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Liu X, Hu X, Jing M, Huang L, You Y, Zhang Y, Li K, Tu Y, Liu Y, Chen X, Su J, Hejtmancik JF, Hou L, Ma X. Death associated protein like 1 acts as a novel tumor suppressor in melanoma by increasing the stability of P21 protein. Mol Cell Biochem 2025; 480:1595-1610. [PMID: 38980592 PMCID: PMC11842415 DOI: 10.1007/s11010-024-05067-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/30/2024] [Indexed: 07/10/2024]
Abstract
Melanoma is a primary malignant tumor with high lethality, which occurs in the skin and eye tissues, while the molecular mechanisms of melanomagenesis remain largely unknown. Here, we show that death-associated protein-like 1 (DAPL1) expression is lower in melanoma tissues than in paracancerous tissues or nevus tissues, and Uveal melanoma patients with lower DAPL1 expression have a poorer survival rate than those with higher expression of DAPL1. Overexpression of DAPL1 inhibits proliferation of cultured melanoma cells, whereas knockdown of DAPL1 increases cell proliferation. Tumor transplantation experiment results also demonstrate that DAPL1 inhibits tumorigenesis of melanoma cells both in subretinal and subcutaneous tissues of nude mice in vivo. Finally, DAPL1 inhibits proliferation of melanoma cells by increasing the protein level of P21 via decreasing the ubiquitin mediated degradation of P21 and promoting its stability. Conversely, knockdown of P21 neutralizes the effects of inhibition of DAPL1 on melanoma cell proliferation and enhances the severity of melanoma tumorigenesis. These results suggest that DAPL1 is a novel melanoma tumor suppressor gene and thus a potential therapeutic target for melanoma.
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Affiliation(s)
- Xiaoyan Liu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaojuan Hu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Meiyu Jing
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Lijin Huang
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yaqi You
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yaru Zhang
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ke Li
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yunhai Tu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Youjia Liu
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaogang Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jianzhong Su
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - J Fielding Hejtmancik
- Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ling Hou
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoyin Ma
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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Bruno PS, Arshad A, Gogu MR, Waterman N, Flack R, Dunn K, Darie CC, Neagu AN. Post-Translational Modifications of Proteins Orchestrate All Hallmarks of Cancer. Life (Basel) 2025; 15:126. [PMID: 39860065 PMCID: PMC11766951 DOI: 10.3390/life15010126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations and environmental stressors, on the one hand, and cancer cell structure, functioning, and behavior. Aberrant PTMs can be considered as enabling characteristics of cancer as long as they orchestrate all malignant modifications and variability in the proteome of cancer cells, cancer-associated cells, and tumor microenvironment (TME). On the other hand, PTMs of proteins can enhance anticancer mechanisms in the tumoral ecosystem or sustain the beneficial effects of oncologic therapies through degradation or inactivation of carcinogenic proteins or/and activation of tumor-suppressor proteins. In this review, we summarized and analyzed a wide spectrum of PTMs of proteins involved in all regulatory mechanisms that drive tumorigenesis, genetic instability, epigenetic reprogramming, all events of the metastatic cascade, cytoskeleton and extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, and metabolism rewiring as the most important hallmarks of cancer. All cancer hallmarks develop due to PTMs of proteins, which modulate gene transcription, intracellular and extracellular signaling, protein size, activity, stability and localization, trafficking, secretion, intracellular protein degradation or half-life, and protein-protein interactions (PPIs). PTMs associated with cancer can be exploited to better understand the underlying molecular mechanisms of this heterogeneous and chameleonic disease, find new biomarkers of cancer progression and prognosis, personalize oncotherapies, and discover new targets for drug development.
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Affiliation(s)
- Pathea Shawnae Bruno
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Aneeta Arshad
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Maria-Raluca Gogu
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, University Street No. 16, 700115 Iasi, Romania;
| | - Natalie Waterman
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Rylie Flack
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Kimberly Dunn
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Costel C. Darie
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (A.A.); (N.W.); (R.F.); (K.D.)
| | - Anca-Narcisa Neagu
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I bvd. 20A, 700505 Iasi, Romania
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Nishida S, Konno T, Kohno T, Ohyanagi M, Nakano M, Ohwada K, Obata K, Kakuki T, Kakiuchi A, Kurose M, Takano K, Kojima T. Treatment with TNFα and lipolysis-stimulated lipoprotein receptor (LSR) antibody in the presence of HDAC inhibitors promotes apoptosis in human salivary duct adenocarcinoma. Tissue Barriers 2024:2437215. [PMID: 39676759 DOI: 10.1080/21688370.2024.2437215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024] Open
Abstract
Lipolysis-stimulated lipoprotein receptor (LSR), a lipid metabolism-related factor localized in tricellular tight junctions (tTJs), plays an important role in maintaining the epithelial homeostasis. LSR is highly expressed in well-differentiated cancers, and its expression decreases during malignancy. The LSR antibody inhibits cell growth and promotes apoptosis in some cancers. Histone deacetylases (HDACs) are thought to play a crucial role in carcinogenesis, and HDAC inhibitors promote differentiation and prevent cell proliferation and migration in cancers. HDAC inhibitors together with TNFα also induce apoptosis via TNFα-related apoptosis-inducing ligand (TRAIL) in some cancers. In this study, we investigated the apoptosis signaling induced by an anti-LSR antibody in human salivary duct adenocarcinoma (SDC) cell line A253, compared to TRAIL-induced apoptosis. A253 cells were treated with human recombinant TNFα with or without HDAC inhibitor trichostatin A (TSA) and quisinostat (JNJ-26481585). Treatment using TNFα with HDAC inhibitors markedly induced apoptosis in A253 cells and the anti-TNFα antibody prevented the induced apoptosis. A253 cells were treated with an antibody against the extracellular N-terminal domain of human LSR (LSR-N-ab) with or without HDAC inhibitors. Treatment with HDAC inhibitors induced LSR expression in the membranes of A253 cells. Treatment using LSR-N-ab with HDAC inhibitors markedly promoted apoptosis in A253 cells. The tricellular signaling pathway JNK inhibitor SP600125 and Hippo pathway MST1/2 inhibitor XMU-MP-1 prevented the apoptosis induced by treatment using TNFα or LSR-N-ab with HDAC inhibitors. Our findings indicated that treatment with TNFα or LSR-N-ab with HDAC inhibitors might be useful in the therapy for human SDC by enhancing apoptosis.
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Affiliation(s)
- Soshi Nishida
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takumi Konno
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Kohno
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiko Ohyanagi
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaya Nakano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kizuku Ohwada
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazufumi Obata
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takuya Kakuki
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akito Kakiuchi
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Kurose
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takashi Kojima
- Department of Cell Science, Institute of Cancer Research, Sapporo Medical University School of Medicine, Sapporo, Japan
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O'Sullivan EA, Wallis R, Mossa F, Bishop CL. The paradox of senescent-marker positive cancer cells: challenges and opportunities. NPJ AGING 2024; 10:41. [PMID: 39277623 PMCID: PMC11401916 DOI: 10.1038/s41514-024-00168-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/15/2024] [Indexed: 09/17/2024]
Abstract
Senescence is an anti-tumour mechanism and hallmark of cancer. Loss or mutation of key senescence effectors, such as p16INK4A, are frequently observed in cancer. Intriguingly, some human tumours are both proliferative and senescent-marker positive (Sen-Mark+). Here, we explore this paradox, focusing on the prognostic consequences and the current challenges in classifying these cells. We discuss future strategies for Sen-Mark+ cell detection together with emerging opportunities to exploit senescence for cancer.
