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Chalepaki AM, Gkoris M, Chondrou I, Kourti M, Georgakopoulos-Soares I, Zaravinos A. A multi-omics analysis of effector and resting treg cells in pan-cancer. Comput Biol Med 2025; 189:110021. [PMID: 40088713 DOI: 10.1016/j.compbiomed.2025.110021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 02/09/2025] [Accepted: 03/11/2025] [Indexed: 03/17/2025]
Abstract
Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.
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Affiliation(s)
- Anna-Maria Chalepaki
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Marios Gkoris
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Irene Chondrou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Malamati Kourti
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Ilias Georgakopoulos-Soares
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
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Meyiah A, Elkord E. What is the relevance of FoxP3 in the tumor microenvironment and cancer outcomes? Expert Rev Clin Immunol 2024; 20:803-809. [PMID: 38512803 DOI: 10.1080/1744666x.2024.2334258] [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: 01/13/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION Forkhead box P3 (FoxP3) transcription factor plays critical roles in controlling immune responses and cancer progression in different cancers. FoxP3 expression within the tumor microenvironment (TME) may influence clinical outcomes negatively or positively, and it could play dual roles in cancer, either by promoting or inhibiting tumor development and progression. Some studies reported that high levels of FoxP3 could be associated with tumor progression and worse prognosis, while others reported contradictory results. AREAS COVERED In this special report, we present a brief account on the role and function of FoxP3 in the TME, and its contribution to the clinical outcomes of cancer patients. Importantly, we give insights on the potential factors that could contribute to different clinical outcomes in cancer patients. EXPERT OPINION Different studies showed that FoxP3 expression can be associated with bad prognoses in cancer patients. However, FoxP3 could have opposing roles by enhancing cancer progression or regression. Location and expression of FoxP3 in T cells or tumor cells can have different impacts on cancer prognoses. Different factors should be considered to establish FoxP3 as a more robust prognostic biomarker and a potential therapeutic target for enhancing anti-tumor immunity and improving clinical outcomes of cancer patients.
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Affiliation(s)
- Abdo Meyiah
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Eyad Elkord
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK
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Mortezaee K. FOXP3 (in)stability and cancer immunotherapy. Cytokine 2024; 178:156589. [PMID: 38547750 DOI: 10.1016/j.cyto.2024.156589] [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: 01/15/2024] [Revised: 03/16/2024] [Accepted: 03/23/2024] [Indexed: 04/12/2024]
Abstract
Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens-associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Gong R, Wang J, Xing Y, Wang J, Chen X, Lei K, Yu Q, Zhao C, Li S, Zhang Y, Wang H, Ren H. Expression landscape of cancer-FOXP3 and its prognostic value in pancreatic adenocarcinoma. Cancer Lett 2024; 590:216838. [PMID: 38561039 DOI: 10.1016/j.canlet.2024.216838] [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: 02/05/2024] [Revised: 03/19/2024] [Accepted: 03/27/2024] [Indexed: 04/04/2024]
Abstract
FOXP3, a key identifier of Treg, has also been identified in tumor cells, which is referred to as cancer-FOXP3 (c-FOXP3). Human c-FOXP3 undergoes multiple alternative splicing events, generating several isoforms, like c-FOXP3FL and c-FOXP3Δ3. Previous research on c-FOXP3 often ignore its cellular source (immune or tumor cells) and isoform expression patterns, which may obscure our understanding of its clinical significance. Our immunohistochemistry investigations which conducted across 18 tumors using validated c-FOXP3 antibodies revealed distinct expression landscapes for c-FOXP3 and its variants, with the majority of tumors exhibited a predominantly expression of c-FOXP3Δ3. In pancreatic ductal adenocarcinoma (PDAC), we further discovered a potential link between nuclear c-FOXP3Δ3 in tumor cells and poor prognosis. Overexpression of c-FOXP3Δ3 in tumor cells was associated with metastasis. This work elucidates the expression pattern of c-FOXP3 in pan-cancer and indicates its potential as a prognostic biomarker in clinical settings, offering new perspectives for its clinical application.
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Affiliation(s)
- Ruining Gong
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jia Wang
- Qingdao Medical College, Qingdao University, Qingdao, 266000, China
| | - Yihai Xing
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jigang Wang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266555, China
| | - Xianghan Chen
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Ke Lei
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Qian Yu
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Chenyang Zhao
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Sainan Li
- Key Laboratory of Biofuels and Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, China
| | - Yuxing Zhang
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hongxia Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - He Ren
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Gong R, Chen X, Sun X, Zhang Y, Wang J, Yu Q, Lei K, Ren H. Identification of FOXP3 + epithelial cells contributing to pancreatic proliferation and angiogenesis. Am J Physiol Cell Physiol 2024; 326:C294-C303. [PMID: 38047300 PMCID: PMC11192472 DOI: 10.1152/ajpcell.00461.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/26/2023] [Indexed: 12/05/2023]
Abstract
Forkhead box protein 3 (FOXP3), traditionally recognized as a specific transcription factor for regulatory T cells (Tregs), has also been identified in various tumor epithelial cells (named as cancer-FOXP3, c-FOXP3). However, the natural state and functional role of FOXP3 positive tumor epithelial cells remain unknown. Monoclonal cells expressing varying levels of c-FOXP3 were isolated from established PANC-1 cells using limited dilution. Whole transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) were conducted on these subsets, followed by in vitro and in vivo functional investigations. In addition, we identified c-FOXP3+E-cadherin- epithelial cells in human pancreatic cancer tissues after radical resection by immunofluorescence co-staining. We also investigated the connection between c-FOXP3+E-cadherin- epithelial cells and their clinicopathological features. Our study uncovered a distinct subset of c-FOXP3+ tumor epithelial cells characterized by reduced E-cadherin expression. C-FOXP3+E-cadherin- cells displayed significant proliferation potential and pro-angiogenic effect through the expression of chemokines, including C-X-C motif ligand 1 (CXCL1), C-X-C motif ligand 5 (CXCL5), and C-X-C motif ligand 8 (CXCL8). Notably, higher counts of c-FOXP3+E-Cadherin- cells correlated with poorer prognosis, lower tumor differentiation, lymph node metastasis, and vascular invasion in pancreatic ductal adenocarcinoma (PDAC). In conclusion, this work revealed the stable expression of FOXP3 in tumor epithelial cells, marking a distinct subset. C-FOXP3+E-cadherin- epithelial cells exhibit active proliferation and promote angiogenesis in a vascular endothelial growth factor A (VEGFA) independent manner. These findings provide novel insights into PDAC prognosis and therapeutic avenues.NEW & NOTEWORTHY In this study, we revealed a novel c-FOXP3+ tumor epithelial cell subset marked by diminished E-cadherin and stable FOXP3 expression. These subpopulations not only show robust proliferation and drive angiogenesis via CXCL1, CXCL5, and CXCL8, bypassing VEGFA pathways, but their heightened presence also correlates with adverse PDAC outcomes. By challenging traditional epithelial cell definitions and extending lymphocyte markers to these cells, our findings present innovative targets for PDAC treatment and enrich our understanding of cell biology.
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Affiliation(s)
- Ruining Gong
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xianghan Chen
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiaoyuan Sun
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yuxing Zhang
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Jia Wang
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Qian Yu
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Ke Lei
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - He Ren
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
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Murakami D, Hijiya M, Iyo T, Hayata S, Ozaki T, Enomoto K, Kono M, Tamagawa S, Hotomi M. Case Report: Solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis. Front Oncol 2023; 13:1150002. [PMID: 38023212 PMCID: PMC10665479 DOI: 10.3389/fonc.2023.1150002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Turner syndrome is associated with an increased risk of developing several neoplasms. In particular, a clinical feature of Turner syndrome with chronic thyroiditis implies a relationship with thyroid malignancies. We report a very rare case of a solid variant of papillary thyroid carcinoma that was identified during a follow-up of chronic thyroiditis in a 22-year-old woman with Turner syndrome. The patient had no notable history of radiation exposure. No genetic mutations relating to the occurrence of the solid variant of papillary thyroid carcinoma, including RET/PTC rearrangements and mutations in the BRAF or RAS, were detected by a gene panel test, namely, the Oncomine™ Dx Target test. To the best of our knowledge, this is the first report of a solid variant of papillary thyroid carcinoma in a young adult with Turner syndrome with chronic thyroiditis. Our case suggests that in patients with Turner syndrome, there may be different pathogeneses from those previously reported, including exposure to radiation or known genetic mutations for the development of a solid variant of papillary thyroid carcinoma.
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Affiliation(s)
- Daichi Murakami
- Department of Otorhinolaryngology Head and Neck Surgery, Kinan Hospital, Wakayama, Japan
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Masayoshi Hijiya
- Department of Otorhinolaryngology Head and Neck Surgery, Kinan Hospital, Wakayama, Japan
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Takuro Iyo
- Department of Otorhinolaryngology Head and Neck Surgery, Kinan Hospital, Wakayama, Japan
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Sachiko Hayata
- Department of Otorhinolaryngology Head and Neck Surgery, Kinan Hospital, Wakayama, Japan
| | - Takashi Ozaki
- Department of Pathology and Clinical laboratory, Kinan Hospital, Wakayama, Japan
| | - Keisuke Enomoto
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Masamitsu Kono
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Shunji Tamagawa
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
| | - Muneki Hotomi
- Department of Otorhinolaryngology Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan
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Garcia-Becerra N, Aguila-Estrada MU, Palafox-Mariscal LA, Hernandez-Flores G, Aguilar-Lemarroy A, Jave-Suarez LF. FOXP3 Isoforms Expression in Cervical Cancer: Evidence about the Cancer-Related Properties of FOXP3Δ2Δ7 in Keratinocytes. Cancers (Basel) 2023; 15:cancers15020347. [PMID: 36672296 PMCID: PMC9856939 DOI: 10.3390/cancers15020347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune system to favor cell transformation. FOXP3, a critical transcription factor involved in the biology of regulatory T cells, has been detected as highly expressed in the tumor cells of CC patients. However, its biological role in CC, particularly in the keratinocytes, remained unclarified. Therefore, this work aimed to uncover the effect of FOXP3 on the biology of the tumoral cells. First, public databases were analyzed to identify the FOXP3 expression levels and the transcribed isoforms in CC and normal tissue samples. The study's findings demonstrated an increased expression of FOXP3 in HPV16+ CC samples. Additionally, the FOXP3Δ2 variant was detected as the most frequent splicing isoform in tumoral cells, with a high differential expression level in metastatic samples. However, the analysis of FOXP3 expression in different CC cell lines, HPV+ and HPV-, suggests no relationship between the presence of HPV and FOXP3 expression. Since the variant FOXP3Δ2Δ7 was found highly expressed in the HPV16+ SiHa cell line, a model with constitutive expression of FOXP3Δ2Δ7 was established to evaluate its role in proliferation, migration, and cell division. Finally, RNAseq was performed to identify differentially expressed genes and enriched pathways modulated by FOXP3Δ2Δ7. The exogenous expression of FOXP3Δ2Δ7 promotes cell division, proliferation, and migration. The transcriptomic analyses highlight the upregulation of multiple genes with protumor activities. Moreover, immunological and oncogenic pathways were detected as highly enriched. These data support the hypothesis that FOXP3Δ2Δ7 in epithelial cells induces cancer-related hallmarks and provides information about the molecular events triggered by this isoform, which could be important for developing CC.
