
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction, Research Center of Genomic Medicine, Saitama Medical University, Saitama, Japan
| | - Shigenori Kakutani
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomohiko Urano
- Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Fukuhara
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yukio Homma
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- Department of Geriatric Medicine and Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.,Division of Gene Regulation and Signal Transduction, Research Center of Genomic Medicine, Saitama Medical University, Saitama, Japan
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35
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Singchat W, Hitakomate E, Rerkarmnuaychoke B, Suntronpong A, Fu B, Bodhisuwan W, Peyachoknagul S, Yang F, Koontongkaew S, Srikulnath K. Genomic Alteration in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Inferred from Karyotyping, Molecular Cytogenetics, and Array Comparative Genomic Hybridization. PLoS One 2016; 11:e0160901. [PMID: 27501229 PMCID: PMC4976893 DOI: 10.1371/journal.pone.0160901] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 07/26/2016] [Indexed: 02/06/2023] Open
Abstract
Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines. Hierarchical clustering revealed that HN31 was closely related to HN4, which shared eight chromosome alteration cases. Large C-positive heterochromatins were found in the centromeric region of chromosome 9 in HN31 and HN4, which suggests complex structural amplification of the repetitive sequence. Array CGH revealed amplification of 7p22.3p11.2, 8q11.23q12.1, and 14q32.33 in all cell lines involved with tumorigenesis and inflammation genes. The amplification of 2p21 (SIX3), 11p15.5 (H19), and 11q21q22.3 (MAML2, PGR, TRPC6, and MMP family) regions, and deletion of 9p23 (PTPRD) and 16q23.1 (WWOX) regions were identified in HN31 and HN12. Interestingly, partial loss of PTPRD (9p23) and WWOX (16q23.1) genes was identified in HN31 and HN12, and the level of gene expression tended to be the down-regulation of PTPRD, with no detectable expression of the WWOX gene. This suggests that the scarcity of PTPRD and WWOX genes might have played an important role in progression of HNSCC, and could be considered as a target for cancer therapy or a biomarker in molecular pathology.
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Affiliation(s)
- Worapong Singchat
- Laboratory of Animal Cytogenetics and Comparative Genomics, Department of Genetics, Faculty of Science, Kasetsart University, 50 Ngamwongwan, Chatuchak, Bangkok, 10900, Thailand
| | - Ekarat Hitakomate
- Faculty of Dentistry, Thammasart University, Pathum Thani, 12121, Thailand
| | - Budsaba Rerkarmnuaychoke
- Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Aorarat Suntronpong
- Laboratory of Animal Cytogenetics and Comparative Genomics, Department of Genetics, Faculty of Science, Kasetsart University, 50 Ngamwongwan, Chatuchak, Bangkok, 10900, Thailand
| | - Beiyuan Fu
- Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
| | - Winai Bodhisuwan
- Department of Statistics, Faculty of Science, Kasetsart University, 50 Ngamwongwan, Chatuchak, Bangkok, 10900, Thailand
| | - Surin Peyachoknagul
- Laboratory of Animal Cytogenetics and Comparative Genomics, Department of Genetics, Faculty of Science, Kasetsart University, 50 Ngamwongwan, Chatuchak, Bangkok, 10900, Thailand.,Center of Advanced Studies in Tropical Natural Resources, National Research University-Kasetsart University, Kasetsart University, Thailand (CASTNAR, NRU-KU, Thailand)
| | - Fengtang Yang
- Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
| | | | - Kornsorn Srikulnath
- Laboratory of Animal Cytogenetics and Comparative Genomics, Department of Genetics, Faculty of Science, Kasetsart University, 50 Ngamwongwan, Chatuchak, Bangkok, 10900, Thailand.,Center of Advanced Studies in Tropical Natural Resources, National Research University-Kasetsart University, Kasetsart University, Thailand (CASTNAR, NRU-KU, Thailand)
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36
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Callegari CC, Cavalli IJ, Lima RS, Jucoski TS, Torresan C, Urban CA, Kuroda F, Anselmi KF, Cavalli LR, Ribeiro EM. Copy number and expression analysis of FOSL1, GSTP1, NTSR1, FADD and CCND1 genes in primary breast tumors with axillary lymph node metastasis. Cancer Genet 2016; 209:331-9. [DOI: 10.1016/j.cancergen.2016.06.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 05/02/2016] [Accepted: 06/06/2016] [Indexed: 12/20/2022]
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37
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Liprin-α1 is a regulator of vimentin intermediate filament network in the cancer cell adhesion machinery. Sci Rep 2016; 6:24486. [PMID: 27075696 PMCID: PMC4830931 DOI: 10.1038/srep24486] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 03/30/2016] [Indexed: 12/13/2022] Open
Abstract