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Affiliation(s)
- Emily A O'Sullivan
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ryan Wallis
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Federica Mossa
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Cleo L Bishop
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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White-Gilbertson S, Lu P, Saatci O, Sahin O, Delaney JR, Ogretmen B, Voelkel-Johnson C. Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization. J Biol Chem 2024; 300:107136. [PMID: 38447798 PMCID: PMC10979113 DOI: 10.1016/j.jbc.2024.107136] [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: 10/07/2023] [Revised: 02/03/2024] [Accepted: 02/15/2024] [Indexed: 03/08/2024] Open
Abstract
Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.
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Affiliation(s)
- Shai White-Gilbertson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ping Lu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozge Saatci
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Joe R Delaney
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christina Voelkel-Johnson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
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Li K, You G, Jiang K, Wang R, Li W, Meng Y, Fang Y, Chen W, Zhu G, Song J, Wang W, Su H, Hu B, Sun F, Jia Z, Li C, Zhu J. Root extract of Hemsleya amabilis Diels suppresses renal cell carcinoma cell growth through inducing apoptosis and G 2/M phase arrest via PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117014. [PMID: 37557938 DOI: 10.1016/j.jep.2023.117014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/16/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hemsleya amabilis Diels, belongs to cucurbitaceae, was traditional Chinese medicine (TCM). It is widely used to treat various diseases. However, these diseases may contribute to the development of RCC. AIM OF THE STUDY investigated the anticancer activities of root extract of Hemsleya amabilis Diels (HRE), and elucidated the underlying molecular mechanism in vivo and in vitro. MATERIALS AND METHODS Dried Hemsleya amabilis Diels roots were extracted by ethyl acetate and used to treat RCC4, OS-RC-2 and ACHN cells. UHPLC-MS was used to analyze the chemical composition of the extract. CCK-8 and colony formation assay were used to investigate proliferation. PI staining was used to detect cell cycle. Annexin-V-FITC, AO/EB and TEM were used to evaluate apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. RNA-seq, Network pharmacology, autodocking for virtual screening and molecular dynamics simulation were used to analyze potential molecular mechanisms and active components of HRE inhibiting proliferation of RCC. LY294002 and UC2288 were used to inhibit PI3K and P21 expression, respectively. IGF-1 was used to activate PI3K. Xenograft tumor model was established to evaluate its anti-tumor potential in vivo. Immunohistochemistry and Western blot were used to test protein expression levels. H&E staining was used to explore the side effects of HRE in vivo. Applying bioinformatics to analyze the effect of P21 on RCC. RESULTS HRE consists of 739 compounds. CCK-8 and colony formation assay showed that HRE significantly inhibited RCC cells proliferation. PI staining indicated that HRE caused G2/M phase arrest. Annexin-V-FITC, AO/EB and TEM experiments revealed that HRE significantly promoted apoptosis of RCC cells. Transwell and wound healing assays showed that HRE can inhibit the migration and invasion of RCC cells. RNA-seq showed that HRE induced 230 gene changes. Network pharmacology analysis found the relationship between HRE-component-target-RCC. Auto-docking found that Epitulipinolide diepoxide in HRE can stably bind to PIK3CA (-7.22 kJ/mol), and molecular dynamics simulation verified the combination between Epitulipinolide diepoxide of PIK3CA. In RCC4 cells, pretreatment with IGF-1, attenuated HRE-induced apoptosis and G2/M arrest. When pretreated with PIK3 inhibitor LY294002, the opposite result appears. Pretreatment with CDKN1A (P21) inhibitor UC2288 attenuated HRE-induced G2/M arrest. Xenograft tumor model showed that HRE inhibited tumor growth. Western blot analysis indicated that HRE can regulating Bax, Bcl-2, PARP, cleared-PARP, Caspase-9, Caspase-8, Caspase-3, Survivin, Cyclin-B1, CDK1, N-cadherin, snail, slug, E-cadherin, MMP-9. Immunohistochemical staining showed that in the treated group, expression of E-cadherin, Bax, P21 was up-regulated, while N-cadherin, PI3K, AKT and Bcl-2 were down-regulated. H&E staining showed that compared to control groups, the main organs in the HRE-treated groups showed no histological abnormalities. The overall survival rate of RCC patients in the high-expression group of P21 was higher than in the low-expression group of P21 on bioinformatics analysis. CONCLUSIONS HRE inhibited RCC migration and invasion through EMT, and inhibited proliferation in vivo and in vitro. In addition, HRE inhibited proliferation through promoting apoptosis and P21-induced G2/M phase arrest via PI3K/AKT signaling pathway. Overall, these results suggest that HRE may be a promising chemotherapy agent for RCC.
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Affiliation(s)
- Kai Li
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China
| | - Ganhua You
- The Second People's Hospital of Guizhou Province, Guiyang, 550002, China
| | - Kehua Jiang
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Rongpin Wang
- Department of Radiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, China
| | - Wuchao Li
- Department of Radiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, China
| | - Yonglu Meng
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China
| | - Yinyi Fang
- Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, China
| | - Weiming Chen
- Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, China
| | - Guohua Zhu
- Department of Pedictric, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Jukun Song
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, China
| | - Wei Wang
- Department of Pedictric, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Hao Su
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China
| | - Bin Hu
- Department of Urology, Kweichow Moutai Hospital, Renhuai, China
| | - Fa Sun
- Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China.
| | - Zhenyu Jia
- University of California of Riverside, Riverside, CA, 92521, USA.
| | - Can Li
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China.
| | - Jianguo Zhu
- Guizhou Provincial Key Laboratory for Rare Animal and Economic Insect of the Mountainous Region, College of Biology and Environmental Engineering, Guiyang University, Guiyang, 550025, China; Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, 550002, China.
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Zhao H, Bi F, Li M, Diao Y, Zhang C. E3 ubiquitin ligase RNF180 impairs IPO4/SOX2 complex stability and inhibits SOX2-mediated malignancy in ovarian cancer. Cell Signal 2024; 113:110961. [PMID: 37923100 DOI: 10.1016/j.cellsig.2023.110961] [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: 05/25/2023] [Revised: 10/17/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023]
Abstract
RING finger protein 180 (RNF180), an E3 ubiquitin ligase, is thought to be a tumor suppressor gene. However, the detailed mechanism of its effect on ovarian cancer (OV) has not been elucidated. Importin 4 (IPO4) which belongs to transport protein is reported to have cancer-promoting effects on OV. Here, we explored the potential signaling pathways related to RNF180 and IPO4. It was first verified that RNF180 is downregulated and IPO4 is upregulated in OV. By overexpressing or knocking down RNF180 in OV cells, we confirmed that RNF180 inhibited the malignant behaviors of OV cells both in vitro and in vivo. Bioinformatics analysis and proteomics experiments found that RNF180 could interact with IPO4 and promote the degradation of IPO4 through ubiquitination. In addition, overexpression of IPO4 removed the inhibitory effect of RNF180 on OV. We subsequently found that IPO4 could bind to the oncogene Sex determining Region Y-box 2 (SOX2). Knockdown of IPO4 in OV cells decreased SOX2 protein level in nucleus and promoted cyclin-dependent kinase inhibitory protein-1 (p21) expression. Overexpression of RNF180 also inhibited the expression of SOX2 in nucleus. All these results indicated that RNF180 inhibited the nuclear translocation of SOX2 by promoting ubiquitination of IPO4, which ultimately promoted the expression of p21 and then suppressed the progression of OV. This study verified the tumor suppressor effect of RNF180 on OV, elucidated the mechanism of the molecule network related to RNF180 and IPO4 in OV and identified for OV.