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Affiliation(s)
- Natalia Garcia-Becerra
- Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Marco Ulises Aguila-Estrada
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Luis Arturo Palafox-Mariscal
- Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Georgina Hernandez-Flores
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
| | - Adriana Aguilar-Lemarroy
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
- Correspondence: (A.A.-L.); (L.F.J.-S.)
| | - Luis Felipe Jave-Suarez
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Mexico
- Correspondence: (A.A.-L.); (L.F.J.-S.)
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Long Q, Cui LK, He SB, Sun J, Chen QZ, Bao HD, Liang TY, Liang BY, Cui LY. Preparation, characteristics and cytotoxicity of green synthesized selenium nanoparticles using Paenibacillus motobuensis LY5201 isolated from the local specialty food of longevity area. Sci Rep 2023; 13:53. [PMID: 36593245 PMCID: PMC9807572 DOI: 10.1038/s41598-022-26396-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/14/2022] [Indexed: 01/03/2023] Open
Abstract
Selenium is an essential micronutrient element. For the extremely biotoxic of selenite, Selenium nanoparticles (SeNPs) is gaining increasing interest. In this work, a selenium-enriched strain with highly selenite-resistant (up to 173 mmol/L) was isolated from the local specialty food of longevity area and identified as Paenibacillus motobuensis (P. motobuensis) LY5201. Most of the SeNPs were accumulated extracellular. SeNPs were around spherical with a diameter of approximately 100 nm. The X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy showed that the purified SeNPs consisted of selenium and proteins. Our results suggested that P. motobuensis LY5201could be a suitable and robust biocatalyst for SeNPs synthesis. In addition, the cytotoxicity effect and the anti-invasive activity of SeNPs on the HepG2 showed an inhibitory effect on HepG2, indicating that SeNPs could be used as a potential anticancer drug.
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Affiliation(s)
- Qian Long
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
- Department of Clinical Laboratory, The Fourth People's Hospital of Nanning, Guangxi AIDS Clinical Treatment Center (Nanning), No. 1 Erli, Changgang Road, Nanning, 530023, Guangxi, People's Republic of China
| | - Lan-Kun Cui
- School of History and Archive, Yunnan University, Kunming, 650000, Yunnan, People's Republic of China
| | - Sheng-Bin He
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Jian Sun
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Quan-Zhi Chen
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Hao-Dong Bao
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Teng-Yue Liang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Bao-Yue Liang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Lan-Yu Cui
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Colleges and Universities, Key Laboratory of Biological Molecular Medicine Research, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China.
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Wang Y, Huang Y, Yang M, Yu Y, Chen X, Ma L, Xiao L, Liu C, Liu B, Yuan X. Comprehensive Pan-Cancer Analyses of Immunogenic Cell Death as a Biomarker in Predicting Prognosis and Therapeutic Response. Cancers (Basel) 2022; 14:cancers14235952. [PMID: 36497433 PMCID: PMC9736000 DOI: 10.3390/cancers14235952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/29/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Immunogenic cell death (ICD), a form of regulated cell death, is related to anticancer therapy. Due to the absence of widely accepted markers, characterizing ICD-related phenotypes across cancer types remained unexplored. Here, we defined the ICD score to delineate the ICD landscape across 33 cancerous types and 31 normal tissue types based on transcriptomic, proteomic and epigenetics data from multiple databases. We found that ICD score showed cancer type-specific association with genomic and immune features. Importantly, the ICD score had the potential to predict therapy response and patient prognosis in multiple cancer types. We also developed an ICD-related prognostic model by machine learning and cox regression analysis. Single-cell level analysis revealed intra-tumor ICD state heterogeneity and communication between ICD-based clusters of T cells and other immune cells in the tumor microenvironment in colon cancer. For the first time, we identified IGF2BP3 as a potential ICD regulator in colon cancer. In conclusion, our study provides a comprehensive framework for evaluating the relation between ICD and clinical relevance, gaining insights into identification of ICD as a potential cancer-related biomarker and therapeutic target.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Bo Liu
- Correspondence: (B.L.); (X.Y.)
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Alfaar AS, Stürzbecher L, Diedrichs-Möhring M, Lam M, Roubeix C, Ritter J, Schumann K, Annamalai B, Pompös IM, Rohrer B, Sennlaub F, Reichhart N, Wildner G, Strauß O. FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration. J Neuroinflammation 2022; 19:260. [PMID: 36273134 PMCID: PMC9588251 DOI: 10.1186/s12974-022-02620-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 10/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background Forkhead-Box-Protein P3 (FoxP3) is a transcription factor and marker of regulatory T cells, converting naive T cells into Tregs that can downregulate the effector function of other T cells. We previously detected the expression of FoxP3 in retinal pigment epithelial (RPE) cells, forming the outer blood–retina barrier of the immune privileged eye. Methods We investigated the expression, subcellular localization, and phosphorylation of FoxP3 in RPE cells in vivo and in vitro after treatment with various stressors including age, retinal laser burn, autoimmune inflammation, exposure to cigarette smoke, in addition of IL-1β and mechanical cell monolayer destruction. Eye tissue from humans, mouse models of retinal degeneration and rats, and ARPE-19, a human RPE cell line for in vitro experiments, underwent immunohistochemical, immunofluorescence staining, and PCR or immunoblot analysis to determine the intracellular localization and phosphorylation of FoxP3. Cytokine expression of stressed cultured RPE cells was investigated by multiplex bead analysis. Depletion of the FoxP3 gene was performed with CRISPR/Cas9 editing. Results RPE in vivo displayed increased nuclear FoxP3-expression with increases in age and inflammation, long-term exposure of mice to cigarette smoke, or after laser burn injury. The human RPE cell line ARPE-19 constitutively expressed nuclear FoxP3 under non-confluent culture conditions, representing a regulatory phenotype under chronic stress. Confluently grown cells expressed cytosolic FoxP3 that was translocated to the nucleus after treatment with IL-1β to imitate activated macrophages or after mechanical destruction of the monolayer. Moreover, with depletion of FoxP3, but not of a control gene, by CRISPR/Cas9 gene editing decreased stress resistance of RPE cells. Conclusion Our data suggest that FoxP3 is upregulated by age and under cellular stress and might be important for RPE function. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02620-w.
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Affiliation(s)
- Ahmad Samir Alfaar
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany.,Department of Ophthalmology, University Hospital of Ulm, 89075, Ulm, Germany
| | - Lucas Stürzbecher
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Maria Diedrichs-Möhring
- Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, 80336, Munich, Germany
| | - Marion Lam
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Christophe Roubeix
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Julia Ritter
- Institut Für Med. Mikrobiologie, Immunologie Und Hygiene, TU München, 81675, Munich, Germany
| | - Kathrin Schumann
- Institut Für Med. Mikrobiologie, Immunologie Und Hygiene, TU München, 81675, Munich, Germany
| | - Balasubramaniam Annamalai
- Department of Ophthalmology, College of Medicine, Medical University South Carolina, Charleston, SC, 29425, USA
| | - Inga-Marie Pompös
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Bärbel Rohrer
- Department of Ophthalmology, College of Medicine, Medical University South Carolina, Charleston, SC, 29425, USA
| | - Florian Sennlaub
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Nadine Reichhart
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Gerhild Wildner
- Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, 80336, Munich, Germany.
| | - Olaf Strauß
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany.
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11
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Wang Z, Meng L, Shan J, Pei L, Bao L, Li X, Lin Y, Gu X, Xu Z. To study the mechanism of Scutellariae Radix and Astragaloside in the treatment of lung cancer based on network pharmacology. Medicine (Baltimore) 2022; 101:e29729. [PMID: 35776995 PMCID: PMC9239597 DOI: 10.1097/md.0000000000029729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The aim of the study wasto explore the target and potential mechanism of Scutellariae Radix and Astragaloside in the treatment of lung cancer infection by network pharmacology. The target information of baicalein and flavonin was mined from CTD database and Swiss database. Genecards database, DRUGBANK database, and OMIM database were used to search for lung cancer related genes. The target protein network map (PPI) was drawn by using the STRING database analysis and Cytoscape3.7.1 software. With the help of Perl language, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene function analysis (GO) enrichment analysis were carried out by using the biological program package of R language. In total, 347 biological targets of Astragaloside and Scutellariae Radix were identified through the collection and analysis of multiple databases. In total, 1526 lung cancer targets were obtained from a multi-disease database. The "component-target" network of Astragaloside and Scutellariae Radix was constructed, and the protein interaction network (PPI) of the overlapping targets was analyzed to identify the key targets of drug-influenced diseases. In addition, KEGG pathway analysis and GO enrichment analysis were performed on the overlapping targets to explore the mechanism of Scutellariae Radix and Astragaloside in the treatment of lung cancer. Scutellariae Radix and Astragaloside have the characteristics of multi-component, multi-target and multi-pathway in the treatment of lung cancer, which provides a new idea and scientific basis for further research on the molecular mechanism of the antilung cancer effect of Scutellariae Radix and Astragaloside.