PPFIA1 is located at the 11q13 region, which is one of the most commonly amplified regions in several epithelial cancers including head and neck squamous cell carcinoma and breast carcinoma. Considering the location of PPFIA1 in this amplicon, we examined whether protein encoded by PPFIA1, liprin-α1, possesses oncogenic properties in relevant carcinoma cell lines. Our results indicate that liprin-α1 localizes to different adhesion and cytoskeletal structures to regulate vimentin intermediate filament network, thereby altering the invasion and growth properties of the cancer cells. In non-invasive cells liprin-α1 promotes expansive growth behavior with limited invasive capacity, whereas in invasive cells liprin-α1 has significant impact on mesenchymal cancer cell invasion in three-dimensional collagen. Current results identify liprin-α1 as a novel regulator of the tumor cell intermediate filaments with differential oncogenic properties in actively proliferating or motile cells.
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38
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Tsai MH, Wuputra K, Lin YC, Lin CS, Yokoyama KK. Multiple functions of the histone chaperone Jun dimerization protein 2. Gene 2016; 590:193-200. [PMID: 27041241 DOI: 10.1016/j.gene.2016.03.048] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 03/12/2016] [Accepted: 03/22/2016] [Indexed: 11/25/2022]
Abstract
The Jun dimerization protein 2 (JDP2) is part of the family of stress-responsible transcription factors such as the activation protein-1, and binds the 12-O-tetradecanoylphorbol-13-acetateresponse element and the cAMP response element. It also plays a role as a histone chaperone and participates in diverse processes, such as cell-cycle arrest, cell differentiation, apoptosis, senescence, and metastatic spread, and functions as an oncogene and anti-oncogene, and as a cellular reprogramming factor. However, the molecular mechanisms underlying these multiple functions of JDP2 have not been clarified. This review summarizes the structure and function of JDP2, highlighting the specific role of JDP2 in cellular-stress regulation and prevention.
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Affiliation(s)
- Ming-Ho Tsai
- Graduated Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kenly Wuputra
- Graduated Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin-Chu Lin
- School of Dentistry, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chang-Shen Lin
- Graduated Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Kazunari K Yokoyama
- Graduated Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, Japan; Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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39
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Xu R, Fang XH, Zhong P. Myosin VI contributes to malignant proliferation of human glioma cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2016; 20:139-45. [PMID: 26937209 PMCID: PMC4770103 DOI: 10.4196/kjpp.2016.20.2.139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 02/13/2015] [Accepted: 03/03/2015] [Indexed: 01/25/2023]
Abstract
Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma.
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Affiliation(s)
- Rong Xu
- Neurosurgical Department of Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xu-Hao Fang
- Neurosurgical Department of Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Ping Zhong
- Neurosurgical Department of Huashan Hospital, Fudan University, Shanghai 200040, China
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40
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Chai SJ, Yap YY, Foo YC, Yap LF, Ponniah S, Teo SH, Cheong SC, Patel V, Lim KP. Identification of Four-Jointed Box 1 (FJX1)-Specific Peptides for Immunotherapy of Nasopharyngeal Carcinoma. PLoS One 2015; 10:e0130464. [PMID: 26536470 PMCID: PMC4633155 DOI: 10.1371/journal.pone.0130464] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 05/20/2015] [Indexed: 01/02/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is highly prevalent in South East Asia and China. The poor outcome is due to late presentation, recurrence, distant metastasis and limited therapeutic options. For improved treatment outcome, immunotherapeutic approaches focusing on dendritic and autologous cytotoxic T-cell based therapies have been developed, but cost and infrastructure remain barriers for implementing these in low-resource settings. As our prior observations had found that four-jointed box 1 (FJX1), a tumor antigen, is overexpressed in NPCs, we investigated if short 9-20 amino acid sequence specific peptides matching to FJX1 requiring only intramuscular immunization to train host immune systems would be a better treatment option for this disease. Thus, we designed 8 FJX1-specific peptides and implemented an assay system to first, assess the binding of these peptides to HLA-A2 molecules on T2 cells. After, ELISPOT assays were used to determine the peptides immunogenicity and ability to induce potential cytotoxicity activity towards cancer cells. Also, T-cell proliferation assay was used to evaluate the potential of MHC class II peptides to stimulate the expansion of isolated T-cells. Our results demonstrate that these peptides are immunogenic and peptide stimulated T-cells were able to induce peptide-specific cytolytic activity specifically against FJX1-expressing cancer cells. In addition, we demonstrated that the MHC class II peptides were capable of inducing T-cell proliferation. Our results suggest that these peptides are capable of inducing specific cytotoxic cytokines secretion against FJX1-expressing cancer cells and serve as a potential vaccine-based therapy for NPC patients.