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Affiliation(s)
- Haiyan Zhao
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fangfang Bi
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Mengyuan Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuhan Diao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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Čižmáriková M, Michalková R, Mirossay L, Mojžišová G, Zigová M, Bardelčíková A, Mojžiš J. Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence. Biomolecules 2023; 13:1653. [PMID: 38002335 PMCID: PMC10669545 DOI: 10.3390/biom13111653] [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: 10/13/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer is a complex and multifaceted disease with a high global incidence and mortality rate. Although cancer therapy has evolved significantly over the years, numerous challenges persist on the path to effectively combating this multifaceted disease. Natural compounds derived from plants, fungi, or marine organisms have garnered considerable attention as potential therapeutic agents in the field of cancer research. Ellagic acid (EA), a natural polyphenolic compound found in various fruits and nuts, has emerged as a potential cancer prevention and treatment agent. This review summarizes the experimental evidence supporting the role of EA in targeting key hallmarks of cancer, including proliferation, angiogenesis, apoptosis evasion, immune evasion, inflammation, genomic instability, and more. We discuss the molecular mechanisms by which EA modulates signaling pathways and molecular targets involved in these cancer hallmarks, based on in vitro and in vivo studies. The multifaceted actions of EA make it a promising candidate for cancer prevention and therapy. Understanding its impact on cancer biology can pave the way for developing novel strategies to combat this complex disease.
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Affiliation(s)
- Martina Čižmáriková
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
| | - Radka Michalková
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
| | - Ladislav Mirossay
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
| | - Gabriela Mojžišová
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia;
| | - Martina Zigová
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
| | - Annamária Bardelčíková
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
| | - Ján Mojžiš
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (M.Č.); (R.M.); (M.Z.); (A.B.)
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Holmannova D, Borsky P, Parova H, Stverakova T, Vosmik M, Hruska L, Fiala Z, Borska L. Non-Genomic Hallmarks of Aging-The Review. Int J Mol Sci 2023; 24:15468. [PMID: 37895144 PMCID: PMC10607657 DOI: 10.3390/ijms242015468] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 10/19/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023] Open
Abstract
Aging is a natural, gradual, and inevitable process associated with a series of changes at the molecular, cellular, and tissue levels that can lead to an increased risk of many diseases, including cancer. The most significant changes at the genomic level (DNA damage, telomere shortening, epigenetic changes) and non-genomic changes are referred to as hallmarks of aging. The hallmarks of aging and cancer are intertwined. Many studies have focused on genomic hallmarks, but non-genomic hallmarks are also important and may additionally cause genomic damage and increase the expression of genomic hallmarks. Understanding the non-genomic hallmarks of aging and cancer, and how they are intertwined, may lead to the development of approaches that could influence these hallmarks and thus function not only to slow aging but also to prevent cancer. In this review, we focus on non-genomic changes. We discuss cell senescence, disruption of proteostasis, deregualation of nutrient sensing, dysregulation of immune system function, intercellular communication, mitochondrial dysfunction, stem cell exhaustion and dysbiosis.
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Affiliation(s)
- Drahomira Holmannova
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (D.H.); (Z.F.); (L.B.)
| | - Pavel Borsky
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (D.H.); (Z.F.); (L.B.)
| | - Helena Parova
- Department of Clinical Biochemistry and Diagnostics, University Hospital, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (H.P.); (T.S.)
| | - Tereza Stverakova
- Department of Clinical Biochemistry and Diagnostics, University Hospital, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (H.P.); (T.S.)
| | - Milan Vosmik
- Department of Oncology and Radiotherapy, University Hospital, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (M.V.); (L.H.)
| | - Libor Hruska
- Department of Oncology and Radiotherapy, University Hospital, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (M.V.); (L.H.)
| | - Zdenek Fiala
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (D.H.); (Z.F.); (L.B.)
| | - Lenka Borska
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Kralove, Czech Republic; (D.H.); (Z.F.); (L.B.)
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10
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Ciou HH, Lee TH, Wang HC, Ding YR, Tseng CJ, Wang PH, Tsai MH, Tzeng SL. Repurposing gestrinone for tumor suppressor through P21 reduction regulated by JNK in gynecological cancer. Transl Res 2022; 243:21-32. [PMID: 34921996 DOI: 10.1016/j.trsl.2021.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 11/23/2021] [Accepted: 12/06/2021] [Indexed: 11/19/2022]
Abstract
Endometriosis has been shown to increase the risk of gynecological cancers. However, the effect of gestrinone, a clinical endometriosis drug, on gynecological cancers remains unclear. This study aimed to understand the effect of gestrinone on gynecological cancers. A retrospective study was conducted using the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database (NHIRD) to observe the risk of gynecological cancers. Medication records from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital CSMUH and cancer records from the Taiwan Cancer Registry were collected to analyze the correlation between gestrinone use and gynecological cancers. Subsequently, human cell lines were used to investigate the effect of gestrinone on gynecological cancers. A total of 8330 endometriosis patients were enrolled, and analyses revealed that endometriosis patients had a higher risk of developing ovarian and endometrial cancer. However, the rate of cervical cancer was not statistically different (P = 0.249). Analyses of both the NHIRD and CSMUH databases revealed that gestrinone may reduce the risk of gynecological cancer. Cellular experiments verified the anticancer effects of gestrinone, which effectively and specifically inhibited the growth of HeLa cervical cancer cells, decreased P21 expression via JNK phosphorylation, and induced apoptosis. Combining the results of clinical database analysis and cell experiments, our findings prove that gestrinone has the potential to protect against cancer through regulation of the JNK-P21 axis. Repurposing the anticancer efficacy of gestrinone may be a strategy for targeted therapy in the future.
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Affiliation(s)
- Huai-How Ciou
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Tsung-Hsien Lee
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan
| | - Hsin-Chieh Wang
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - You-Ren Ding
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Chih-Jen Tseng
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan; Medical Information Department, Chung Shan Medical University Hospital, Taichung 40203, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan
| | - Meng-Hsiun Tsai
- Department of Management Information Systems, National Chung Hsing University, Taichung 40227, Taiwan; Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shu-Ling Tzeng
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40203, Taiwan.
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11
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Cai J, Wu D, Jin Y, Bao S. Effect of CMB Carrying PTX and CRISPR/Cas9 on Endometrial Cancer Naked Mouse Model. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:7119195. [PMID: 35368966 PMCID: PMC8975627 DOI: 10.1155/2022/7119195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 11/17/2022]
Abstract
Endometrial cancer, one of the most common gynecological cancers in women. Patients with advanced or recurrent disease have poor long-term outcomes. The current experiment explore the roles of cationic microbubbles (CMBs) carrying paclitaxel (PTX) and CRISPR/Cas9 plasmids on the xenotransplantation model of mice with endometrial cancer. The tumor histology, tumor cell viability, cell cycle, and invasion ability were investigated. Meanwhile, the P27, P21, GSK-3, Bcl-2 associated death promoter (Bad), mammalian target of rapamycin (mTOR), and C-erbB-2 expressions were evaluated by qRT-PCR and western blotting, respectively. CMB-PTX-CRISPR/Cas9 had an inhibitory action on the tumor growth, tumor cell viability, cell cycle, and invasion ability of the mouse xenograft model of endometrial cancer. The CMB-PTX-CRISPR/Cas9 increased the GSK-3, P21, P27, and Bad expression levels, while reduced the C-erbB-2 and mTOR expressions. CMBs loaded with both PTX and CRISPR/Cas9 plasmids may be a new combination treatment with much potential. CMB-PTX-CRISPR/Cas9 may regulate the tumor cell viability, invasion, and metastasis of endometrial cancer naked mouse model by upregulating expressions of GSK-3, P21, P27, and Bad.