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Affiliation(s)
- Zijuan Wang
- Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Lingpeng Meng
- Intensive Care Unit, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Jingyi Shan
- Department of Gastroenterology, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Liangyu Pei
- Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Leri Bao
- Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Xi Li
- Department of Hematology, Longhua Hospital Shanghai University of TCM, Shanghai, China
| | - Yudong Lin
- Department of Neurology, Shanghai TCM-Integrated Hospital Shanghai University of TCM, Shanghai, China
| | - Xian Gu
- Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai, China
- *Correspondence: Xian Gu, Zhenye Xu, Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai 200032, China (e-mail: ;
| | - Zhenye Xu
- Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai, China
- *Correspondence: Xian Gu, Zhenye Xu, Department of Oncology, Longhua Hospital Shanghai University of TCM, Shanghai 200032, China (e-mail: ;
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12
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Liu Y, Ruan X, Li J, Wang B, Chen J, Wang X, Wang P, Tu X. The Osteocyte Stimulated by Wnt Agonist SKL2001 Is a Safe Osteogenic Niche Improving Bioactivities in a Polycaprolactone and Cell Integrated 3D Module. Cells 2022; 11:cells11050831. [PMID: 35269452 PMCID: PMC8909416 DOI: 10.3390/cells11050831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 02/05/2023] Open
Abstract
Finding and constructing an osteogenic microenvironment similar to natural bone tissue has always been a frontier topic in orthopedics. We found that osteocytes are targeting cells controlling bone anabolism produced by PTH (JBMR 2017, PMID: 27704638), and osteocytes with activated Wnt signaling orchestrate bone formation and resorption (PNAS 2015, PMID: 25605937). However, methods for taking advantage of the leading role of osteocytes in bone regeneration remain unexplored. Herein, we found that the osteocytes with SKL2001-activated Wnt signaling could be an osteogenic microenvironment (SOOME) which upregulates the expression of bone transcription factor Runx2 and Bglap and promotes the differentiation of bone marrow stromal cell ST2 into osteoblasts. Interestingly, 60 μM SKL2001 treatment of osteocytic MLO-Y4 for 24 h maintained Wnt signaling activation for three days after removal, which was sufficient to induce osteoblast differentiation. Triptonide, a Wnt inhibitor, could eliminate this differentiation. Moreover, on day 5, the Wnt signaling naturally decreased to the level of the control group, indicating that this method of Wnt-signaling induction is safe to use. We quickly verified in vivo function of SOOME to a good proximation in 3D bioprinted modules composed of reciprocally printed polycaprolactone bundles (for support) and cell bundles (for bioactivity). In the cell bundles, SOOME stably supported the growth and development of ST2 cells, the 7-day survival rate was as high as 91.6%, and proliferation ability increased linearly. Similarly, SOOME greatly promoted ST2 differentiation and mineralization for 28 days. In addition, SOOME upregulated the expression of angiopoietin 1, promoted endothelial cell migration and angiogenesis, and increased node number and total length of tubes and branches. Finally, we found that the function of SOOME could be realized through the paracrine pathway. This study reveals that osteocytes with Wnt signaling activated by SKL2001 are a safe osteogenic microenvironment. Both SOOME itself and its cell-free culture supernatant can improve bioactivity for osteoblast differentiation, with composite scaffolds especially bearing application value.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaolin Tu
- Correspondence: ; Tel.: +86-185-2382-0685
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13
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Sadaf, Akhter N, Alharbi RA, Sindi AAA, Najm MZ, Alhumaydhi FA, Khan MA, Deo SVS, Husain SA. Epigenetic Alteration and its Association With Downregulated FOXP3 Gene in Indian Breast Cancer Patients. Front Genet 2021; 12:781400. [PMID: 34938323 PMCID: PMC8686762 DOI: 10.3389/fgene.2021.781400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/26/2021] [Indexed: 12/05/2022] Open
Abstract
Background:FOXP3 gene, known to be a potential tumor suppressor, has been identified to interact with HER2 in mammary cancer. Moreover, the high expression of FOXP3 serves as a good predictor of the survival of patients in breast cancer, prostate cancer, and gastric cancer. The expression and epigenetic alterations were evaluated in female breast cancer patients. Material and Methods: Expression studies at the mRNA level and protein level were conducted in 140 breast cancer cases by real-time PCR and immunohistochemistry, respectively. Epigenetic studies were also conducted by analyzing the methylation status at the promoter region of the gene using MS-PCR. Results:FOXP3 mRNA expression and protein expression were downregulated in breast cancer patients. The absence of FOXP3 protein expression is significantly associated with promoter methylation, where 70 methylated cases exhibited protein loss (70/95, 73.6%). Statistically, we also found a significant correlation between FOXP3 protein expression and TNM stage, promoter methylation, and histological grade. The methylated FOXP3 cases that did not express protein were also significantly associated with positive lymph node metastasis and HER-2 status. Conclusion: The expression profile of FOXP3 may serve as a prognostic factor. In short, FOXP3 may stand in the most crucial list of biomarkers for breast cancer, bringing compelling results in terms of treatment and management of the disease.
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Affiliation(s)
- Sadaf
- Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Naseem Akhter
- Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Raed A Alharbi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Abdulmajeed A A Sindi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | | | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | | | - S V S Deo
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
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14
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Abd-Allah MYY, Abdel-Salam RA, Refat S. Immunohistochemical expression of FOXP3 in gastric carcinoma; its relation to Ki-67 proliferation marker, HER2/neu expression, and other clinicopathological parameters. J Immunoassay Immunochem 2021; 43:1959341. [PMID: 34806545 DOI: 10.1080/15321819.2021.1959341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Gastric cancer is common cancer in the world. Contradictory results regarding FOXP3 expression in gastric carcinoma were detected and the role of Ki-67 in prognosis is not completely understood. Furthermore, due to increasing use of anti-HER2 drug trastuzumab for gastric cancer, assessment of HER2 expression becomes important. This study tried to assess the FOXP3 expression in gastric carcinoma and to study the relation between its expression and Ki-67 and HER2/neu expression and relation between their expression and other clinicopathological variables. This retrospective study was carried out on 60 gastric adenocarcinoma cases. Tissue microarrays and immunohistochemical staining for FOXP3, Ki-67 and HER2/neu were done and then assessed and scored. HER2/neu expression showed significant relation to Lauren histological type and lymph node status. High Ki-67 index was related significantly to patients' age, lympho-vascular tumor emboli, peri-neural invasion, tumor grade, lymph node status, and cancer stage. There was significant relation between high FOXP3 expression and patients' age, lympho-vascular tumor emboli, peri-neural invasion, tumor grade, lymph node status, and cancer stage. Direct positive significant relationships between HER2/neu, Ki-67, and FOXP3 expression were noticed. Finally, high FOXP3 expression, positive HER2/neu, and high Ki-67 nuclear proliferation index may be an indication of the aggressiveness of gastric carcinoma.
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Affiliation(s)
- Mona Y Y Abd-Allah
- Associate Professor of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Assistant Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt
| | - Ramy Ahmed Abdel-Salam
- Associate Professor of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Assistant Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt
| | - Sherine Refat
- Associate Professor of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Assistant Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt.,Lecturer of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah Egypt
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15
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Huang Z, Liu F, Wang W, Ouyang S, Sang T, Huang Z, Liao L, Wu J. Deregulation of circ_003912 contributes to pathogenesis of erosive oral lichen planus by via sponging microRNA-123, -647 and -31 and upregulating FOXP3. Mol Med 2021; 27:132. [PMID: 34670484 PMCID: PMC8527710 DOI: 10.1186/s10020-021-00382-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 09/17/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The FOXP3/miR-146a/NF-κB axis was previously reported to modulate the induction and function of CD4+ Treg cells to alleviate oral lichen planus. Also, other signaling pathways including microRNA-155-IFN-γ loop and FOXP3/miR-146a/TRAF6 pathways were reported to be involved in the pathogenesis of oral lichen planus. In this study, we aimed to investigate the molecular mechanism underlying the pathogenesis of EOLP. METHOD CircRNA microarray was used to observe the expression of candidate circRNAs in CD4+ T-cells collected from different groups. Real-time PCR and Western blot were conducted to observe the changes in the expression of different miRNAs, mRNAs and proteins. Flow cytometry was performed to compare the counts of Treg cells in the HC and EOLP groups, and ELISA was performed to evaluate the changes in the expression of inflammatory cytokines. RESULT No obvious differences were seen between the HC and EOLP groups in terms of age and gender. Among all candidate circRNAs, the expression of circ_003912 was most dramatically elevated in CD4+ T-cells collected from the EOLP group. The levels of miR-1231, miR-31, miR-647, FOXP3 mRNA and miR-146a were decreased while the expression of TRAF6 mRNA was increased in CD4+ T-cells collected from the EOLP group. The count of Treg cells in the EOLP group was dramatically increased. The levels of inflammatory cytokines including IL-4 IFN-γ, IL-10 and IL-2 were influenced by the presence of circ_003912. In CD4+ T-cells in the EOLP group, the levels of IL-4 and IL-10 were decreased while the levels of IFN-γ and IL-2 were increased. The presence of miR-1231, miR-31 and miR-647 all obviously inhibited the expression of circ_003912, which was validated to sponge the expression of above miRNAs. Also, FOXP3 mRNA was proved to be targeted by miR-1231, miR-31 and miR-647. Transfection of circ_003912 up-regulated the expression of circ_003912, miR-146a and FOXP3 mRNA/protein while down-regulating the expression of miR-1231, miR-31, miR-647, and TRAF6 mRNA/protein. The levels of inflammatory cytokines including IL-4 IFN-γ, IL-10 and IL-2 as well as the speed of cell proliferation were influenced by circ_003912. CONCLUSION In this study, we investigated the molecular mechanisms underlying the pathogenesis of EOLP which involved the functioning of circ_003912. We first demonstrated that circ_003912 was up-regulated in CD4+ T-cells of the EOLP group. And miRNAs including miR-1231, miR-31 and miR-647 were sponged by circ_003912 and down-regulated in CD4+ T cells of the EOLP group, which subsequently up-regulated the expression of FOXP3 and miR-146a, and resulted in the inhibition of NF-kB.