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Affiliation(s)
- San Jiun Chai
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Yoke Yeow Yap
- Department of Surgery, Clinical Campus Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Yoke Ching Foo
- Department of Oncology, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Lee Fah Yap
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Sathibalan Ponniah
- Department of Surgery, Cancer Vaccine Development Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
| | - Soo Hwang Teo
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Sok Ching Cheong
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Vyomesh Patel
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
| | - Kue Peng Lim
- Cancer Research Initiatives Foundation (CARIF), Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
- * E-mail:
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41
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Vincent-Chong VK, Salahshourifar I, Razali R, Anwar A, Zain RB. Immortalization of epithelial cells in oral carcinogenesis as revealed by genome-wide array comparative genomic hybridization: A meta-analysis. Head Neck 2015; 38 Suppl 1:E783-97. [PMID: 25914319 DOI: 10.1002/hed.24102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This purpose of this meta-analysis study was to identify the most frequent and potentially significant copy number alteration (CNA) in oral carcinogenesis. METHODS Seven oral squamous cell carcinoma (OSCC)-related publications, corresponding to 312 samples, were identified for this meta-analysis. The data were analyzed in a 4-step process that included the genome assembly coordination of multiple platforms, assignment of chromosomal position anchors, calling gains and losses, and functional annotation analysis. RESULTS Gains were more frequent than losses in the entire dataset. High-frequency gains were identified in chromosomes 5p, 14q, 11q, 7p, 17q, 20q, 8q, and 3q, whereas high-frequency losses were identified in chromosomes 3p, 8p, 6p, 18q, and 4q. Ingenuity pathway analysis showed that the top biological function was associated with immortalization of the epithelial cells (p = 1.93E-04). CONCLUSION This study has identified multiple recurrent CNAs that are involved in various biological annotations associated with oral carcinogenesis. © 2015 Wiley Periodicals, Inc. Head Neck 38: E783-E797, 2016.
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Affiliation(s)
- Vui King Vincent-Chong
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.,Department of Oro-maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia
| | - Iman Salahshourifar
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia
| | - Rozaimi Razali
- Sengenics Sdn Bhd, High Impact Research (HIR) Building, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia
| | - Arif Anwar
- Sengenics Sdn Bhd, High Impact Research (HIR) Building, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia
| | - Rosnah Binti Zain
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.,Department of Oro-maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia
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42
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Samman M, Wood HM, Conway C, Stead L, Daly C, Chalkley R, Berri S, Senguven B, Ross L, Egan P, Chengot P, Ong TK, Pentenero M, Gandolfo S, Cassenti A, Cassoni P, Al Ajlan A, Samkari A, Barrett W, MacLennan K, High A, Rabbitts P. A novel genomic signature reclassifies an oral cancer subtype. Int J Cancer 2015; 137:2364-73. [PMID: 26014678 DOI: 10.1002/ijc.29615] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/15/2015] [Indexed: 12/22/2022]
Abstract
Verrucous carcinoma of the oral cavity (OVC) is considered a subtype of classical oral squamous cell carcinoma (OSCC). Diagnosis is problematic, and additional biomarkers are needed to better stratify patients. To investigate their molecular signature, we performed low-coverage copy number (CN) sequencing on 57 OVC and exome and RNA sequencing on a subset of these and compared the data to the same OSCC parameters. CN results showed that OVC lacked any of the classical OSCC patterns such as gain of 3q and loss of 3p and demonstrated considerably fewer genomic rearrangements compared to the OSCC cohort. OVC and OSCC samples could be clearly differentiated. Exome sequencing showed that OVC samples lacked mutations in genes commonly associated with OSCC (TP53, NOTCH1, NOTCH2, CDKN2A and FAT1). RNA sequencing identified genes that were differentially expressed between the groups. In silico functional analysis showed that the mutated and differentially expressed genes in OVC samples were involved in cell adhesion and keratinocyte proliferation, while those in the OSCC cohort were enriched for cell death and apoptosis pathways. This is the largest and most detailed genomic and transcriptomic analysis yet performed on this tumour type, which, as an example of non-metastatic cancer, may shed light on the nature of metastases. These three independent investigations consistently show substantial differences between the cohorts. Taken together, they lead to the conclusion that OVC is not a subtype of OSCC, but should be classified as a distinct entity.