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Affiliation(s)
- Junhong Cai
- Central Laboratory, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Dongcai Wu
- Department of Gynecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Yanbin Jin
- Department of Gynecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Shan Bao
- Department of Gynecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
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12
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Ghosal S, Banerjee S. In silico bioinformatics analysis for identification of differentially expressed genes and therapeutic drug molecules in Glucocorticoid-resistant Multiple myeloma. Med Oncol 2022; 39:53. [PMID: 35150335 DOI: 10.1007/s12032-022-01651-w] [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: 10/05/2021] [Accepted: 01/08/2022] [Indexed: 11/24/2022]
Abstract
Multiple myeloma (MM), second most common hematological malignancy, still remains irremediable because of acquisition of drug resistance. Glucocorticoid (GC) therapy, which is used as one of the key therapies against MM, is hindered by the incidence of GC resistance. The underlying mechanism of this acquired GC resistance in MM is not fully elucidated. Therefore, the present study was aimed to identify the differentially expressed genes (DEGs), associated micro RNAs (miRNAs), and transcription factors (TFs) from the microarray datasets of GC-resistant and GC-sensitive MM cell lines, obtained from Gene Expression Omnibus (GEO) database. DEGs were identified using GEO2R tool from two datasets and common DEGs were obtained by constructing Venn diagram. Then the Gene ontology (GO) and pathway enrichment analysis were performed using DAVID database. Genetic alterations in DEGs were examined using COSMIC database. Protein-protein interaction (PPI) network of DEGs was constructed using STRING database and Cytoscape tool. Network of interaction of DEGs and miRNAs as well as TFs were obtained and constructed using mirDIP, TRRUST, and miRNet tools. Drug gene interaction was studied to identify potential drug molecules by DGIdb tool. Six common DEGs, CDKN1A, CDKN2A, NLRP11, BTK, CD52, and RELN, were found to be significantly upregulated in GC-resistant MM and selected for further analysis. miRNA analysis detected hsa-mir-34a-5p that could interact with maximum target DEGs. Two TFs, Sp1 and Sp3, were found to regulate the expression of selected DEGs. The entire study may provide a new understanding about the GC resistance in MM.
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Affiliation(s)
- Somnath Ghosal
- School of Biological Sciences, Ramakrishna Mission Vivekananda Educational and Research Institute (RKMVERI), Narendrapur, Kolkata, West Bengal, India.
| | - Subrata Banerjee
- School of Biological Sciences, Ramakrishna Mission Vivekananda Educational and Research Institute (RKMVERI), Narendrapur, Kolkata, West Bengal, India
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13
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Saleh SAK, Adly HM, Aljahdali IA, Khafagy AA. Correlation of Occupational Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbons (cPAHs) and Blood Levels of p53 and p21 Protiens. Biomolecules 2022; 12:biom12020260. [PMID: 35204761 PMCID: PMC8961663 DOI: 10.3390/biom12020260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/01/2022] [Indexed: 01/27/2023] Open
Abstract
Carcinogenic polycyclic aromatic hydrocarbons (cPAHs) are considered the most serious cancer risk. This study was conducted to assess the effect of acute exposure to cPAHs on cancer biomarker proteins p53 and p21 in occupational workers during the hajj season in Makkah. One hundred five participants were recruited, including occupational workers and apparently healthy individuals; air samples were collected using personal sample monitors to identify the subjects’ exposure to cPAHs. Quantitative analyses of benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), benzo(a)pyrene (BaP), dibenzo(a,h)fluronathene (DBA), indeno(1,2,3-c,d)pyrene (IND) and chyresene (CRY) were carried out using the GC/Mass technique. Serum p53 and p21 proteins were analyzed using ELISA. The ambient air samples collected by the occupationally exposed group were more highly polluted by cPAHs, (90.25 ± 14.1) ng/m3, than those of the unexposed control groups, (30.12 ± 5.56) ng/m3. The concentration of distributive cPAHs was markedly more elevated in the air samples of the exposed group than in those taken from the non-exposed group. The study results demonstrated significant links between short-term exposure to cPAHs and serum p53 and p21 levels. Serum p53 and p21 proteins potentially influence biomarkers when exposed to ambient air cPAHs.
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Affiliation(s)
- Saleh A. K. Saleh
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
- Oncology Diagnostic Unit, Faculty of Medicine, Ain Shams University, Cairo 11435, Egypt
| | - Heba M. Adly
- Community Medicine and Pilgrims Healthcare Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia; (I.A.A.); (A.A.K.)
- Correspondence:
| | - Imad A. Aljahdali
- Community Medicine and Pilgrims Healthcare Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia; (I.A.A.); (A.A.K.)
| | - Abdullah A. Khafagy
- Community Medicine and Pilgrims Healthcare Department, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia; (I.A.A.); (A.A.K.)
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14
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Peng S, Cai J, Bao S. CMBs carrying PTX and CRISPR/Cas9 targeting C‑erbB‑2 plasmids interfere with endometrial cancer cells. Mol Med Rep 2021; 24:830. [PMID: 34590151 PMCID: PMC8503745 DOI: 10.3892/mmr.2021.12470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/06/2021] [Indexed: 12/27/2022] Open
Abstract
Development of combination therapy to decrease side effects of chemotherapeutic drugs and increase their utilization rate in combination with gene editing is a key research topic in tumor treatment. The present study aimed to investigate the effect of cationic microbubbles (CMBs) carrying paclitaxel (PTX) and C-erbB-2 knockout plasmid on the endometrial cancer cell line HEC-1A and to determine how C-erbB-2 regulates the function of endometrial cancer cells. Cells were treated with CMB, PTX, PTX-CMBs, cationic plasmid-carrying or cationic PTX-carrying plasmid groups. After verifying the most effective combination of PTX-CMBs and plasmids, HEC-1A cells were transfected. Reverse transcription-quantitative (RT-q)PCR and western blotting were used to measure C-erbB-2 and protein expression. After verifying C-erbB-2 knockout, invasion, healing, clone formation and proliferation of HEC-1A cells were assessed. Simultaneously, expression levels of the genes for P21, P27, mammalian target of rapamycin (mTOR), and Bcl-2 associated death promoter (Bad) were measured by RT-qPCR. Compared with the PTX group, CMBs significantly enhanced the absorption efficiency of PTX by HEC-1A cells. C-erbB-2 knockout had an inhibitory effect on the proliferation, migration and invasion of HEC-1A cells; cell proliferation and invasion of the group carrying PTX and plasmids simultaneously were significantly weakened. The C-erbB-2-knockout group exhibited increased expression of P21 and P27. Simultaneously loading PTX and plasmid may be novel combination therapy with great potential. C-erbB-2 may regulate the proliferation of HEC-1A cells by downregulating expression of P21 and P27.