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Affiliation(s)
- Zhen Huang
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Orthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
| | - Fen Liu
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Orthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
| | - Wenjuan Wang
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Orthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
| | - Shaobo Ouyang
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Oral Prosthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
| | - Ting Sang
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Orthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
| | - Zikun Huang
- Clinical Laboratory Center, the First Affiliated Hospital of Nanchang University, No.49 Fuzhou Road, Nanchang, 330006, Jiangxi, China.
| | - Lan Liao
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Oral Prosthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China.
| | - Jun Wu
- Jiangxi Provincial Key Laboratory of Oral Biomedicine, Department of Orthodontics, the Affiliated Stomatological Hospital of Nanchang University, Nanchang, 330006, China
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16
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Liu C, Han J, Li X, Huang T, Gao Y, Wang B, Zhang K, Wang S, Zhang W, Li W, Hao Q, Li M, Zhang Y, Zhang C. FOXP3 Inhibits the Metastasis of Breast Cancer by Downregulating the Expression of MTA1. Front Oncol 2021; 11:656190. [PMID: 34307133 PMCID: PMC8293273 DOI: 10.3389/fonc.2021.656190] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/16/2021] [Indexed: 12/09/2022] Open
Abstract
Background FOXP3, as a tumour suppressor gene, has a vital function in inhibiting the metastasis of breast cancer cells, but the mechanisms by which it inhibits metastasis have not been fully elucidated. This study intended to explore a new mechanism by which FOXP3 inhibits breast cancer metastasis. Methods Bioinformatic analysis was performed to identify potential downstream molecules of FOXP3. The function of FOXP3 in inhibiting MTA1 expression at the mRNA and protein levels was verified by real-time PCR and Western blot analysis. The interaction between FOXP3 and the MTA1 promoter was verified by transcriptomic experiments. In vitro and in vivo experiments were used to determine whether the regulation of MTA1 by FOXP3 affected the invasion and migration of breast cancer cells. Immunohistochemistry was adopted to explore the correlation between the expression levels of FOXP3 and MTA1 in breast cancer samples. Results Bioinformatics-based sequencing suggested that MTA1 is a potential downstream molecule of FOXP3. FOXP3 downregulated the expression of MTA1 in breast cancer cells by directly inhibiting MTA1 promoter activity. Importantly, FOXP3’s regulation of MTA1 affected the ability of breast cancer cells to invade and metastasize in vitro and in vivo. Moreover, analysis of clinical specimens showed a significant negative correlation between the expression levels of FOXP3 and MTA1 in breast cancer. Conclusion We systematically explored a new mechanism by which FOXP3 inhibits breast cancer metastasis via the FOXP3-MTA1 pathway.
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Affiliation(s)
- Chenlin Liu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Jun Han
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Xiaoju Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Tonglie Huang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Yuan Gao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Baolong Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
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Li C, Wang H, Fang H, He C, Pei Y, Gai X. FOXP3 facilitates the invasion and metastasis of non-small cell lung cancer cells through regulating VEGF, EMT and the Notch1/Hes1 pathway. Exp Ther Med 2021; 22:958. [PMID: 34335900 PMCID: PMC8290412 DOI: 10.3892/etm.2021.10390] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Forkhead box P3 (FOXP3) is a specific marker of regulatory T cells (Tregs) that is also expressed in tumour cells. Previous studies have revealed that FOXP3 can promote metastasis in several types of cancer, including non-small cell lung cancer (NSCLC); however, the underlying mechanism of FOXP3 remains unclear. The aim of the present study was to investigate the effect of FOXP3 on vascular endothelial growth factor (VEGF), epithelial-to-mesenchymal transition (EMT) and the Notch1/Hes1 pathway in NSCLC. After FOXP3 small interfering RNA (siRNAs) were transfected into A549 cells, the expression of FOXP3 mRNA and protein was determined by reverse transcription-quantitative PCR and western blotting. Cell migration and invasion were analyzed by Transwell assays. The concentrations of matrix metalloproteinase (MMP)-2, MMP-9 and VEGF in the cell supernatant were evaluated by ELISA. The expression of relevant proteins involved in EMT and Notch1/Hes1 pathway were assessed via western blotting. Additionally, the expression of FOXP3, CD31 and E-cadherin was detected by immunohistochemical (IHC) staining of 55 human NSCLC tissue samples. The results demonstrated that FOXP3 knockdown significantly inhibited the cell migratory and invasive abilities, decreased the concentrations of MMP-2, MMP-9 and VEGF, downregulated the protein expression of vimentin, N-cadherin, Notch1 and Hes family BHLH transcription factor 1 (Hes1), and upregulated the protein expression of E-cadherin. Furthermore, FOXP3 expression was positively associated with CD31+ vascular endothelial cells and negatively correlated with E-cadherin in NSCLC tissues. In addition, the Notch1/Hes1 pathway inhibitor DAPT significantly downregulated the expression of FOXP3 in a dose-dependent manner. Taken together, these findings demonstrated that FOXP3 may facilitate the invasive and migratory abilities of NSCLC cells via regulating the angiogenic factor VEGF, the EMT and the Notch1/Hes1 pathway.
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Affiliation(s)
- Chun Li
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Hefei Wang
- Department of Gynecology, The Third Affiliated Hospital of Xiang Ya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hui Fang
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China.,Department of Laboratory, Chifeng Clinical Medical School, Inner Mongolia Medical University, Chifeng, Inner Mongolia 024000, P.R. China
| | - Chengyuan He
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Yijie Pei
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
| | - Xiaodong Gai
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin, Jilin 132013, P.R. China
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18
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Yong F, Wang H, Li C, Jia H. Sevoflurane represses the migration and invasion of gastric cancer cells by regulating forkhead box protein 3. J Int Med Res 2021; 49:3000605211005936. [PMID: 33906525 PMCID: PMC8108091 DOI: 10.1177/03000605211005936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE Previous studies suggested that sevoflurane exerts anti-proliferative, anti-migratory, and anti-invasive effects on cancer cells. To determine the role of sevoflurane on gastric cancer (GC) progression, we evaluated its effects on the proliferation, migration, and invasion of SGC7901, AGS, and MGC803 GC cells. METHODS GC cells were exposed to different concentrations of sevoflurane (1.7, 3.4, or 5.1% v/v). Cell viability, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays. Immunohistochemical staining and immunoblotting were performed to analyze forkhead box protein 3 (FOXP3) protein expression in tissue specimens and cell lines, respectively. RESULTS FOXP3 was downregulated in human GC specimens and cell lines. Functionally, FOXP3 overexpression significantly inhibited the proliferation, migration, and invasion of GC cells and accelerated their apoptosis. Moreover, sevoflurane significantly blocked GC cell migration and invasion compared with the findings in the control group. However, FOXP3 silencing neutralized sevoflurane-induced apoptosis and the inhibition of GC cell migration and invasion. Sevoflurane-induced apoptosis and the suppression of migration and invasion might be associated with FOXP3 overactivation in GC cells. CONCLUSIONS Sevoflurane activated FOXP3 and prevented GC progression via inhibiting cell migration and invasion in vitro.
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Affiliation(s)
- Fangfang Yong
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Hemei Wang
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Chao Li
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Huiqun Jia
- Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
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Zhang Q, Zhou X, Wan M, Zeng X, Luo J, Xu Y, Ji L, Zhang JA, Fan P, Zhong J, Wu J. FoxP3-miR-150-5p/3p suppresses ovarian tumorigenesis via an IGF1R/IRS1 pathway feedback loop. Cell Death Dis 2021; 12:275. [PMID: 33723215 PMCID: PMC7961150 DOI: 10.1038/s41419-021-03554-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 12/24/2022]
Abstract
Ovarian cancer (OC) causes more deaths than any other gynecological cancer. Many cellular pathways have been elucidated to be associated with OC development and progression. Specifically, the insulin-like growth factor 1 receptor/insulin receptor substrate 1 (IGF1R/IRS1) pathway participates in OC development. Moreover, accumulating evidence has shown that microRNA deregulation contributes to tumor initiation and progression. Here, our study aimed to investigate the molecular functions and regulatory mechanisms of miR-150, specifically, in OC. We found that the expression of miR-150-5p/3p and their precursor, mir-150, was downregulated in OC tissues; lower mir-150 levels were associated with poor OC patient outcomes. Ectopic mir-150 expression inhibited OC cell growth and metastasis in vitro and in vivo. Furthermore, both IRS1 and IGF1R were confirmed as direct targets of miR-150-5p/3p, and the miR-150-IGF1R/IRS1 axis exerted antitumor effects via the PI3K/AKT/mTOR pathway. Forkhead box protein 3 (FoxP3) positively regulated the expression of miR-150-5p/3p by binding to the mir-150 promoter. In turn, the PI3K/AKT/mTOR pathway downregulated FoxP3 and miR-150-5p/3p. Taken together, these findings indicate that a complex FoxP3-miR-150-IGF1R/IRS1-PI3K/AKT/mTOR feedback loop regulates OC pathogenesis, providing a novel mechanism for miR-150 as a tumor suppressor miRNA in OC.
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Affiliation(s)
- Qinkai Zhang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Xunzhu Zhou
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Maoping Wan
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Xixi Zeng
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Jiarong Luo
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Yesha Xu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Liying Ji
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Jian-An Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Pei Fan
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
| | - Jianing Zhong
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, P.R. China.
| | - Jianmin Wu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
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Searching for Peptide Inhibitors of T Regulatory Cell Activity by Targeting Specific Domains of FOXP3 Transcription Factor. Biomedicines 2021; 9:biomedicines9020197. [PMID: 33671179 PMCID: PMC7922534 DOI: 10.3390/biomedicines9020197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/13/2021] [Accepted: 02/14/2021] [Indexed: 12/03/2022] Open
Abstract
(1) Background: The ability of cancer cells to evade the immune system is due in part to their capacity to induce and recruit T regulatory cells (Tregs) to the tumor microenvironment. Strategies proposed to improve antitumor immunity by depleting Tregs generally lack specificity and raise the possibility of autoimmunity. Therefore, we propose to control Tregs by their functional inactivation rather than depletion. Tregs are characterized by the expression of the Forkhead box protein 3 (FOXP3) transcription factor, which is considered their “master regulator”. Its interaction with DNA is assisted primarily by its interaction with other proteins in the so-called “Foxp3 interactome”, which elicits much of the characteristic Treg cell transcriptional signature. We speculated that the disruption of such a protein complex by using synthetic peptides able to bind Foxp3 might have an impact on the functionality of Treg cells and thus have a therapeutic potential in cancer treatment. (2) Methods: By using a phage-displayed peptide library, or short synthetic peptides encompassing Foxp3 fragments, or by studying the crystal structure of the Foxp3:NFAT complex, we have identified a series of peptides that are able to bind Foxp3 and inhibit Treg activity. (3) Results: We identified some peptides encompassing fragments of the leuzin zipper or the C terminal domain of Foxp3 with the capacity to inhibit Treg activity in vitro. The acetylation/amidation of linear peptides, head-to-tail cyclization, the incorporation of non-natural aminoacids, or the incorporation of cell-penetrating peptide motifs increased in some cases the Foxp3 binding capacity and Treg inhibitory activity of the identified peptides. Some of them have shown antitumoral activity in vivo. (4) Conclusions: Synthetic peptides constitute an alternative to inhibit Foxp3 protein–protein interactions intracellularly and impair Treg immunosuppressive activity. These peptides might be considered as potential hit compounds on the design of new immunotherapeutic approaches against cancer.