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Affiliation(s)
- Manar Samman
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.,Pathology and Clinical Laboratory Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Henry M Wood
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Caroline Conway
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Lucy Stead
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Catherine Daly
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Rebecca Chalkley
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Stefano Berri
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Burcu Senguven
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Lisa Ross
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Philip Egan
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Preetha Chengot
- St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
| | - Thian K Ong
- Leeds Dental Institute, Leeds General Infirmary, Leeds, United Kingdom
| | - Monica Pentenero
- Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Torino, Turin, Italy
| | - Sergio Gandolfo
- Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Torino, Turin, Italy
| | - Adele Cassenti
- Pathology Unit, Department of Medical Sciences, University of Torino, Turin, Italy
| | - Paola Cassoni
- Pathology Unit, Department of Medical Sciences, University of Torino, Turin, Italy
| | | | - Alaa Samkari
- National Guard Health Affairs, Riyadh, Saudi Arabia
| | | | - Kenneth MacLennan
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.,St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom
| | - Alec High
- St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom.,Leeds Dental Institute, Leeds General Infirmary, Leeds, United Kingdom
| | - Pamela Rabbitts
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
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43
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Laurila K, Autio R, Kong L, Närvä E, Hussein S, Otonkoski T, Lahesmaa R, Lähdesmäki H. Integrative genomics and transcriptomics analysis of human embryonic and induced pluripotent stem cells. BioData Min 2014; 7:32. [PMID: 25649046 PMCID: PMC4298950 DOI: 10.1186/s13040-014-0032-2] [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: 01/16/2014] [Accepted: 12/04/2014] [Indexed: 11/13/2022] Open
Abstract
Background Human genomic variations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), are associated with several phenotypic traits varying from mild features to hereditary diseases. Several genome-wide studies have reported genomic variants that correlate with gene expression levels in various tissue and cell types. Results We studied human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) measuring the SNPs and CNVs with Affymetrix SNP 6 microarrays and expression values with Affymetrix Exon microarrays. We computed the linear relationships between SNPs and expression levels of exons, transcripts and genes, and the associations between gene CNVs and gene expression levels. Further, for a few of the resulted genes, the expression value was associated with both CNVs and SNPs. Our results revealed altogether 217 genes and 584 SNPs whose genomic alterations affect the transcriptome in the same cells. We analyzed the enriched pathways and gene ontologies within these groups of genes, and found out that the terms related to alternative splicing and development were enriched. Conclusions Our results revealed that in the human pluripotent stem cells, the expression values of several genes, transcripts and exons were affected due to the genomic variation. Electronic supplementary material The online version of this article (doi:10.1186/s13040-014-0032-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kirsti Laurila
- Department of Information and Computer Science, Aalto University School of Science, Espoo, Finland
| | - Reija Autio
- Department of Signal Processing, Tampere University of Technology, Tampere, Finland.,School of Health Sciences, University of Tampere, Tampere, Finland
| | - Lingjia Kong
- Department of Signal Processing, Tampere University of Technology, Tampere, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Elisa Närvä
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Samer Hussein
- Samuel Lunenfeld Research Institute, Toronto, Canada.,Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
| | - Timo Otonkoski
- Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
| | - Riitta Lahesmaa
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Harri Lähdesmäki
- Department of Information and Computer Science, Aalto University School of Science, Espoo, Finland.,Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