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Affiliation(s)
- Siyuan Peng
- Department of Gynaecology and Obstetrics, Hainan Hospital Affiliated to University of South China, Haikou, Hainan 570311, P.R. China
| | - Junhong Cai
- Key Laboratory of Cell and Molecular Genetic Translational Medicine in Hainan Province, Hainan General Hospital, Haikou, Hainan 570311, P.R. China
| | - Shan Bao
- Department of Gynaecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China
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15
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Fares B, Berger L, Bangiev-Girsh E, Kakun RR, Ghannam-Shahbari D, Tabach Y, Zohar Y, Gottlieb E, Perets R. PAX8 plays an essential antiapoptotic role in uterine serous papillary cancer. Oncogene 2021; 40:5275-5285. [PMID: 34244607 DOI: 10.1038/s41388-021-01925-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/31/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023]
Abstract
Endometrial carcinoma (EC) is the fourth-most common cancer in women in the United States, and generally carries a favorable prognosis. However, about 10% of EC patients have a rare and aggressive form, uterine serous papillary carcinoma (USPC), which carries a much higher mortality rate. The developmental transcription factor PAX8 is expressed in nearly 100% of USPCs. We show that PAX8 plays a critical antiapoptotic role in USPC and this role is established via transcriptional activation of two aberrant signaling pathways. First, PAX8 positively regulates mutated p53, and missense p53 mutations have an oncogenic gain of function effect. Second, PAX8 directly transcriptionally regulates p21, in a p53-independent manner, and p21 acquires a growth promoting role that is mediated via cytoplasmic localization of the protein. We propose that mutated p53 and cytoplasmic p21 can independently mediate the pro-proliferative role of PAX8 in USPC. In addition, we performed a genome-wide transcriptome analysis to detect pathways that are regulated by PAX8, and propose that metabolism and HIF-1alpha -related pathways are potential candidates for mediating the role of PAX8 in USPC. Taken together our findings demonstrate for the first time that PAX8 is an essential lineage marker in USPC, and suggest its mechanism of action.
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MESH Headings
- PAX8 Transcription Factor/genetics
- PAX8 Transcription Factor/metabolism
- Humans
- Female
- Uterine Neoplasms/genetics
- Uterine Neoplasms/pathology
- Uterine Neoplasms/metabolism
- Apoptosis/genetics
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Cell Line, Tumor
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Gene Expression Regulation, Neoplastic
- Paired Box Transcription Factors/genetics
- Paired Box Transcription Factors/metabolism
- Signal Transduction/genetics
- Cystadenocarcinoma, Serous/genetics
- Cystadenocarcinoma, Serous/pathology
- Cystadenocarcinoma, Serous/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/metabolism
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Affiliation(s)
- Basem Fares
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel
| | - Liron Berger
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel
| | - Einav Bangiev-Girsh
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel
| | - Reli Rachel Kakun
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel
| | - Dima Ghannam-Shahbari
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel
| | - Yuval Tabach
- Department of Developmental Biology & Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yaniv Zohar
- Department of Pathology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel
| | - Eyal Gottlieb
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ruth Perets
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
- Division of Oncology, The Clinical Research Institute at Rambam (CRIR), Rambam Health Care Campus, Haifa, Israel.
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16
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Santarelli R, Pompili C, Gilardini Montani MS, Romeo MA, Gonnella R, D'Orazi G, Cirone M. Lovastatin reduces PEL cell survival by phosphorylating ERK1/2 that blocks the autophagic flux and engages a cross-talk with p53 to activate p21. IUBMB Life 2021; 73:968-977. [PMID: 33987937 PMCID: PMC8361952 DOI: 10.1002/iub.2503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 03/10/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022]
Abstract
Statins are inhibitors of the mevalonate pathway that besides being cholesterol lowering agents, display anti‐cancer properties. This is because cholesterol is an essential component of cell membranes but also because the mevalonate pathway controls protein farnesylation and geranylation, processes essential for the activity of GTPase family proteins. In this study, we found that Lovastatin exerted a dose‐ and time‐dependent cytotoxic effect against PEL cells, an aggressive B cell lymphoma strictly associated with the gammaherpesvirus KSHV and characterized by a poor response to conventional chemotherapies. At molecular level, Lovastatin by dephosphorylating STAT3, induced ERK1/2 activation that inhibited autophagy and phosphorylated p53ser15 that in turn maintained ERK1/2 activated and up‐regulated p21. However, p21 played a pro‐survival role in this setting, as its inhibition by UC2288 further reduced cell survival in PEL cells undergoing Lovastatin treatment. In conclusion, this study suggests that Lovastatin may represent a valid therapeutic alternative against PEL cells, especially if used in combination with p21 inhibitors.
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Affiliation(s)
- Roberta Santarelli
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Chiara Pompili
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Maria Saveria Gilardini Montani
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Maria Anele Romeo
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Roberta Gonnella
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Gabriella D'Orazi
- Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.,Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
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17
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Torres-Martinez Z, Delgado Y, Ferrer-Acosta Y, Suarez-Arroyo IJ, Joaquín-Ovalle FM, Delinois LJ, Griebenow K. Key genes and drug delivery systems to improve the efficiency of chemotherapy. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:163-191. [PMID: 34142021 PMCID: PMC8208690 DOI: 10.20517/cdr.2020.64] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer cells can develop resistance to anticancer drugs, thereby becoming tolerant to treatment through different mechanisms. The biological mechanisms leading to the generation of anticancer treatment resistance include alterations in transmembrane proteins, DNA damage and repair mechanisms, alterations in target molecules, and genetic responses, among others. The most common anti-cancer drugs reported to develop resistance to cancer cells include cisplatin, doxorubicin, paclitaxel, and fluorouracil. These anticancer drugs have different mechanisms of action, and specific cancer types can be affected by different genes. The development of drug resistance is a cellular response which uses differential gene expression, to enable adaptation and survival of the cell to diverse threatening environmental agents. In this review, we briefly look at the key regulatory genes, their expression, as well as the responses and regulation of cancer cells when exposed to anticancer drugs, along with the incorporation of alternative nanocarriers as treatments to overcome anticancer drug resistance.
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Affiliation(s)
- Zally Torres-Martinez
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Yamixa Delgado
- Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas, PR 00726, USA
| | - Yancy Ferrer-Acosta
- Neuroscience Department, Universidad Central del Caribe, Bayamon, PR 00956, USA
| | | | - Freisa M Joaquín-Ovalle
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Louis J Delinois
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
| | - Kai Griebenow
- Chemistry Department, University of Puerto Rico- Rio Piedras campus, San Juan, PR 00936, USA
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18
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Hu K, Li J, Wu G, Zhou L, Wang X, Yan Y, Xu Z. The novel roles of virus infection-associated gene CDKN1A in chemoresistance and immune infiltration of glioblastoma. Aging (Albany NY) 2021; 13:6662-6680. [PMID: 33621203 PMCID: PMC7993694 DOI: 10.18632/aging.202519] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/29/2020] [Indexed: 02/05/2023]
Abstract
Chemoresistance is a common limitation for successful treatment of glioblastoma multiforme (GBM). Recently, virus infections have been demonstrated to be associated with tumorigenesis and chemoresistance in tumors. However, the role of infection-related genes in GBM haven’t been clearly demonstrated. Here, we explored the roles and mechanisms of human T-lymphotropic virus type-1 (HTLV-1) infections in tumorigenesis and chemoresistance in GBM. Four candidate genes, CDKN1A, MSX1, MYC and CHEK2, were identified to be the codifferentially expressed genes between three temozolomide (TMZ) chemotherapy datasets and one HTLV-1 infection gene set. Next, comprehensive bioinformatics data from several databases indicated that only CDKN1A was significantly upregulated in both GBM tissues and cells and showed the greatest prognostic value in GBM patients. Clinical data identified the correlations between CDKN1A expression and clinicopathological parameters of GBM patients. Moreover, CDKN1A was found to be involved in AKT-mediated TMZ resistance of glioma cells. In addition, KEGG analysis of CDKN1A-associated coexpression genes showed that CDKN1A was potentially involved in complement and coagulation cascades pathways in GBM. Finally, TISIDB database was used to investigate the role of CDKN1A in tumor-immune system interactions in GBM. These findings enhanced our understanding of the roles of CDKN1A in tumorigenesis and therapy response in GBM.