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21
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Zhang S, Feng R, Yuan F, Luo Q, Chen X, Li N, Yang S. The Therapeutic Effects of Dihydroartemisinin on Cisplatin-Resistant Gastric Cancer Cells. Curr Pharm Biotechnol 2021; 23:276-286. [PMID: 33596797 DOI: 10.2174/1389201022666210217114825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/26/2020] [Accepted: 01/05/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Dihydroartemisinin (DHA) exhibited anti-tumor effect in a variety of cancer cells but its mechanism of action is unclear. OBJECTIVE To investigate the therapeutic effects of DHA on Cisplatin (DDP)-resistant gastric cancer cell strain SGC7901/DDP and the possible molecular mechanism. METHODS Cells were treated with DHA in dose- and time-dependent manners, after which their proliferation, apoptosis, invasion and migration abilities were evaluated. We further evaluated autophagy with mRFP-GFP-LC3 adenovirus transfection and transmission electron microscopy, and also detected the expression levels of proteins (related to autophagy and apoptosis) via western blot. Meanwhile, the influence of DHA on cisplatin resistance was detected through a sensitization test and the evaluation of P-gp expression levels. RESULTS DHA effectively inhibited the proliferation, invasion, and migration of SGC7901/DDP cells and induced cell apoptosis which was accompanied by caspase-8/9/3 activation. Furthermore, exposure of DHA resulted in a pronounced increase in autophagy proteins including Beclin-1 and LC3 II with PI3K/AKT/mTOR pathway inhibition. Additionally, enhancement of cisplatin sensitivity occurred in SGC7901/DDP cells treated with DHA, which was accompanied by P-gp downregulation. CONCLUSION DHA exerts an anti-cancer effect on SGC7901/DDP cells and the mechanisms possibly include enhancement of autophagy via PI3K/AKT/mTOR inhibition, inducement of apoptosis through caspase-dependent and mitochondrial pathway, and enhancement of cisplatin sensitivity through P-gp inhibition.
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Affiliation(s)
- Suyun Zhang
- Departments of Oncology, Fujian Medical University Union Hospital, Fujian Medical University Fuzhou, Fujian. China
| | - Rui Feng
- Departments of Oncology, Fujian Medical University Union Hospital, Fujian Medical University Fuzhou, Fujian. China
| | - Fang Yuan
- Departments of Respiratory Medicine, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian. China
| | - Qiong Luo
- Departments of Oncology, Fujian Medical University Union Hospital, Fujian Medical University Fuzhou, Fujian. China
| | - Xiangqi Chen
- Departments of Respiratory Medicine, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian. China
| | - Nan Li
- Departments of Chinese Medicine, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian. China
| | - Sheng Yang
- Departments of Oncology, Fujian Medical University Union Hospital, Fujian Medical University Fuzhou, Fujian. China
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Inhibition of long non-coding RNA XIST upregulates microRNA-149-3p to repress ovarian cancer cell progression. Cell Death Dis 2021; 12:145. [PMID: 33542185 PMCID: PMC7862378 DOI: 10.1038/s41419-020-03358-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 01/02/2023]
Abstract
Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in human diseases. We aimed to clarify the role of lncRNA X-inactive specific transcript (XIST)/miR-149-3p/forkhead box P3 (FOXP3) axis in ovarian cancer (OC) cell growth. XIST, miR-149-3p and FOXP3 expression in OC tissues and cell lines was assessed, and the predictive role of XIST in prognosis of OC patients was analyzed. The OC cell lines were screened and accordingly treated with silenced/overexpressed XIST plasmid or miR-149-3p mimic/inhibitor, and then the proliferation, invasion, migration, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Effect of altered XIST and miR-149-3p on tumor growth in vivo was observed. Online website prediction and dual luciferase reporter gene were implemented to detect the targeting relationship of lncRNA XIST, miR-149-3p, and FOXP3. XIST and FOXP3 were upregulated, whereas miR-149-3p was downregulated in OC tissues and cells. High XIST expression indicated a poor prognosis of OC. Inhibition of XIST or elevation of miR-149-3p repressed proliferation, invasion, migration, and colony formation ability, and promoted apoptosis and cell cycle arrest of HO-8910 cells. In SKOV3 cells upon treatment of overexpressed XIST or reduction of miR-149-3p, there exhibited an opposite tendency. Based on online website prediction, dual luciferase reporter gene, and RNA pull-down assays, we found that there was a negative relationship between XIST and miR-149-3p, and miR-149-3p downregulated FOXP3 expression. This study highlights that knockdown of XIST elevates miR-149-3p expression to suppress malignant behaviors of OC cells, thereby inhibiting OC development.
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23
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Zhang L, Li Q, Xu J, Sun G, Xu Z. Cimetidine promotes STUB1-mediated degradation of tumoral FOXP3 by activating PI3K-Akt pathway in gastric cancer. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1304. [PMID: 33209884 PMCID: PMC7661906 DOI: 10.21037/atm-20-6070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Previous studies have confirmed the antitumor effects of cimetidine, while the therapeutic targets and the mechanisms are not yet fully understood. We previously reported the protumoral role of endogenous FOXP3 in gastric cancer (GC), but whether cimetidine plays an antitumor role by targeting FOXP3 is still unknown. Methods A series of assays were used to examine the role of cimetidine on the malignant behaviors and the expression of endogenous FOXP3 in GC cells. The role of cimetidine on ligase E3-STUB1and the role of STUB1 on FOXP3 level were examined, with the signaling pathway involved in these processes also being explored. Results Cimetidine inhibited the malignant behaviors of GC cells, and led to the ubiquitination/degradation of FOXP3. Moreover, cimetidine promoted STUB1 expression, STUB1 knockdown rescued the decline of FOXP3 in cimetidine-treated GC cells, and reduced the turnover effect of cimetidine on GC cells, but had minimal effect in untreated cells. Immunoprecipitation (IP) assay confirmed the formation of the STUB1-FOXP3 complex in cimetidine-treated GC cells. Furthermore, Cimetidine promoted STUB1 expression by activating PI3K/Akt pathway, and the inhibition of PI3K/Akt pathway rescued the decline of FOXP3 by suppressing the upregulation of STUB1. Conclusions Cimetidine suppressed GC development by promoting STUB1-mediated ubiquitination/degradation of endogenous FOXP3 through the activation of the PI3K/Akt pathway.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qingya Li
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianghao Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guangli Sun
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
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24
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Ding H, Fan GL, Yi YX, Zhang W, Xiong XX, Mahgoub OK. Prognostic Implications of Immune-Related Genes' (IRGs) Signature Models in Cervical Cancer and Endometrial Cancer. Front Genet 2020; 11:725. [PMID: 32793281 PMCID: PMC7385326 DOI: 10.3389/fgene.2020.00725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/15/2020] [Indexed: 01/30/2023] Open
Abstract
Cervical cancer and endometrial cancer remain serious threats to women's health. Even though some patients can be treated with surgery plus chemoradiotherapy as a conventional option, the overall efficacy is deemed unsatisfactory. As such, the development for new treatment approaches is truly necessary. In recent years, immunotherapy has been widely used in clinical practice and it is an area of great interest that researchers are keeping attention on. However, a thorough immune-related genes (IRGs) study for cervical cancer and endometrial cancer is still lacking. We therefore aim to make a comprehensive evaluation of IRGs through bioinformatics and large databases, and also investigate the relationship between the two types of cancer. We reviewed the transcriptome RNAs of IRGs and clinical data based on the TCGA database. Survival-associated IRGs in cervical/endometrial cancer were identified using univariable and multivariable Cox proportional-hazard regression analysis for developing an IRG signature model to evaluate the risk of patients. In the end, this model was validated based on the enrichment analyses through GO, KEGG, and GSEA pathways, Kaplan-Meier survival curve, ROC curves, and immune cell infiltration. Our results showed that out of 25/23 survival-associated IRGs for cervical/endometrial cancer, 13/12 warranted further examination by multivariate Cox proportional-hazard regression analysis and were selected to develop an IRGs signature model. As a result, enrichment analyses for high-risk groups indicated main enriched pathways were associated with tumor development and progression, and statistical differences were found between high-risk and low-risk groups as shown by Kaplan-Meier survival curve. This model could be used as an independent measure for risk assessment and was considered relevant to immune cell infiltration, but it had nothing to do with clinicopathological characteristics. In summary, based on comprehensive analysis, we obtained the IRGs signature model in cervical cancer (LTA, TFRC, TYK2, DLL4, CSK, JUND, NFATC4, SBDS, FLT1, IL17RD, IL3RA, SDC1, PLAU) and endometrial cancer (LTA, PSMC4, KAL1, TNF, SBDS, HDGF, LTB, HTR3E, NR2F1, NR3C1, PGR, CBLC), which can effectively evaluate the prognosis and risk of patients and provide justification in immunology for further researches.
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Affiliation(s)
- Hao Ding
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Guan-Lan Fan
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yue-Xiong Yi
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Zhang
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiao-Xing Xiong
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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Wang Z, Zhang J. FOXP3 promotes colorectal carcinoma liver metastases by evaluating MMP9 expression via regulating S-adenosylmethionine metabolism. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:592. [PMID: 32566619 PMCID: PMC7290543 DOI: 10.21037/atm-20-3287] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Growing evidence has proved that Forkhead box protein 3 (FOXP3), which is a master regulatory gene in the development and function of regulatory T-cells, is expressed in human cancer cells. This expression indicates the crucial role FOXP3 takes up as the disease progresses. However, its role in colorectal cancer (CRC) liver metastasis is still mostly unknown. This study set out to explore the molecular characteristics of FOXP3 in driving the liver metastasis within CRC. Methods We downloaded the RNA-seq data from the GSE50760. Weighted gene co-expression network analysis (WGCNA)WGCNA and RNA-Seq analysis were applied to find the key gene network associated with colorectal cancer liver metastasis. Then we performed pathway enrichment analysis on liver metastasis-associated gene set. Immunohistochemistry, in vitro and in vivo studies were conducted to test expression and function of FOXP3 in CRC tissues and liver metastasis tissues. Non-targeted metabolomics analysis was performed to identify the alteration of FOXP3 expression in metabolites of colorectal cancer liver metastasis. Western blot was performed to confirm changes of matrix metalloproteinase 9MMP9 expression were downstream events of S-adenosyl-methionine (SAM). Results We found that FOXP3 and MMP9 exhibited co-expression relationships and affected liver metastasis in CRC. Upregulation of FOXP3 promotes cell migration and invasion in CRC, which suggests a pro-cancer effect. Moreover, metabolomics analysis showed that knockdown of FOXP3 significantly reduced SAM levels, and changes of MMP9 expression were downstream events of SAM, which is concentration-dependent. Besides, The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Western blot analysis confirmed that overexpression of FOXP3 activates the Wnt pathway to promote colon cancer metastasis. Conclusions Our results altogether suggested that FOXP3 expression inhibited the SAM cycle to reduce SAMe levels, resulting in altered MMP9 expression and helped CRC liver metastasis.