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Luo Q, Lin H, Ye X, Huang J, Lu S, Xu L. Trim44 facilitates the migration and invasion of human lung cancer cells via the NF-κB signaling pathway. Int J Clin Oncol 2014; 20:508-17. [PMID: 25345539 DOI: 10.1007/s10147-014-0752-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 09/04/2014] [Indexed: 11/25/2022]
Abstract
BACKGROUND Trim44 is an important member of the tripartite motif-containing protein (TRIM) family. Recent research reported that Trim44 might play an important role in tumorigenesis, although its role in non-small cell lung cancer (NSCLC) and the related mechanisms is not yet known. METHODS In this study we analyzed 30 pairs of NSCLC tumors and the matched adjacent normal tissue to define the relationship between Trim44 and NSCLC tumors. The function of Trim44 in cell migration and invasion was determined by overexpression of Trim44 in normal bronchial epithelial cell line 16HE or knockdown of Trim44 in A549 cells, respectively. Whether Trim44-mediated NF-κB signaling activation was involved in Trim44-mediated promotion of lung cancer was tested by q-PCR analysis and cell migration and invasion assay using PDTC, an inhibitor of NF-κB. RESULTS We found that Trim44 was upregulated in NSCLC tumors (14/30 cases; 46.7%). Furthermore, Trim44 was upregulated in many NSCLC cell lines, especially in A549 and H441. Moreover, Trim44 significantly enhanced cell migration and invasion ability, which was related to increased CXCR6 and matrix metalloproteinase 9 (MMP9). Knockdown of Trim44 in A549 cells by siRNA showed a diminished effect in cell migration and invasion. Further investigation revealed that blocking the NF-κB signaling pathway using PDTC, an inhibitor of NF-κB, reversed the expression of CXCR6 and MMP9, and alleviated the promotion of migration and invasion mediated by Trim44. CONCLUSIONS Our data suggest that Trim44 promotes NSCLC development through activation of NF-κB signaling via upregulating CXCL16 and MMP9 expression.
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Affiliation(s)
- Qingquan Luo
- Nanjing Medical University, Nanjing, 210029, China
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45
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Gollin SM. Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: a next generation window to the biology of disease. Genes Chromosomes Cancer 2014; 53:972-90. [PMID: 25183546 DOI: 10.1002/gcc.22214] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 08/15/2014] [Indexed: 01/14/2023] Open
Abstract
Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14-15, 8q11-12, and 20q12-13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21-24, 11q14-23, 13q12-14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC.
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Affiliation(s)
- Susanne M Gollin
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Departments of Otolaryngology and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA
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46
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Vincent-Chong VK, Karen-Ng LP, Abdul Rahman ZA, Yang YH, Anwar A, Zakaria Z, Jayaprasad Pradeep P, Kallarakkal TG, Kiong Tay K, Thomas Abraham M, Mazlipah Ismail S, Zain RB. Distinct pattern of chromosomal alterations and pathways in tongue and cheek squamous cell carcinoma. Head Neck 2014; 36:1268-1278. [PMID: 31615169 DOI: 10.1002/hed.23448] [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: 05/17/2012] [Revised: 05/10/2013] [Accepted: 08/01/2013] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the cause of behavioral difference between tongue and cheek squamous cell carcinomas (SCCs) by verifying the copy number alterations (CNAs). METHODS Array comparative genomic hybridization (aCGH) was used to profile unique deletions and amplifications that are involved with tongue and cheek SCC, respectively. This was followed by pathway analysis relating to CNA genes from both sites. RESULTS The most frequently amplified regions in tongue SCC were 4p16.3, 11q13.4, and 13q34; whereas the most frequently deleted region was 19p12. For cheek SCC, the most frequently amplified region was identified on chromosome 9p24.1-9p23; whereas the most common deleted region was located on chromosome 8p23.1. Further analysis revealed that the most significant unique pathway related to tongue and cheek SCCs was the cytoskeleton remodeling and immune response effect on the macrophage differentiation pathway. CONCLUSION This study has showed the different genetic profiles and biological pathways between tongue and cheek SCCs. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1268-1278, 2014.