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Affiliation(s)
- Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Juanni Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Geting Wu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Lei Zhou
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410008, Hunan, China
| | - Xiang Wang
- Department of Pharmacy, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yuanliang Yan
- Department of Pharmacy, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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19
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Cui Y, Hunt A, Li Z, Birkin E, Lane J, Ruge F, Jiang WG. Lead DEAD/H box helicase biomarkers with the therapeutic potential identified by integrated bioinformatic approaches in lung cancer. Comput Struct Biotechnol J 2020; 19:261-278. [PMID: 33425256 PMCID: PMC7779375 DOI: 10.1016/j.csbj.2020.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/02/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
DEAD/H box helicases are implicated in lung cancer but have not been systematically investigated for their clinical significance and function. In this study, we aimed to evaluate the potential of DEAD/H box helicases as prognostic biomarkers and therapeutic targets in lung cancer by integrated bioinformatic analysis of multivariate large-scale databases. Survival and differential expression analysis of these helicases enabled us to identify four biomarkers with the most significant alterations. These were found to be the negative prognostic factors DDX11, DDX55 and DDX56, and positive prognostic factor DDX5. Pathway enrichment analysis indicates that MYC signalling is negatively associated with expression levels of the DDX5 gene while positively associated with that of DDX11, DDX55 and DDX56. High expression levels of the DDX5 gene is associated with low mutation levels of TP53 and MUC16, the two most frequently mutated genes in lung cancer. In contrast, high expression levels of DDX11, DDX55 and DDX56 genes are associated with high levels of TP53 and MUC16 mutation. The tumour-infiltrated CD8 + T and B cells positively correlate with levels of DDX5 gene expression, while negatively correlate with that of the other three DEAD box helicases, respectively. Moreover, the DDX5-associated miRNA profile is distinguished from the miRNA profiles of DDX11, DDX55 and DDX56, although each DDX has a different miRNA signature. The identification of these four DDX helicases as biomarkers will be valuable for prognostic prediction and targeted therapeutic development in lung cancer.
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Affiliation(s)
- Yuxin Cui
- Cardiff China Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Adam Hunt
- Cardiff China Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Zhilei Li
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, PR China
| | - Emily Birkin
- Cardiff & Vale University Health Board, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK
| | - Jane Lane
- Cardiff China Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Fiona Ruge
- Cardiff China Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Wen G Jiang
- Cardiff China Research Collaborative, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
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20
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Lin J, Fan X, Chen J, Xie X, Yu H. Small interfering RNA-mediated knockdown of KRT80 suppresses colorectal cancer proliferation. Exp Ther Med 2020; 20:176. [PMID: 33101466 PMCID: PMC7579811 DOI: 10.3892/etm.2020.9306] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/17/2020] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world and its development is associated with oncogenic dysfunction. Therefore, the present study aimed to identify differentially expressed genes (DEGs) in CRC tissues and to determine the role of keratin 80 (KRT80) in CRC cell proliferation. DEGs were initially screened in 32 paired CRC tissues and matched adjacent normal tissues from RNA-Seq datasets in The Cancer Genome Atlas database using the limma package in R software. In total, 2,114 DEGs were identified, of which KRT80 was discovered to be the most upregulated in CRC tissues. Moreover, increased KRT80 expression levels were confirmed in tissues collected from 50 patients with CRC using reverse transcription-quantitative PCR, and its increased expression levels were significantly associated with increased lymph node and distant metastasis and a higher pathological stage. Furthermore, KRT80 knockdown using siRNA decreased the viability and proliferation of CRC cells. Finally, pathway analysis revealed that the proteins co-expressed with KRT80 in CRC were enriched in the cell cycle, DNA replication, immune system, metabolism of protein and RNA, signal transduction and other cellular processes. Among them, the cell cycle and DNA replication pathways contained the highest number of the proteins identified. In conclusion, the findings of the present study suggested that KRT80 may be overexpressed in CRC tissues. Furthermore, KRT80 may be involved in the proliferation of CRC cells, which is likely through its ability to regulate the cell cycle and DNA replication pathways, thus it may serve as a potential therapeutic target for patients with CRC.
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Affiliation(s)
- Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xiaoqin Fan
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Junhui Chen
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xina Xie
- Guangdong Key Laboratory of Systems and Synthetic Biology for Urogenital Tumors, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Hongjian Yu
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Dr Hongjian Yu, Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China
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21
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Zaleski M, Kalhor N, Moran CA. Typical and Atypical Carcinoid Tumors of the Mediastinum: A Biomarker Analysis of 27 Cases With Clinical Correlation. Int J Surg Pathol 2020; 29:358-367. [PMID: 33243039 DOI: 10.1177/1066896920976845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Thymic typical and atypical carcinoids are rare and appear to be more aggressive than similar tumors in other sites. We retrospectively analyzed a group of biomarkers that hold therapeutic and prognostic utility, in 27 of these tumors. All cases were immunohistochemically stained with PAX5, MET, CRMP5, paxillin, p21, p27, EZH2, PDL-1, and Ki-67, and then H-scored. Clinicopathologic and survival data were statistically analyzed against staining (χ2 test). Five- and 10-year-survival rates were 53% and 18%, respectively. Mitotic counts ≥4 per 2 mm2 and tumor size ≥5 cm, associated with death of disease (DoD; P = .010 and .016). Ki-67 expression ≥1% associated with DoD (P = .003) and death within 5 years (P = .031). Biomarkers stained tumor cases as follows: PDL-1 = 0%, PAX-5 = 0%, MET = 7.4%, paxillin = 41%, CRMP5 = 78%, p21 = 63%, p27 = 63%, EZH2 = 37%, and MASH1 = 59%. Overall ± staining did not associate with survival or grade. Cases with low CRMP5 H-scores (<80) associated with DoD (P = .002), while CRMP5 H-scores >80 associated with 10-year survival (P = .022). Cases with high MASH1 H-score (>100) associated with DoD (P = .021). Accurate grading and staging remain paramount in predicting clinical outcome. Biomarkers may have significance in subsets of patients and the use of these studies likely should be focused on a more personalize type of approach.
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Affiliation(s)
- Michael Zaleski
- 4002The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neda Kalhor
- 4002The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cesar A Moran
- 4002The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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22
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Fu T, Liang A, Liu Y. [Role of P21 in Resistance of Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:597-602. [PMID: 32434295 PMCID: PMC7406443 DOI: 10.3779/j.issn.1009-3419.2020.101.16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Lung cancer is the most common malignant tumor in the world with the highest incidence of deaths. In recent years, the treatment of lung cancer has made a significant breakthrough. However, as the tumor progresses, lung cancer cells inevitably acquire resistance and the efficacy of the treatment are greatly reduced. P21 protein plays a dual role in tumors, which not only regulates the cell cycle, induces apoptosis, inhibits cell proliferation, but also protects cells against apoptosis and promotes tumor cell resistance. This article reviews the research on P21 and lung cancer resistance, to provide new ideas for individualized treatment of lung cancer and overcoming lung cancer resistance.