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Affiliation(s)
- Zhe Wang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China
| | - Jingdong Zhang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China
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Ren J, Liu Y, Wang S, Wang Y, Li W, Chen S, Cui D, Yang S, Li MY, Feng B, Lai PBS, Chen GG. The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3. J Biol Chem 2020; 295:5484-5495. [PMID: 32198183 PMCID: PMC7170510 DOI: 10.1074/jbc.ra120.012518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/12/2020] [Indexed: 01/16/2023] Open
Abstract
The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.
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Affiliation(s)
- Jianwei Ren
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute (SZRI), Chinese University of Hong Kong, Shenzhen 518057, China
| | - Yi Liu
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Shanshan Wang
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yu Wang
- Division of Cellular & Molecular Research, National Cancer Centre, Singapore 169610
| | - Wende Li
- Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, China
| | - Siyu Chen
- Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, China
| | - Dexuan Cui
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Shengli Yang
- Union Hospital Tumour Center, Wuhan 430022, China
| | - Ming-Yue Li
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510320, China
| | - Bo Feng
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Paul B S Lai
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China.
| | - George G Chen
- Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute (SZRI), Chinese University of Hong Kong, Shenzhen 518057, China; Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China; Department of Otorhinolaryngology, Head and Neck Surgery, Chinese University of Hong Kong, Hong Kong, China.
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FOXP3 rs2280883 polymorphism confers susceptibility to colorectal cancer in a Chinese Han population. Gene X 2020; 734:144395. [DOI: 10.1016/j.gene.2020.144395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
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The Communication Between the PI3K/AKT/mTOR Pathway and Y-box Binding Protein-1 in Gynecological Cancer. Cancers (Basel) 2020; 12:cancers12010205. [PMID: 31947591 PMCID: PMC7017275 DOI: 10.3390/cancers12010205] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/04/2020] [Accepted: 01/10/2020] [Indexed: 12/19/2022] Open
Abstract
Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.
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Interleukin-10 production by B cells is regulated by cytokines, but independently of GATA-3 or FoxP3 expression. Cell Immunol 2020; 347:103987. [DOI: 10.1016/j.cellimm.2019.103987] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/21/2019] [Accepted: 09/12/2019] [Indexed: 02/07/2023]
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Downregulation of FOXP3 in neutrophils by IL-8 promotes the progression of oral squamous cell carcinoma. Oncol Lett 2019; 18:4771-4777. [PMID: 31611987 PMCID: PMC6781744 DOI: 10.3892/ol.2019.10828] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 07/03/2019] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to investigate the effects of the transcription factor forkhead box P3 (FOXP3) in neutrophils on the progression of oral squamous cell carcinoma (OSCC). Cancer tissue samples and paracarcinoma tissues were collected from 23 patients with OSCC for the current study. In addition, SCC-9, a human tongue carcinoma cell line, was co-cultured with primary human neutrophils and treated with recombinant interleukin 8 (IL-8). The effect of FOXP3 on the proliferation of SCC-9 cells was analyzed using a Cell Counting Kit 8 assay. FOXP3 expression in neutrophils was analyzed by quantitative PCR following IL-8 treatment. FOXP3 protein expression in neutrophils and the amount of IL-8 protein in the OSCC tumor microenvironment were determined by immunofluorescence analysis. The present study demonstrated that IL-8 downregulated FOXP3 mRNA expression in neutrophils. Neutrophils and peptide P60, a specific inhibitor of FOXP3, increased proliferation of SCC-9 cells. In patients with OSCC, FOXP3 protein expression in neutrophils of the stage IV group was significantly lower compared with that of the stage II and stage III groups, while IL-8 protein expression was higher in cancer tissues compared with that in paracarcinoma tissues. In summary, IL-8 in the tumor microenvironment may recruit neutrophils, and downregulation of FOXP3 in neutrophils by IL-8 may promote the progression of OSCC.
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Jia H, Qi H, Gong Z, Yang S, Ren J, Liu Y, Li MY, Chen GG. The expression of FOXP3 and its role in human cancers. Biochim Biophys Acta Rev Cancer 2019; 1871:170-178. [PMID: 30630091 DOI: 10.1016/j.bbcan.2018.12.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/28/2018] [Accepted: 12/10/2018] [Indexed: 01/11/2023]
Abstract
FOXP3 is a transcription factor, which belongs to the family of FOX protein. FOXP3 was initially discovered in regulatory T cells and supposed to play a significant role in the process of regulatory T cell differentiation. Increasing evidence has shown that FOXP3 is also expressed in tumor cells. However, the results of tumor FOXP3 is inconsistent and even the opposite. In some types of human cancers, the expression of FOXP3 is upregulated, and it can promote the development of cancers, leading to a poor prognosis. While in some other types of cancers, it is a different story. The reason for the contradictory data is unknown. The discovery of FOXP3 isoforms, interaction between tumor cells and lymphocytes in the tumor microenvironment, subcellular location, and mutation of FOXP3 may provide some clues. In this review, we first summarize and analyze the recent development. The final section focuses on the regulation of FOXP3 expression.
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Affiliation(s)
- Hao Jia
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - Haolong Qi
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - Zhongqin Gong
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - Shucai Yang
- Department of Clinical Laboratory, Pingshan District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Jianwei Ren
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - Yi Liu
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - Ming-Yue Li
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
| | - George Gong Chen
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China.
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MicroRNA-340 inhibits squamous cell carcinoma cell proliferation, migration and invasion by downregulating RhoA. J Dermatol Sci 2018; 92:197-206. [PMID: 30262127 DOI: 10.1016/j.jdermsci.2018.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 08/23/2018] [Accepted: 09/04/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND MicroRNAs are reported to play an important role in tumor growth and metastasis, including squamous cell carcinoma (SCC). Accumulative evidence has revealed that dysregulated miR-340 expression contributed to the carcinogenesis and development of various cancers. OBJECTIVE The aim of the current study was to investigate the role and the underlying mechanism of miR-340 in SCC cell proliferation, migration and invasion. METHODS Quantitative real-time PCR was performed to examine the expression of miR-340 in SCC tissues and cell lines. The function of miR-340 in SCC was investigated through Cell Counting Kit-8, wound healing, transwell migration and invasion assays. Bioinformatics analysis, luciferase reporter assay, western blotting and immunohistochemical analysis were conducted to predict and confirm the target gene of miR-340. RESULTS In the present study, we first found that miR-340 was significantly decreased in both SCC tissues and cell lines. Moreover, ectopic expression of miR-340 remarkably attenuated SCC cell proliferation, migration and invasion, whereas inhibition of endogenous miR-340 promoted SCC cell proliferation, migration and invasion in vitro. Our subsequent bioinformatics analysis and luciferase reporter assay showed that RhoA was a novel direct target of miR-340 in SCC cells, and the knockdown of RhoA expression rescued the effects of miR-340 inhibition on SCC cell proliferation, migration and invasion. More importantly, the expression of RhoA and miR-340 was negatively correlated in SCC tissues. CONCLUSION Our findings demonstrate the tumor suppressor role of miR-340 in SCC by directly regulating RhoA. Therefore, restoration of miR-340 expression can be a potential therapeutic approach for SCC treatment.
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Yonekura S, Itoh M, Shiratori E, Ohtaka M, Tohda S. FOXP3 knockdown inhibits the proliferation and reduces NOTCH1 expression of T cell acute lymphoblastic leukemia cells. BMC Res Notes 2018; 11:582. [PMID: 30103821 PMCID: PMC6090594 DOI: 10.1186/s13104-018-3700-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/09/2018] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling. RESULTS Two T-ALL cell lines Jurkat and KOPT-K1, harboring activating NOTCH1 mutations, were transfected with small interfering RNA against FOXP3. Cell growth was assessed with a colorimetric assay and morphology was observed under a microscope. FOXP3 knockdown significantly reduced cell growth and induced morphological changes suggesting apoptosis. Quantitative polymerase chain reaction revealed that FOXP3 knockdown caused the downregulation of mRNA expression of NOTCH1 and HES1. These findings suggest that FOXP3 supports the growth of T-ALL cells although this can not be generalized because we examined only two cell lines. The observed growth suppression can be partly due to the downregulation of NOTCH1 signaling. FOXP3 may be a potential therapeutic target in T-ALL.
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Affiliation(s)
- Satoru Yonekura
- Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Mai Itoh
- Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Erika Shiratori
- Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Mika Ohtaka
- Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Shuji Tohda
- Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan.
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Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples. NPJ Genom Med 2018; 3:14. [PMID: 29928512 PMCID: PMC5998068 DOI: 10.1038/s41525-018-0054-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 05/01/2018] [Accepted: 05/10/2018] [Indexed: 12/20/2022] Open
Abstract
Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n = 135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival. This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome. A new genetic test could help predict responses to therapy and survival outcomes among cancer patients with tumors that are infiltrated with large numbers of regulatory T cells (Tregs). Kevin B. Givechian of NantOmics in Los Angeles, California, USA, and colleagues measured gene activity levels in tumor samples taken from 135 patients with Treg-enriched cancers of all kinds. They singled out genes with particularly variable expression levels to create a 32-gene signature that revealed two distinct clusters of patients: those who responded to their prescribed drugs and lived longer, and those who were treatment-resistant and died sooner. The researchers also validated the gene panel in a larger, independent cohort of 626 tumor samples, showing that it could identify patients with immunogenic tumors who are more likely have favorable clinical outcomes.
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Skarmoutsou E, Bevelacqua V, D' Amico F, Russo A, Spandidos DA, Scalisi A, Malaponte G, Guarneri C. FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma. Int J Mol Med 2018; 42:392-404. [PMID: 29620159 PMCID: PMC5979787 DOI: 10.3892/ijmm.2018.3618] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/04/2018] [Indexed: 12/18/2022] Open
Abstract
Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.
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Affiliation(s)
- Eva Skarmoutsou
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Valentina Bevelacqua
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Fabio D' Amico
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Angela Russo
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP‑Catania, 95100 Catania, Italy
| | - Grazia Malaponte
- Research Unit of the Catania Section of the Italian League Against Cancer, 95122 Catania, Italy
| | - Claudio Guarneri
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, 98122 Messina, Italy
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Abstract
FOXP3 is the lineage-defining transcription factor of CD4+ CD25+ regulatory T cells. While many aspects of its regulation, interaction, and function are conserved among species, alternatively spliced FOXP3 isoforms are expressed only in human cells. This review summarizes current knowledge about alternative splicing of FOXP3 and the specific functions of FOXP3 isoforms in health and disease. Future perspectives in research and the therapeutic potential of manipulating alternative splicing of FOXP3 are discussed.
