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Tian H, Chu X, Guan Q, Liu J, Liu Y. Hypotaurine promotes glioma cell invasion by hypermethylating the Wnt5a promoter. PLoS One 2025; 20:e0312055. [PMID: 40373156 PMCID: PMC12080842 DOI: 10.1371/journal.pone.0312055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 04/09/2025] [Indexed: 05/17/2025] Open
Abstract
Glioma is a particularly lethal central nervous system tumor. Identifying the boundary between gliomas and normal tissues is difficult due to their infiltrative and invasive growth characteristics. This can result in the inevitable recurrence of the tumor after surgery. Preventing the residual tumor from growing or spreading is a major obstacle in treating gliomas. An earlier study suggested that hypotaurine could enhance the invasion of glioma cells while inhibiting the activity of demethylases. The hypotaurine synthesis-deficient U251 cell line usage showed a decrease in the cells' invasion capability. Analysis of gene expression profiles showed that reducing the activity of a critical enzyme in hypotaurine production, 2-aminoethanethiol dioxygenase (ADO), had a notable effect on the extracellular matrix-receptor interaction. Decreased intracellular ADO expression led to a significant increase in Wnt5a expression. Cells exposed to hypotaurine exhibited decreased levels of both intracellular Wnt5a protein and its corresponding mRNA. The observed characteristic was linked to increased methylation of the Wnt5a gene promoter, possibly due to hypotaurine's ability to inhibit demethylase enzymes. To sum up, the research showed that U251 cells lacking hypotaurine synthesis were susceptible to epigenetic changes, and Wnt5a seemed to function as a cancer inhibitor in this scenario. It would be beneficial to reevaluate this tumor suppressive effect in real tumor samples, which may contribute to the development of new glioma interference strategies.
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Affiliation(s)
- Hong Tian
- Department of Oncology, The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, P. R. China
| | - Xiaoli Chu
- Department of Oncology, The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, P. R. China
| | - Qi Guan
- Department of Oncology, The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, P. R. China
| | - Juan Liu
- Department of Oncology, The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, P. R. China
| | - Ying Liu
- Department of Oncology, The 4th People’s Hospital of Shenyang, China Medical University, Shenyang, P. R. China
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Harada A, Yasumizu Y, Harada T, Fumoto K, Sato A, Maehara N, Sada R, Matsumoto S, Nishina T, Takeda K, Morii E, Kayama H, Kikuchi A. Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression. Nat Commun 2025; 16:3653. [PMID: 40246836 PMCID: PMC12006413 DOI: 10.1038/s41467-025-58748-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 03/31/2025] [Indexed: 04/19/2025] Open
Abstract
Wnt5a, a representative Wnt ligand that activates the β-catenin-independent pathway, has been shown to promote tumorigenesis. However, it is unclear where Wnt5a is produced and how it affects colon cancer aggressiveness. In this study, we demonstrate that Wnt5a is expressed in fibroblasts near the luminal side of the tumor, and its depletion suppresses mouse colon cancer formation. To characterize the specific fibroblast subtype, a meta-analysis of human and mouse colon fibroblast single-cell RNA-seq data is performed. The results show that Wnt5a is expressed in hypoxia-induced inflammatory fibroblast (InfFib), accompanied by the activation of HIF2. Moreover, Wnt5a maintains InfFib through the suppression of angiogenesis mediated by soluble VEGF receptor1 (Flt1) secretion from endothelial cells, thereby inducing further hypoxia. InfFib also produces epiregulin, which promotes colon cancer growth. Here, we show that Wnt5a acts on endothelial cells, inducing a hypoxic environment that maintains InfFib, thereby contributing to colon cancer progression through InfFib.
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Affiliation(s)
- Akikazu Harada
- Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Suita, Osaka, Japan.
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan.
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
| | - Yoshiaki Yasumizu
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan
- Laboratory of Experimental Immunology, WPI Frontier Immunology Research Center, The University of Osaka, Suita, Osaka, Japan
| | - Takeshi Harada
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Katsumi Fumoto
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Akira Sato
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Natsumi Maehara
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Ryota Sada
- Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Shinji Matsumoto
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Takashi Nishina
- Department of Biochemistry, Faculty of Medicine, Toho University, Ota-ku, Tokyo, Japan
| | - Kiyoshi Takeda
- Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan
- Laboratory of Mucosal Immunology, WPI Frontier Immunology Research Center, The University of Osaka, Suita, Osaka, Japan
- Department of Microbiology and Immunology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
| | - Hisako Kayama
- Laboratory of Mucosal Immunology, WPI Frontier Immunology Research Center, The University of Osaka, Suita, Osaka, Japan
- Department of Microbiology and Immunology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan
- Institute for Advanced Co-Creation Studies, The University of Osaka, Suita, Osaka, Japan
| | - Akira Kikuchi
- Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Suita, Osaka, Japan.