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Affiliation(s)
- Tian Fu
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Biochemistry and Molecular Biology and Department of Clinical Biochemistry in Guangdong Medical University, Dongguan 523808, China
| | - Ailing Liang
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Clinical Laboratory Biochemistry of Guangdong Medical University, Dongguan 523808, China
| | - Yongjun Liu
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Biochemistry and Molecular Biology and Department of Clinical Biochemistry in Guangdong Medical University, Dongguan 523808, China
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23
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Wang X, Chang K, Gao J, Wei J, Xu G, Xiao L, Song G. MicroRNA-504 functions as a tumor suppressor in oral squamous cell carcinoma through inhibiting cell proliferation, migration and invasion by targeting CDK6. Int J Biochem Cell Biol 2020; 119:105663. [DOI: 10.1016/j.biocel.2019.105663] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/24/2019] [Accepted: 12/03/2019] [Indexed: 12/19/2022]
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24
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Kreis NN, Louwen F, Yuan J. The Multifaceted p21 (Cip1/Waf1/ CDKN1A) in Cell Differentiation, Migration and Cancer Therapy. Cancers (Basel) 2019; 11:cancers11091220. [PMID: 31438587 PMCID: PMC6770903 DOI: 10.3390/cancers11091220] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/15/2019] [Accepted: 08/17/2019] [Indexed: 12/12/2022] Open
Abstract
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
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Affiliation(s)
- Nina-Naomi Kreis
- Department of Gynecology and Obstetrics, University Hospital, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
| | - Frank Louwen
- Department of Gynecology and Obstetrics, University Hospital, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
| | - Juping Yuan
- Department of Gynecology and Obstetrics, University Hospital, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
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25
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Shamloo B, Usluer S. p21 in Cancer Research. Cancers (Basel) 2019; 11:cancers11081178. [PMID: 31416295 PMCID: PMC6721478 DOI: 10.3390/cancers11081178] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/05/2019] [Accepted: 08/12/2019] [Indexed: 12/21/2022] Open
Abstract
p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies.
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Affiliation(s)
- Bahar Shamloo
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
| | - Sinem Usluer
- Department of Molecular Biology & Biochemistry, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, 8010 Graz, Austria
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26
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Jiang Z, Slater CM, Zhou Y, Devarajan K, Ruth KJ, Li Y, Cai KQ, Daly M, Chen X. LincIN, a novel NF90-binding long non-coding RNA, is overexpressed in advanced breast tumors and involved in metastasis. Breast Cancer Res 2017; 19:62. [PMID: 28558830 PMCID: PMC5450112 DOI: 10.1186/s13058-017-0853-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 05/05/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recent genome-wide profiling by sequencing and distinctive chromatin signatures has identified thousands of long non-coding RNA (lncRNA) species (>200 nt). LncRNAs have emerged as important regulators of gene expression, involving in both developmental and pathological processes. While altered expression of lncRNAs has been observed in breast cancer development, their roles in breast cancer progression and metastasis are still poorly understood. METHODS To identify novel breast cancer-associated lncRNA candidates, we employed a high-density SNP array-based approach to uncover intergenic lncRNA genes that are aberrantly expressed in breast cancer. We first evaluated the potential value as a breast cancer prognostic biomarker for one breast cancer-associated lncRNA, LincIN, using a breast cancer cohort retrieved from The Cancer Genome Atlas (TCGA) Data Portal. Then we characterized the role of LincIN in breast cancer progression and metastasis by in vitro invasion assay and a mouse tail vein injection metastasis model. To study the action of LincIN, we identified LincIN-interacting protein partner(s) by RNA pull-down experiments followed with protein identification by mass spectrometry. RESULTS High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancer. Importantly, analysis of TCGA data further suggest that high expression of LincIN is associated with poor overall survival in patients with breast cancer (P = 0.044 and P = 0.011 after adjustment for age). The functional experiments demonstrate that knockdown of LincIN inhibits tumor cell migration and invasion in vitro, which is supported by the results of transcriptome analysis in the LincIN-knockdown cells. Furthermore, knockdown of LincIN diminishes lung metastasis in a mouse tail vein injection model. We also identified a LincIN-binding protein, NF90, through which overexpression of LincIN may repress p21 protein expression by inhibiting its translation, and upregulation of p21 by LincIN knockdown may be associated with less aggressive metastasis phenotypes. CONCLUSIONS Our studies provide clear evidence to support LincIN as a new regulator of tumor progression-metastasis at both transcriptional and translational levels and as a promising prognostic biomarker for breast cancer.
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Affiliation(s)
- Zhengyu Jiang
- Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.,Present Address: Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, 10032, USA
| | - Carolyn M Slater
- Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Yan Zhou
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Karthik Devarajan
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Karen J Ruth
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Yueran Li
- Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.,Present Address: The Third Xiangya Hospital of Central South University, Changsha, China
| | - Kathy Q Cai
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Mary Daly
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Xiaowei Chen
- Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
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27
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Chen Y, Huang Y, Hou P, Zhang Z, Zhang Y, Wang W, Sun G, Xu L, Zhou J, Bai J, Zheng J. ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer. Oncotarget 2016; 7:79017-79031. [PMID: 27806345 PMCID: PMC5346695 DOI: 10.18632/oncotarget.12984] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 10/22/2016] [Indexed: 12/27/2022] Open
Abstract
ING4, a potential tumor suppressor, is implicated in cell cycle arrest, apoptosis, cell migration and angiogenesis. Here, we investigated the clinical value of ING4 and its impact on angiogenesis in colorectal cancer (CRC). In this study, we found that ING4 expression was significantly reduced in CRC tissues versus paired normal colon tissues. Moreover, low ING4 expression was significantly associated with increased lymph node metastasis, advanced TNM stage and poor overall survival. Multivariate Cox regression analysis showed that ING4 expression was an independent favourable prognostic factor for CRC (hazard ratio = 0.45, P = 0.001). In addition, we found that ING4 strongly inhibited CRC angiogenesis by suppressing Sp1 expression and transcriptional activity through ubiquitin degradation and down-regulating the expressions of Sp1 downstream pro-angiogenic genes, MMP-2 and COX-2. Moreover, ING4 might inhibit phosphorylation activity of cyclin/CDK2 complexes to trigger Sp1 degradation by inducing p21 expression in despite of p53 status. Our findings imply that reduced ING4 expression in CRC resulted in increased angiogenesis and contributed to CRC metastasis and poor prognosis. Restoration of ING4 may be a novel strategy for the treatment of metastatic CRC.