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Affiliation(s)
- Reiner K W Mailer
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Cardiovascular Medicine Unit, Department of Medicine, Karolinska Insititutet, Stockholm, Sweden
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Tang J, Yang Z, Wang Z, Li Z, Li H, Yin J, Deng M, Zhu W, Zeng C. Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World J Surg Oncol 2017; 15:173. [PMID: 28923073 PMCID: PMC5604510 DOI: 10.1186/s12957-017-1221-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 08/07/2017] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Recent observations revealed Foxp3 participated in the development of cervical cancer. Furthermore, Foxp3 has a vital function in the lymphatic metastasis of cervical cancer. However, it is unclear whether Foxp3 is correlated with lymphangiogenesis of cervical cancer. METHODS In this experiment, expression of Foxp3 and VEGF-C was detected in 50 cervical cancer samples by immunohistochemistry. In addition, we evaluated the association between Foxp3 and VEGF-C expression and lymphangiogenesis of cervical cancer evaluated by lymphatic vessel density. RESULTS These data demonstrate Foxp3 is positively correlated with VEGF-C expression. Furthermore, Foxp3 is associated with lymphangiogenesis of cervical cancer. CONCLUSIONS These results revealed Foxp3 play an important role in lymphangiogenesis of cervical cancer. TRIAL REGISTRATION Gunagdong Medical University, PJ2013049.
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Affiliation(s)
- Jiabu Tang
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Zheng Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 74, Guangzhou, 510080, China
| | - Zhuo Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 74, Guangzhou, 510080, China
| | - Zhen Li
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Hongmei Li
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Jinbao Yin
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China
| | - Min Deng
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, 510095, China.
| | - Wei Zhu
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China.
| | - Chao Zeng
- Department of Pathology, Guangdong Medical University, 1 Xincheng Road, Dongguan, 523808, China.
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Shi JY, Ma LJ, Zhang JW, Duan M, Ding ZB, Yang LX, Cao Y, Zhou J, Fan J, Zhang X, Zhao YJ, Wang XY, Gao Q. FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway. BMC Cancer 2017; 17:648. [PMID: 28903735 PMCID: PMC5598072 DOI: 10.1186/s12885-017-3633-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 08/28/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND FOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in human hepatocellular carcinoma (HCC). METHODS Expression profile of FOXP3 was analyzed using real-time RT-PCR, western blotting and immunofluorescence on HCC cell lines, and immunostaing of a tissue microarray containing of 240 primary HCC samples. The potential regulatory roles of FOXP3 were dissected by an integrated approach, combining biochemical assays, analysis of patient survival, genetic manipulation of HCC cell lines, mouse xenograft tumor models and chromatin immunoprecipitation (ChIP) sequencing. RESULTS FOXP3 was constitutively expressed in HCC cells with the existence of splice variants (especially exon 3 and 4 deleted, Δ3,4-FOXP3). High expression of FOXP3 significantly correlated with low serum α-fetoprotein (AFP) level, absence of vascular invasion and early TNM stage. Survival analyses revealed that increased FOXP3 expression was significantly associated with better survival and reduced recurrence, and served as an independent prognosticator for HCC patients. Furthermore, FOXP3 could potently suppress the proliferation and invasion of HCC cells in vitro and reduce tumor growth in vivo. However, Δ3,4-FOXP3 showed a significant reduction in the tumor-inhibiting effect. The inhibition of FOXP3 on HCC aggressiveness was acted probably by enhancing the TGF-β/Smad2/3 signaling pathway. CONCLUSION Our findings suggest that FOXP3 suppresses tumor progression in HCC via TGF-β/Smad2/3 signaling pathway, highlighting the role of FOXP3 as a prognostic factor and novel target for an optimal therapy against this fatal malignancy.
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Affiliation(s)
- Jie-Yi Shi
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Li-Jie Ma
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Ji-Wei Zhang
- Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
| | - Meng Duan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Zhen-Bin Ding
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Liu-Xiao Yang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan People’s Republic of China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
- Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
- Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Ying-Jun Zhao
- Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China
| | - Xiao-Ying Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, Shanghai, 200032 People’s Republic of China
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Won KY, Kim GY, Kim HK, Choi SI, Kim SH, Bae GE, Lim JU, Lim SJ. Tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma: the tumor suppressor function of tumoral FOXP3 is related with the P21 expression in gastric adenocarcinoma. Hum Pathol 2017; 68:112-118. [PMID: 28882702 DOI: 10.1016/j.humpath.2017.08.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 08/17/2017] [Accepted: 08/25/2017] [Indexed: 12/15/2022]
Abstract
The function and contribution of tumoral FOXP3 in gastric cancer development remain poorly understood. Thus, we studied the expression of tumoral FOXP3 and its relationship with the well-known tumor suppressor proteins P21 and P53 in gastric adenocarcinoma. The tissue microarray was constructed from 182 cases of gastric adenocarcinoma. The immunohistochemistry was performed on 4-μm tissue sections from each tissue microarray block. We found that positive tumoral FOXP3 expression was significantly correlated with a lower T category, a lower N category, a lower recurrence rate, and less lymphatic invasion. Furthermore, the survival analysis revealed that the tumoral FOXP3-positive group had significantly increased overall survival and disease-free survival rates compared with the tumoral FOXP3-negative group. Additionally, P21 expression showed a significant positive correlation with tumoral FOXP3 expression in gastric adenocarcinoma cells. Taken together, these findings demonstrate that tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma through increased expression of the tumor suppression protein P21.
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Affiliation(s)
- Kyu Yeoun Won
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Gou Young Kim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Hyung Kyung Kim
- Department of Pathology, Graduate School, Kyung Hee University, Seoul, 02453, Republic of Korea
| | - Sung Il Choi
- Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Sang Hyun Kim
- Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea
| | - Go Eun Bae
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 21431, Republic of Korea
| | - Jun Uk Lim
- Department of Gastroenterology, Sejong General Hospital, Bucheon, 14754, Republic of Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, 05278, Republic of Korea.
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Characterization and Purification of Bergamottin from Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou and Its Antiproliferative Activity and Effect on Glucose Consumption in HepG2 cells. Molecules 2017; 22:molecules22071227. [PMID: 28726768 PMCID: PMC6152415 DOI: 10.3390/molecules22071227] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 07/18/2017] [Accepted: 07/19/2017] [Indexed: 12/26/2022] Open
Abstract
Bergamottin is a natural furanocoumarin compound with weak polarity. Characterization and quantification of bergamottin were carried out in different fruit tissues of various citrus cultivars. Among the four citrus tissues tested, i.e., flavedo, albedo, segment membrane (SM), and juice sacs (JS) in eight citrus cultivars, the highest bergamottin content was found in the flavedo of Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou (YJZXY, 666.54 μg·g−1 DW). A combination of silica gel column chromatography and high-speed counter-current chromatography (HSCCC) was established to efficiently purify bergamottin from the flavedo of YJZXY. Bergamottin showed significant antiproliferative activity on three cancer cell lines, i.e., human liver cancer HepG2, promyelocytic leukemia HL-60, and gastric cancer BGC-823 cells, which showed a marked inhibition effect on these cell lines in a dose-dependent manner. In addition, bergamottin significantly increased glucose consumption in HepG2 cells also in a dose-dependent manner, which is the first report of its potential in anti-diabetes applications.
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41
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Yang S, Liu Y, Li MY, Ng CSH, Yang SL, Wang S, Zou C, Dong Y, Du J, Long X, Liu LZ, Wan IYP, Mok T, Underwood MJ, Chen GG. FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer. Mol Cancer 2017; 16:124. [PMID: 28716029 PMCID: PMC5514503 DOI: 10.1186/s12943-017-0700-1] [Citation(s) in RCA: 301] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
Background The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). Methods One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. Results NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. Conclusions FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0700-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shucai Yang
- Department of Clinical Laboratory, Pingshan District People's Hospital Of Shenzhen, Shenzhen, China.,Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Yi Liu
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.,Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Ming-Yue Li
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.,Shenzhen Research Institute, the Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Calvin S H Ng
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Sheng-Li Yang
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.,Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shanshan Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Chang Zou
- Clinical Research Centre, Shenzhen People's Hospital, the Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Yujuan Dong
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Jing Du
- Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Xiang Long
- Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Li-Zhong Liu
- Faculty of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Innes Y P Wan
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Tony Mok
- Department of Clinical Oncology, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - Malcolm J Underwood
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China
| | - George G Chen
- Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China. .,Shenzhen Research Institute, the Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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42
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Chen YJ, Liu WH, Chang LS. Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells. Arch Toxicol 2017; 91:983-997. [PMID: 27307158 DOI: 10.1007/s00204-016-1753-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/08/2016] [Indexed: 12/17/2022]
Abstract
Hydroquinone (1,4-benzenediol; HQ), a major marrow metabolite of the leukemogen benzene, has been proven to evoke benzene-related hematological disorders and myelotoxicity in vitro and in vivo. The goal of the present study was to explore the role of FOXP3 in HQ-induced malignant progression of U937 human leukemia cells. U937 cells were treated with 5 μM HQ for 24 h, and the cells were re-suspended in serum-containing medium without HQ for 2 days. The same procedure was repeated three times, and the resulting U937/HQ cells were maintained in cultured medium containing 5 μM HQ. Proliferation and colony formation of U937/HQ cells were notably higher than those of U937 cells. Ten-eleven translocation methylcytosine dioxygenase-mediated demethylation of the Treg-specific demethylated region in FOXP3 gene resulted in higher FOXP3 expression in U937/HQ cells than in U937 cells. FOXP3-induced miR-183 expression reduced β-TrCP mRNA stability and suppressed β-TrCP-mediated Sp1 degradation, leading to up-regulation of Sp1 expression in U937/HQ cells. Sp1 up-regulation further increased ADAM17 and Lyn expression, and ADAM17 up-regulation stimulated Lyn activation in U937/HQ cells. Moreover, U937/HQ cells showed higher Lyn-mediated Akt activation and cytoplasmic p21 expression than U937 cells did. Abolishment of Akt activation decreased cytoplasmic p21 expression in U937/HQ cells. Suppression of FOXP3, ADAM17, and Lyn expression, as well as Akt inactivation, repressed proliferation and clonogenicity of U937/HQ cells. Together with the finding that cytoplasmic p21 shows anti-apoptotic and oncogenic activities in cancer cells, the present data suggest a role of FOXP3/ADAM17/Lyn/Akt/p21 signaling axis in HQ-induced hematological disorders.