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan.
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
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Pereira P, Panier J, Nater M, Herbst M, Calvanese AL, Köksal H, Castañón H, Cecconi V, Tallón de Lara P, Pascolo S, van den Broek M. Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy. Cell Rep 2025; 44:115388. [PMID: 40023846 DOI: 10.1016/j.celrep.2025.115388] [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: 08/05/2024] [Revised: 12/06/2024] [Accepted: 02/11/2025] [Indexed: 03/04/2025] Open
Abstract
Metastases arise from disseminated cancer cells (DCCs) that detach from the primary tumor and seed distant organs. There, quiescent DCCs can survive for an extended time, a state referred to as metastatic dormancy. The mechanisms governing the induction, maintenance, and awakening from metastatic dormancy are unclear. We show that the differentiation of dormancy-inducing CD8+ T cells requires CD4+ T cell help and that interferon (IFN)γ directly induces dormancy in DCCs. The maintenance of metastatic dormancy, however, is independent of T cells. Instead, awakening from dormancy requires an inflammatory signal, and we identified CD4+ T cell-derived interleukin (IL)-17A as an essential wake-up signal for dormant DCCs in the lungs. Thus, the induction of and awakening from metastatic dormancy require an external stimulus, while the maintenance of dormancy does not rely on continuous surveillance by lymphocytes.
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Affiliation(s)
- Paulo Pereira
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Joshua Panier
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Marc Nater
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Michael Herbst
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | | | - Hakan Köksal
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Héctor Castañón
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Virginia Cecconi
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | | | - Steve Pascolo
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Maries van den Broek
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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4
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Hong Z, Wang D, Qiao X, Xie Y, Yang S, Hao K, Han C, Liu H, Liu Z. Wnt5a negatively regulates melanogenesis in primary Arctic fox epidermal melanocytes. Gene 2025; 934:149045. [PMID: 39461575 DOI: 10.1016/j.gene.2024.149045] [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: 07/12/2024] [Revised: 09/16/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Abstract
Melanocytes, which are mainly found in the epidermis, are responsible for the melanin of skin and hair, and thereby contribute to the appearance of skin and provide protection from damage by ultraviolet radiation. Our previous study revealed that the Wnt5a, one of the many genes that affect melanin production, might be involved in the coat color seasonal change of the Arctic fox by influencing skin melanogenesis. Although the role of Wnt5a in melanocyte lines and melanoma cells has been extensively studied, its role in primary epidermal melanocytes has not been explored. This study aimed to investigate the role and mechanism of the Wnt5a in influencing melanogenesis in Arctic fox primary epidermal melanocytes. We constructed the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout plasmid targeting exons of the Wnt5a and transfected it into primary epidermal melanocytes. The results of the amplification knockout region assay, RT-qPCR assay, and western blot assay showed the success of Wnt5a knockout. RT-qPCR assay and melanin content assay showed that melanin production in melanocytes was significantly increased after Wnt5a knockout, and melanin-related key genes, such as microphthalmia-associated transcription factor, tyrosinase and tyrosinase-related protein 1, were significantly elevated. In addition, we also found that the expression of the β-catenin gene of the Wnt canonical pathway was significantly elevated after Wnt5a knockout. In conclusion, our results indicate that the Wnt5a plays a negative regulatory role in melanogenesis in primary epidermal melanocytes, and is presumably involved in antagonizing or inhibiting canonical Wnt signaling.
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Affiliation(s)
- Zhilin Hong
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Dongxian Wang
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Xian Qiao
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Yuchun Xie
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Shanshan Yang
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Kexing Hao
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Cong Han
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Huayun Liu
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Zhengzhu Liu
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China.