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Affiliation(s)
- Vui King Vincent-Chong
- Department of Oral Maxillofacial Surgery, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Lee Peng Karen-Ng
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Zainal Ariff Abdul Rahman
- Department of Oral Maxillofacial Surgery, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Yi-Hsin Yang
- Department of Dental Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung
| | - Arif Anwar
- Sengenics Sdn Bhd, Petaling Jaya, Selangor Darul Ehsan, Malaysia
| | - Zubaidah Zakaria
- Department of Haematology, Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia
| | - Padmaja Jayaprasad Pradeep
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Thomas George Kallarakkal
- Department of Oral Pathology, Oral Medicine and Periodontology, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Keng Kiong Tay
- Oral Health Division, Ministry of Health, Putrajaya, Malaysia
| | | | - Siti Mazlipah Ismail
- Department of Oral Maxillofacial Surgery, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Rosnah Binti Zain
- Oral Cancer Research and Coordinating Center, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.,Department of Oral Pathology, Oral Medicine and Periodontology, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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47
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Dickman CTD, Towle R, Saini R, Garnis C. Molecular characterization of immortalized normal and dysplastic oral cell lines. J Oral Pathol Med 2014; 44:329-36. [PMID: 25169794 DOI: 10.1111/jop.12236] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Cell lines have been developed for modeling cancer and cancer progression. The molecular background of these cell lines is often unknown to those using them to model disease behaviors. As molecular alterations are the ultimate drivers of cell phenotypes, having an understanding of the molecular make-up of these systems is critical for understanding the disease biology modeled. METHODS Six immortalized normal, one immortalized dysplasia, one self-immortalized dysplasia, and two primary normal cell lines derived from oral tissues were analyzed for DNA copy number changes and changes in both mRNA and miRNA expression using SMRT-v.2 genome-wide tiling comparative genomic hybridization arrays, Agilent Whole Genome 4x44k expression arrays, and Exiqon V2.M-RT-PCR microRNA Human panels. RESULTS DNA copy number alterations were detected in both normal and dysplastic immortalized cell lines-as well as in the single non-immortalized dysplastic cell line. These lines were found to have changes in expression of genes related to cell cycle control as well as alterations in miRNAs that are deregulated in clinical oral squamous cell carcinoma tissues. Immortal lines-whether normal or dysplastic-had increased disruption in expression relative to primary lines. All data are available as a public resource. CONCLUSIONS Molecular profiling experiments have identified DNA, mRNA, and miRNA alterations for a panel of normal and dysplastic oral tissue cell lines. These data are a valuable resource to those modeling diseases of the oral mucosa, and give insight into the selection of model cell lines and the interpretation of data from those lines.
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Affiliation(s)
- Christopher T D Dickman
- Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
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48
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Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme. Proc Natl Acad Sci U S A 2013; 111:E54-61. [PMID: 24367089 DOI: 10.1073/pnas.1308768111] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
APIP, Apaf-1 interacting protein, has been known to inhibit two main types of programmed cell death, apoptosis and pyroptosis, and was recently found to be associated with cancers and inflammatory diseases. Distinct from its inhibitory role in cell death, APIP was also shown to act as a 5-methylthioribulose-1-phosphate dehydratase, or MtnB, in the methionine salvage pathway. Here we report the structural and enzymatic characterization of human APIP as an MtnB enzyme with a Km of 9.32 μM and a Vmax of 1.39 μmol min(-1) mg(-1). The crystal structure was determined at 2.0-Å resolution, revealing an overall fold similar to members of the zinc-dependent class II aldolase family. APIP/MtnB exists as a tetramer in solution and exhibits an assembly with C4 symmetry in the crystal lattice. The pocket-shaped active site is located at the end of a long cleft between two adjacent subunits. We propose an enzymatic reaction mechanism involving Glu139* as a catalytic acid/base, as supported by enzymatic assay, substrate-docking study, and sequence conservation analysis. We explored the relationship between two distinct functions of APIP/MtnB, cell death inhibition, and methionine salvage, by measuring the ability of enzymatic mutants to inhibit cell death, and determined that APIP/MtnB functions as a cell death inhibitor independently of its MtnB enzyme activity for apoptosis induced by either hypoxia or etoposide, but dependently for caspase-1-induced pyroptosis. Our results establish the structural and biochemical groundwork for future mechanistic studies of the role of APIP/MtnB in modulating cell death and inflammation and in the development of related diseases.