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Affiliation(s)
- Ying-Jung Chen
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Wen-Hsin Liu
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Long-Sen Chang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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43
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Sun Z, Zhang B, Wang C, Fu T, Li L, Wu Q, Cai Y, Wang J. Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway. Cancer Sci 2017; 108:61-72. [PMID: 27862679 PMCID: PMC5276829 DOI: 10.1111/cas.13118] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 11/03/2016] [Accepted: 11/05/2016] [Indexed: 12/25/2022] Open
Abstract
Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real‐time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase‐activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial–mesenchymal transition markers E‐cadherin and N‐cadherin, which is important given that epithelial–mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.
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Affiliation(s)
- Zhen Sun
- The Graduate School, Tianjin Medical University, Tianjin, China
| | - Biao Zhang
- Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Chen Wang
- Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Tao Fu
- The Graduate School, Tianjin Medical University, Tianjin, China
| | - Lianling Li
- The Graduate School, Tianjin Medical University, Tianjin, China
| | - Qiaoli Wu
- Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Ying Cai
- Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Jinhuan Wang
- Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China
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44
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45
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Zhang H, Prado K, Zhang KX, Peek EM, Lee J, Wang X, Huang J, Li G, Pellegrini M, Chin AI. Biased Expression of the FOXP3Δ3 Isoform in Aggressive Bladder Cancer Mediates Differentiation and Cisplatin Chemotherapy Resistance. Clin Cancer Res 2016; 22:5349-5361. [PMID: 27189164 DOI: 10.1158/1078-0432.ccr-15-2581] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 05/11/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE The transcriptional regulation mediating cancer cell differentiation into distinct molecular subtypes and modulating sensitivity to existing treatments is an enticing therapeutic target. Our objective was to characterize the ability of the forkhead/winged transcription factor FOXP3 to modulate the differentiation of bladder cancer. EXPERIMENTAL DESIGN Expression of FOXP3 was analyzed by immunohistochemistry in a tumor microarray of 587 samples and overall survival in a subset of 187 patients following radical cystectomy. Functional assays were performed in SW780 and HT1376 cell lines in vitro and in vivo and gene expression profiling performed by RNA-Seq. Validation was undertaken using gene expression profiles of 131 patients from The Cancer Genome Atlas (TCGA) consortium in bladder cancer. RESULTS FOXP3 expression correlates with bladder cancer stage and inversely with overall survival, with biased expression of the FOXP3Δ3 isoform. Functional assays of FOXP3Δ3 demonstrated resistance to chemotherapy in vitro, whereas subcutaneous xenografts overexpressing FOXP3Δ3 developed larger and more poorly differentiated bladder cancers. RNA expression profiling revealed a unique FOXP3Δ3 gene signature supporting a role in chemotherapy resistance. Accordingly, knockdown of Foxp3 by siRNA in HT1376 cells conferred sensitivity to cisplatin- and gemcitabine-induced cytotoxicity. Validation in TCGA dataset demonstrated increased expression of FOXP3 in subtypes II to IV and skewing of molecular subtypes based on FOXP3Δ3-specific gene expression. CONCLUSIONS (i) Biased expression of the FOXP3Δ3 isoform in bladder cancer inversely correlates with overall survival, (ii) FOXP3Δ3 induces a unique gene program that mediates cancer differentiation, and (iii) FOXP3Δ3 may augment chemotherapy resistance. Clin Cancer Res; 22(21); 5349-61. ©2016 AACR.
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Affiliation(s)
- Hanwei Zhang
- Department of Urology, UCLA, Los Angeles, California.,Broad Stem Cell Research Center, UCLA, Los Angeles, California
| | - Kris Prado
- Department of Urology, UCLA, Los Angeles, California
| | - Kelvin X Zhang
- Department of Biological Chemistry, UCLA, Los Angeles, California
| | | | - Jane Lee
- Department of Urology, UCLA, Los Angeles, California
| | - Xiaoyan Wang
- Department of Biostatistics, UCLA, Los Angeles, California
| | - Jiaoti Huang
- Department of Pathology, UCLA, Los Angeles, California
| | - Gang Li
- Department of Biostatistics, UCLA, Los Angeles, California.,Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
| | - Matteo Pellegrini
- Broad Stem Cell Research Center, UCLA, Los Angeles, California.,Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California.,Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, California
| | - Arnold I Chin
- Department of Urology, UCLA, Los Angeles, California. .,Broad Stem Cell Research Center, UCLA, Los Angeles, California.,Molecular Biology Institute, UCLA, Los Angeles, California.,Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
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46
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Wang YW, Zhang JH, Yu Y, Yu J, Huang L. Inhibition of Store-Operated Calcium Entry Protects Endothelial Progenitor Cells from H2O2-Induced Apoptosis. Biomol Ther (Seoul) 2016; 24:371-9. [PMID: 27169819 PMCID: PMC4930280 DOI: 10.4062/biomolther.2015.130] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 11/09/2015] [Accepted: 11/17/2015] [Indexed: 01/09/2023] Open
Abstract
Store-operated calcium entry (SOCE), a major mode of extracellular calcium entry, plays roles in a variety of cell activities. Accumulating evidence indicates that the intracellular calcium ion concentration and calcium signaling are critical for the responses induced by oxidative stress. The present study was designed to investigate the potential effect of SOCE inhibition on H2O2-induced apoptosis in endothelial progenitor cells (EPCs), which are the predominant cells involved in endothelial repair. The results showed that H2O2-induced EPC apoptosis was reversed by SOCE inhibition induced either using the SOCE antagonist ML-9 or via silencing of stromal interaction molecule 1 (STIM1), a component of SOCE. Furthermore, SOCE inhibition repressed the increases in intracellular reactive oxygen species (ROS) levels and endoplasmic reticulum (ER) stress and ameliorated the mitochondrial dysfunction caused by H2O2. Our findings provide evidence that SOCE inhibition exerts a protective effect on EPCs in response to oxidative stress induced by H2O2 and may serve as a potential therapeutic strategy against vascular endothelial injury.
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Affiliation(s)
- Yan-Wei Wang
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Ji-Hang Zhang
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Yang Yu
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Jie Yu
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China
| | - Lan Huang
- Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China
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Overexpression of the transcription factor FOXP3 in lung adenocarcinoma sustains malignant character by promoting G1/S transition gene CCND1. Tumour Biol 2015; 37:7395-404. [DOI: 10.1007/s13277-015-4616-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/08/2015] [Indexed: 02/07/2023] Open
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48
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Effects of soluble and particulate Cr(VI) on genome-wide DNA methylation in human B lymphoblastoid cells. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2015; 792:12-8. [PMID: 26433257 DOI: 10.1016/j.mrgentox.2015.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 08/06/2015] [Accepted: 08/11/2015] [Indexed: 12/15/2022]
Abstract
Several previous studies highlighted the potential epigenetic effects of Cr(VI), especially DNA methylation. However, few studies have compared the effects of Cr(VI) on DNA methylation profiles between soluble and particulate chromate in vitro. Accordingly, Illumina Infinium Human Methylation 450K BeadChip array was used to analyze DNA methylation profiles of human B lymphoblastoid cells exposed to potassium dichromate or lead chromate, and the cell viability was also studied. Array based DNA methylation analysis showed that the impacts of Cr(VI) on DNA methylation were limited, only about 40 differentially methylated CpG sites, with an overlap of 15CpG sites, were induced by both potassium dichromate and lead chromate. The results of mRNA expression showed that after Cr(VI) treatment, mRNA expression changes of four genes (TBL1Y, FZD5, IKZF2, and KIAA1949) were consistent with their DNA methylation alteration, but DNA methylation changes of other six genes did not correlate with mRNA expression. In conclusion, both of soluble and particulate Cr(VI) could induce a small amount of differentially methylated sites in human B lymphoblastoid cells, and the correlations between DNA methylation changes and mRNA expression varied between different genes.
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49
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Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion. Tumour Biol 2015; 36:9611-9. [PMID: 26142732 DOI: 10.1007/s13277-015-3701-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/22/2015] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern with a high morbidity and mortality rate worldwide. However, the mechanism underlying hepatocarcinogenesis remains unclear. Forkhead box P2 (FOXP2) has been implicated in various human cancer types. However, the role of FOXP2 in HCC remains unknown. Western blot and immunohistochemistry were used to measure the expression of FOXP2 protein in HCC and adjacent normal tissues in 50 patients. Wound healing and transwell assays were used to determine the cell invasion ability. We showed that the level of FOXP2 was significantly reduced in HCC compared with the adjacent non-tumorous tissue. There was statistical significance between the expression of FOXP2 and vein invasion (P = 0.017), number of tumor nodes (P = 0.028), and AFP (P = 0.033). Low expression of FOXP2 correlated with poor survival. Moreover, wound healing and transwell assays showed that FOXP2 could decrease cell invasion and affect the expression of vimentin and E-cadherin. Our results suggested that FOXP2 expression was downregulated in HCC tumor tissues, and reduced FOXP2 expression was associated with poor overall survival. In addition, downregulation of FOXP2 significantly enhanced cell invasiveness. These findings uncover that FOXP2 might be a new prognostic factor and be closely correlated with HCC cell invasion.
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50
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PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget 2015; 5:8466-77. [PMID: 25193865 PMCID: PMC4226697 DOI: 10.18632/oncotarget.2327] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
c-Myc serves as a crucial regulator in multiple cellular events. Cumulative evidences demonstrate that anomalous c-Myc overexpression correlates with proliferation, invasion and metastasis in various human tumors. However, the transcriptionally activating mechanisms responsible for c-Myc overexpression are complex and continue to be intangible. Here we showed that Piwi-Like RNA-Mediated Gene Silencing 2 (PIWIL2) can upregulate c-Myc via binding with NME/NM23 nucleoside diphosphate kinase 2 (NME2). PIWIL2 promotes c-Myc transcription by interacting with and facilitating NME2 to bind to G4-motif region within c-Myc promoter. Interestingly, in a c-Myc-mediated manner, PIWIL2 upregulates RhoA, which in turn induces filamentary F-actin. Deficiency of PIWIL2 results in obstacle for c-Myc expression, cell cycle progress and cell proliferation. Taken together, our present work demonstrates that PIWIL2 modulates tumor cell proliferation and F-actin filaments via promoting c-Myc expression.
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