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Iluta S, Nistor M, Buruiana S, Dima D. Wnt Signaling Pathway in Tumor Biology. Genes (Basel) 2024; 15:1597. [PMID: 39766864 PMCID: PMC11675244 DOI: 10.3390/genes15121597] [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: 10/30/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Relapse and metastasis are the major challenges that stand in the way of cancer healing and survival, mainly attributed to cancer stem cells (CSCs). Their capabilities of self-renewal and tumorigenic potential leads to treatment resistance development. CSCs function through signaling pathways such as the Wnt/β-catenin cascade. While commonly involved in embryogenesis and adult tissues homeostasis, the dysregulation of the Wnt pathway has direct correlations with tumorigenesis, metastasis, and drug resistance. The development of therapies that target CSCs and bulk tumors is both crucial and urgent. However, the extensive crosstalk present between Wnt and other signaling networks (Hedgehog and Notch) complicates the development of efficient long-term therapies with minimal side-effects on normal tissues. Despite the obstacles, the emergence of Wnt inhibitors and subsequent modulation of the signaling pathways would provide dynamic therapeutic approaches to impairing CSCs and reversing resistance mechanisms.
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Affiliation(s)
- Sabina Iluta
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania;
| | - Madalina Nistor
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj Napoca, Romania
| | - Sanda Buruiana
- Department of Hematology, Nicolae Testemitanu University of Medicine and Pharmacy, 2004 Chisinau, Moldova;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 400015 Cluj Napoca, Romania
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Abdallah MM, Yahia M, Tagelsir Ahmed Y, Alfaki M. WNT5A in Cancer: A Pan-Cancer Analysis Revealing Its Diagnostic and Prognostic Biomarker Potential. Cureus 2024; 16:e65190. [PMID: 39176352 PMCID: PMC11340256 DOI: 10.7759/cureus.65190] [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] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND AND OBJECTIVE The wingless-related integration site family (WNT) signaling pathway is critical for tumor progression and development. It is associated with various neoplasms produced by WNT pathway deregulation; WNT5A, a member of the WNT family, has been linked to carcinogenesis, exhibiting either oncogenic or tumor-suppressive effects. The study investigates how the gene affects certain types of cancer. The study aimed to evaluate the potential prognostic significance of WNT5A genes as diagnostic biomarkers for various types of cancer. METHODOLOGY We investigated WNT5A gene expression in a pan-cancer analysis using various bioinformatics databases, including GEPIA (Gene Expression Profiling Interactive Analysis), TIMER2 (Tumor Immune Estimation Resource, Version 2), the University of Alabama at Birmingham Cancer Data Analysis Portal UACLAN databases, the Kaplan-Meier (K-M) plotter, cBioPortal, and Gene Set Cancer Analysis (GSCA). We aimed to gain insight into the expression of WNT5A in various tumors and its relationship with immune infiltration, overall survival, and genetic changes. Public datasets validated WNT5A expression in lung squamous cell carcinoma (LUSC) and stomach adenocarcinoma (STAD) samples. RESULTS WNT5A pan-cancer analysis was highly expressed in two cancer types, including STAD and LUSC. Additionally, TIMER results showed a positive association of WNT5A with immune cell infiltration in LUSC and STAD. Survival analysis indicated that LUSC cancer exhibits better overall survival, while STAD has lower overall survival levels, which means a poor prognosis in the STAD cancer type. Furthermore, mutation analysis revealed that the WNT5A gene was mutated in 1.4% of cases, with most alterations being deletions followed by amplifications. CONCLUSIONS The WNT5A gene's high expression in many malignancies, including LUSC and STAD, suggests it could be used as a diagnostic biomarker. This study shows a relationship between WNT5A expression and immune cell abundance in LUSC and STAD. Our pan-cancer analysis of this gene is the first of its type, and it will inform future research, comprehensive investigation, and wet lab experiments.