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Affiliation(s)
- Yansu Chen
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Yefei Huang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Pingfu Hou
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Zhe Zhang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Yafei Zhang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Weimin Wang
- Department of Oncology, Yixing People's Hospital, Yixing 214200, Jiangsu Province, China
| | - Guixiang Sun
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Lichun Xu
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jin Bai
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
| | - Junnian Zheng
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
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28
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Leisibach P, Schneiter D, Soltermann A, Yamada Y, Weder W, Jungraithmayr W. Prognostic value of immunohistochemical markers in malignant thymic epithelial tumors. J Thorac Dis 2016; 8:2580-2591. [PMID: 27747012 DOI: 10.21037/jtd.2016.08.82] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Thymic epithelial tumors (TET) are rare neoplasms with inconsistent treatment strategies. When researching for molecular pathways to find new therapies, the correlation between specific molecular markers and outcome has only rarely been investigated. The aim of this study was to investigate the correlation between survival, metastatic potential and invasiveness of aggressive subtypes of TET and immunohistochemical markers. METHODS Overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and metastasis-free survival (MFS) of patients with WHO type B2/B3 mixed type thymoma (MT), thymoma type B3 (B3) and thymic carcinoma (TC), undergoing surgery [1998-2013] were determined. Tumor specimens were stained using a tissue microarray (TMA) (CD117, CD5, p63, p40, p21, p27, p53, Bcl-2, Ki67, podoplanin, synaptophysin, PTEN and Pax8). Invasive behavior of primary tumors and the presence of extrathoracic metastases were assessed. RESULTS We found in 23 patients included into this study (four MT, ten B3, nine TC) that (I) p21 expression in the cytoplasm significantly correlated with a decrease of OS (P=0.016), PFS (P=0.034) and MFS (P=0.005); (II) MFS was significantly shorter when the combination of p21-low p27-low p53-high was present (P=0.029); and (III) nuclear p27 (P=0.042), Ki-67 (P=0.024) and podoplanin (P=0.05) expression correlated with the presence of extrathoracic metastases. CONCLUSIONS The main finding of this study is that cytoplasmic p21 expression negatively influences the outcome of malignant TETs and correlates with metastatic activity. Additionally, selected immunohistochemical markers correlate with the distant metastatic potential of TETs. These results may contribute to the stratification of diagnosis and improvement of treatment strategies for thymic malignancies.
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Affiliation(s)
- Priska Leisibach
- Division of Thoracic Surgery, University Hospital Zurich, Zurich 8091, Switzerland
| | - Didier Schneiter
- Division of Thoracic Surgery, University Hospital Zurich, Zurich 8091, Switzerland
| | - Alex Soltermann
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland
| | - Yoshi Yamada
- Division of Thoracic Surgery, University Hospital Zurich, Zurich 8091, Switzerland
| | - Walter Weder
- Division of Thoracic Surgery, University Hospital Zurich, Zurich 8091, Switzerland
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29
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Ohkoshi S, Hirono H, Watanabe K, Hasegawa K, Kamimura K, Yano M. Natural regression of fibrosis in chronic hepatitis B. World J Gastroenterol 2016; 22:5459-5466. [PMID: 27350724 PMCID: PMC4917606 DOI: 10.3748/wjg.v22.i24.5459] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 04/20/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
The fibrosis of liver cirrhosis was considered to be irreversible before the anti-viral drugs showed that it is reversible when they lead to continuous suppression of viral replication and inflammation. However, several reports previously showed that fibrosis of type B liver cirrhosis was almost completely absorbed after the natural remission of chronic inflammation. This phenomenon might not be limited to exceptional patients, but rather occur commonly, considering the dynamic clinical features of chronic hepatitis B (CHB), where inactive carrier stage normally follows aggravation of hepatitis and progression of fibrosis at the time of HBeAg seroconversion. Thus, fibrosis levels of CHB as a hepatocellular carcinoma (HCC)-surveillance marker, particularly those of the inactive stage, could be underestimated, because some of them might have been (pre)cirrhotic in the past and recovered with the natural regression of fibrosis. We argue that cirrhosis-induced HCC mechanisms, rather than direct action of viral genome, may be more common than generally considered in CHB patients. This may have some impact on reconsidering the surveillance rationale for HCC in CHB, from where advanced HCCs tended to be missed. In addition, a molecular marker to assess the cancer-prone characteristics of the liver will definitely be needed to resolve the issue.
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30
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Chen Y, Huang Y, Zhu L, Chen M, Huang Y, Zhang J, He S, Li A, Chen R, Zhou J. SOX2 inhibits metastasis in gastric cancer. J Cancer Res Clin Oncol 2016; 142:1221-30. [PMID: 26960758 DOI: 10.1007/s00432-016-2125-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 01/25/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate the potential role of SOX2 in gastric cancer (GC) metastasis. METHODS The SOX2 expression was detected using immunohistochemistry on a GC tissue microarray. The correlations of SOX2 expression with clinicopathological factors and 5-year survival were evaluated. To test the role of SOX2 in inhibiting GC metastasis, the cell transwell assay was performed. Real-time PCR and Western blot were used to explore the possible mechanism that SOX2 inhibits GC metastasis. RESULTS In the present study, SOX2 expression was downregulated in GC tissues when compared to matching normal tissues. Moreover, patients with high SOX2 expression in cancerous tissues had less lymph node metastasis and better treatment outcome. At the subcellular level, SOX2 inhibited the GC cell migration and invasion by upregulating p21 expression. Moreover, SOX2 was determined to associate with the nuclear p21 expression. GC patients with high SOX2 and nuclear p21 expression had synergistically less lymph node metastasis and the better overall survival. CONCLUSION Our results suggest that SOX2 is a promising and favorable metastatic biomarker for GC.
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Affiliation(s)
- Yansu Chen
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
- School of Public Health, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, People's Republic of China
| | - Yefei Huang
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
- School of Public Health, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, People's Republic of China
| | - Liwen Zhu
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Minjuan Chen
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Yulin Huang
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Jianbing Zhang
- Department of Pathology, Nantong Cancer Hospital, 30 North Tongyang Road, Pingchao, Nantong, 226361, Jiangsu Province, People's Republic of China
| | - Song He
- Department of Pathology, Nantong Cancer Hospital, 30 North Tongyang Road, Pingchao, Nantong, 226361, Jiangsu Province, People's Republic of China
| | - Aiping Li
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China
| | - Rui Chen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China.
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, People's Republic of China.
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Ohkoshi S, Yano M, Matsuda Y. Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy. World J Gastroenterol 2015; 21:12150-6. [PMID: 26576099 PMCID: PMC4641132 DOI: 10.3748/wjg.v21.i42.12150] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/30/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.
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MESH Headings
- Active Transport, Cell Nucleus/drug effects
- Animals
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Drug Design
- Humans
- Karyopherins/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Targeted Therapy
- Oncogene Proteins/metabolism
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction
- Tumor Suppressor Proteins/metabolism
- Exportin 1 Protein
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Manojlovic Gacic E, Skender-Gazibara M, Soldatovic I, Dundjerovic D, Boricic N, Raicevic S, Popovic V. Immunohistochemical Expression of p16 and p21 in Pituitary Tissue Adjacent to Pituitary Adenoma versus Pituitary Tissue Obtained at Autopsy: Is There a Difference? Endocr Pathol 2015; 26:104-10. [PMID: 25678367 DOI: 10.1007/s12022-015-9358-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Normal pituitary tissue is frequently used for comparison with protein expression in tumor tissue, being obtained either at surgery or at autopsy. p16 and p21 proteins are cyclin-dependent kinase inhibitors, belonging to INK4 and Cip/Kip family, respectively. Their expression is increased in response to DNA damage or other cellular stressors, resulting in the activation of cell cycle checkpoints. They also play important roles in cellular senescence. The purpose of this study was to investigate differences in p16 and p21 immunohistochemical expression in normal pituitary tissue adjacent to pituitary adenoma obtained during neurosurgical procedure with pituitary tissue obtained at autopsy, from patients who died from non-endocrinological diseases. Our results show significant difference in p16 nuclear and p21 cytoplasmic immunohistochemical expression between two types of normal pituitary tissues. One of the reasons for this difference could be the age of subjects because those who underwent autopsy for a non-endocrinological disease were significantly older than subjects who underwent neurosurgery for a pituitary adenoma. Our finding that differences are probably not influenced by postmortem changes is supported by no significant correlation between postmortem interval and immunohistochemical p16 and p21 expression. The influence of the presence of a pituitary adenoma could not be evaluated in these specimens.
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