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49
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González-Márquez R, Llorente JL, Rodrigo JP, García-Pedrero JM, Álvarez-Marcos C, Suárez C, Hermsen MA. SOX2 expression in hypopharyngeal, laryngeal, and sinonasal squamous cell carcinoma. Hum Pathol 2013; 45:851-7. [PMID: 24656096 DOI: 10.1016/j.humpath.2013.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 12/08/2013] [Accepted: 12/11/2013] [Indexed: 12/21/2022]
Abstract
Squamous cell carcinoma (SCC) of the head and neck display high frequencies of DNA copy number gains at chromosomal region 3q26-27. Recently SOX2 has been postulated as a driver oncogene for these amplifications; however, its role as a prognostic marker is still a matter of debate. The aim of this study was to evaluate the involvement of SOX2 protein expression in three different sublocalizations of head and neck SCC and its possible role as prognostic marker. SOX2 expression was analyzed by immunohistochemistry in 102 pharyngeal, 67 laryngeal, and 51 sinonasal SCCs, and the relation to clinicopathological and follow-up data was studied by χ(2) and Kaplan-Meier analysis. SOX2 expression was significantly (P = .002) more frequent in hypopharyngeal and laryngeal SCC (38%, 39/101) and (42%, 28/67), respectively, compared to sinonasal cancer SCC (14%, 7/51). SOX2 expression did not correlate to disease stage, T or N classification, lymph node metastasis, recurrence or clinical outcome in any of the three sublocalizations. These results indicate that SOX2 expression is a common event in hypopharynx and larynx, but not in sinonasal SCC. The absence of correlation to clinical outcome, may suggest a role for SOX2 in tumor initiation, but not in tumor progression.
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Affiliation(s)
- Rocío González-Márquez
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - José Luis Llorente
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - Juan P Rodrigo
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - Juana M García-Pedrero
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - César Álvarez-Marcos
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - Carlos Suárez
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - Mario A Hermsen
- Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Spain.
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50
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Al-Greene NT, Means AL, Lu P, Jiang A, Schmidt CR, Chakravarthy AB, Merchant NB, Washington MK, Zhang B, Shyr Y, Deane NG, Beauchamp RD. Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. PLoS One 2013; 8:e69660. [PMID: 23922772 PMCID: PMC3726759 DOI: 10.1371/journal.pone.0069660] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 06/11/2013] [Indexed: 01/08/2023] Open
Abstract
Angiogenesis, the recruitment and re-configuration of pre-existing vasculature, is essential for tumor growth and metastasis. Increased tumor vascularization often correlates with poor patient outcomes in a broad spectrum of carcinomas. We identified four jointed box 1 (FJX1) as a candidate regulator of tumor angiogenesis in colorectal cancer. FJX1 mRNA and protein are upregulated in human colorectal tumor epithelium as compared with normal epithelium and colorectal adenomas, and high expression of FJX1 is associated with poor patient prognosis. FJX1 mRNA expression in colorectal cancer tissues is significantly correlated with changes in known angiogenesis genes. Augmented expression of FJX1 in colon cancer cells promotes growth of xenografts in athymic mice and is associated with increased tumor cell proliferation and vascularization. Furthermore, FJX1 null mice develop significantly fewer colonic polyps than wild-type littermates after combined dextran sodium sulfate (DSS) and azoxymethane (AOM) treatment. In vitro, conditioned media from FJX1 expressing cells promoted endothelial cell capillary tube formation in a HIF1-α dependent manner. Taken together our results support the conclusion that FJX1 is a novel regulator of tumor progression, due in part, to its effect on tumor vascularization.
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Affiliation(s)
- Nicole T. Al-Greene
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Anna L. Means
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Pengcheng Lu
- Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Aixiang Jiang
- Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Carl R. Schmidt
- Department of Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
| | - A. Bapsi Chakravarthy
- Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Nipun B. Merchant
- Department of Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, United States of America
| | - M. Kay Washington
- Department of Pathology, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Bing Zhang
- Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Natasha G. Deane
- Department of Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, United States of America
- Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee, United States of America
| | - R. Daniel Beauchamp
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Surgery, Vanderbilt University, Nashville, Tennessee, United States of America
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- * E-mail:
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