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Affiliation(s)
| | - Mawada Yahia
- Medical Laboratory Science/Medical Microbiology, University of Khartoum, Khartoum, SDN
| | - Yousra Tagelsir Ahmed
- Microbiology, Faculty of Medical Laboratory Science, Alzaiem Alazhari University, Khartoum, SDN
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7
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Strope AM, Phillips C, Khadgi S, Jenkinson SA, Coschigano KT, Malgor R. Differential expression of WNT5A long and short isoforms in non-muscle-invasive bladder urothelial carcinoma. Histol Histopathol 2024; 39:715-727. [PMID: 38445662 DOI: 10.14670/hh-18-723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Wnt ligands belong to a family of secreted glycoproteins in which binding to a range of receptors/co-receptors activates several intracellular pathways. WNT5A, a member of the Wnt family, is classified as a non-canonical Wnt whose activation triggers planar cell polarity (PCP) and Ca+2 downstream pathways. Aberrant expression of WNT5A has been shown to play both protective and harmful roles in an array of conditions, such as inflammatory disease and cancer. In the present study, using histological, immunohistochemical, and molecular methods, we investigated the expression of two isoforms of WNT5A, WNT5A-Short (WNT5A-S) and WNT5A-Long (WNT5A-L) in bladder urothelial carcinoma (UC). Three UC cell lines (RT4, J82, and T24), as well as a normal urothelial cell line, and formalin-fixed, paraffin-embedded (FFPE) transurethral resection (TUR) tissue samples from 17 patients diagnosed with UC were included in the study. WNT5A-L was the predominantly expressed isoform in urothelial cells, although WNT5A-S was also detectable. Further, although no statistically significant difference was found between the percentage of WNT5A-S transcripts in low-grade versus high-grade tumors, we did find a difference between the percentage of WNT5A-S transcripts found in non-invasion versus invasion of the lamina propria, subgroups of non-muscle-invasive tumors. In conclusion, both WNT5A-S and WNT5A-L isoforms are expressed in UC, and the percentage of their expression levels suggests that a higher proportion of WNT5A-S transcription may be associated with lamina propria invasion, a process preceding muscle invasion.
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Affiliation(s)
- Amy M Strope
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Cody Phillips
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Sabin Khadgi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Scott A Jenkinson
- OhioHealth O'Bleness Laboratory Services, O'Bleness Hospital, Athens, Ohio, USA
| | - Karen T Coschigano
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
| | - Ramiro Malgor
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
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Wang C, Li Y, Miao X, Wang Y, Yang G. Knockdown of LRP5 Promotes Proliferation and Invasion of Tongue Squamous Cell Carcinoma through Compensatory Activation of Akt Signaling. J Cancer 2024; 15:3215-3226. [PMID: 38706907 PMCID: PMC11064261 DOI: 10.7150/jca.93585] [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: 12/25/2023] [Accepted: 04/03/2024] [Indexed: 05/07/2024] Open
Abstract
The role of LRP5, a critical receptor in the Wnt signaling pathway, remains unexplored in tongue squamous cell carcinoma (TSCC). This study investigates the impact of LRP5 knockdown on the biological behaviors of TSCC cell lines both in vitro and in vivo. Our findings indicate that LRP5 knockdown significantly enhances cell proliferation, migration, and invasion in CAL27 and SCC25 cell lines. RNA-seq analysis reveals compensatory activation of the Akt pathway, with 119 genes significantly upregulated post-LRP5 knockdown. Elevated MMP1 expression suggests its potential involvement in TSCC progression. Western blot analysis demonstrates increased Akt phosphorylation, upregulated proliferation-related PCNA, and downregulated apoptosis-related caspase-3 after LRP5 knockdown. Down-regulation of E-cadherin and β-Catenin, proteins associated with cell adhesion and invasion, further elucidates the molecular mechanism underlying increased cell migration and invasion. Our study concludes that compensatory Akt pathway activation is essential for the LRP5 knockdown-induced migration and proliferation of CAL27 and SCC25 cells. These results highlight LRP5 as a potential therapeutic target for TSCC. Simultaneous inhibition of Wnt and Akt signaling emerges as a promising approach for TSCC treatment.
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Affiliation(s)
| | | | | | | | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Diseases of Zhejiang Province, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China
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Meagher M, Krause H, Elliott A, Farrell A, Antonarakis ES, Bastos B, Heath EI, Jamieson C, Stewart TF, Bagrodia A, Nabhan C, Oberley M, McKay RR, Salmasi A. Characterization and impact of non-canonical WNT signaling on outcomes of urothelial carcinoma. Cancer Med 2024; 13:e7148. [PMID: 38558536 PMCID: PMC10983807 DOI: 10.1002/cam4.7148] [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: 01/11/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Non-canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non-canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. METHODS NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and RESULTS WNT5A pathway gene expression varied significantly between primary versus metastatic sites: WNT5A (25.2 vs. 16.8 TPM), FZD2 (3.2 vs. 4.05), ROR1 (1.7 vs. 2.1), and ROR2 (2.4 vs. 2.6) p < 0.05 for all. Comparison of high- and low-expression subgroups revealed variation in the prevalence of TP53, FGFR3, and RB1 pathogenic mutations, as well as increasing T cell-inflamed scores as expression of the target gene increased. High gene expression for ROR2 (HR 1.31, 95% CI 1.15-1.50, p < 0.001) and FZD2 (HR 1.16, 95% CI 1.02-1.32, p = 0.024) was associated with worse OS. CONCLUSION Distinct genomic and immune landscapes for the four investigated WNT5A pathway components were observed in patients with UC. External validation studies are needed.
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Affiliation(s)
- Margaret Meagher
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
| | | | | | | | | | - Bruno Bastos
- Miami Cancer InstituteMiamiFloridaUSA
- Karmanos Cancer Institute, Department of OncologyWayne State University School of MedicineDetroitMichiganUSA
| | - Elisabeth I. Heath
- Department of MedicineUC San Diego School of MedicineLa JollaCaliforniaUSA
| | - Christina Jamieson
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
| | - Tyler F. Stewart
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
| | - Aditya Bagrodia
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
| | | | | | - Rana R. McKay
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
- Barbara Ann Karmanos Cancer InstituteDetroitUSA
| | - Amirali Salmasi
- Department of UrologyUC San Diego School of MedicineLa JollaCaliforniaUSA
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10
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Tulkens D, Boelens M, Naert T, Carron M, Demuynck S, Dewaele S, Van Isterdael G, Creytens D, Pieters T, Goossens S, Van Vlierberghe P, Vleminckx K. Mutations in the histone methyltransferase Ezh2 drive context-dependent leukemia in Xenopus tropicalis. Leukemia 2023; 37:2404-2413. [PMID: 37794102 DOI: 10.1038/s41375-023-02052-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/06/2023]
Abstract
CRISPR-mediated simultaneous targeting of candidate tumor suppressor genes in Xenopus tropicalis allows fast functional assessment of co-driver genes for various solid tumors. Genotyping of tumors that emerge in the mosaic mutant animals rapidly exposes the gene mutations under positive selection for tumor establishment. However, applying this simple approach to the blood lineage has not been attempted. Multiple hematologic malignancies have mutations in EZH2, encoding the catalytic subunit of the Polycomb Repressive Complex 2. Interestingly, EZH2 can act as an oncogene or a tumor suppressor, depending on cellular context and disease stage. We show here that mosaic CRISPR/Cas9 mediated ezh2 disruption in the blood lineage resulted in early and penetrant acute myeloid leukemia (AML) induction. While animals were co-targeted with an sgRNA that induces notch1 gain-of-function mutations, sequencing of leukemias revealed positive selection towards biallelic ezh2 mutations regardless of notch1 mutational status. Co-targeting dnm2, recurrently mutated in T/ETP-ALL, induced a switch from myeloid towards acute T-cell leukemia. Both myeloid and T-cell leukemias engrafted in immunocompromised hosts. These data underline the potential of Xenopus tropicalis for modeling human leukemia, where mosaic gene disruption, combined with deep amplicon sequencing of the targeted genomic regions, can rapidly and efficiently expose co-operating driver gene mutations.
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Affiliation(s)
- Dieter Tulkens
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Marthe Boelens
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Thomas Naert
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Marjolein Carron
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Suzan Demuynck
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Sylviane Dewaele
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- VIB Center for Inflammation Research, Ghent, Belgium
| | - Gert Van Isterdael
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium
| | - David Creytens
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Tim Pieters
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Center for Medical Genetics, Ghent University, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Steven Goossens
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Pieter Van Vlierberghe
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Center for Medical Genetics, Ghent University, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Kris Vleminckx
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
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11
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Stevenson MJ, Phanor SK, Patel U, Gisselbrecht SS, Bulyk ML, O'Brien LL. Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor. Dis Model Mech 2023; 16:dmm050208. [PMID: 37815464 PMCID: PMC10668032 DOI: 10.1242/dmm.050208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/27/2023] [Indexed: 10/11/2023] Open
Abstract
Wilms tumors present as an amalgam of varying proportions of tissues located within the developing kidney, one being the nephrogenic blastema comprising multipotent nephron progenitor cells (NPCs). The recurring missense mutation Q177R in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional regulatory consequences of SIX1/2-Q177R that might promote tumor progression and recurrence have not been investigated extensively. Utilizing multiple Wilms tumor transcriptomic datasets, we identified upregulation of the gene encoding non-canonical WNT ligand WNT5A in addition to other WNT pathway effectors in SIX1/2-Q177R mutant tumors. SIX1 ChIP-seq datasets from Wilms tumors revealed shared binding sites for SIX1/SIX1-Q177R within a promoter of WNT5A and at putative distal cis-regulatory elements (CREs). We demonstrate colocalization of SIX1 and WNT5A in Wilms tumor tissue and utilize in vitro assays that support SIX1 and SIX1-Q177R activation of expression from the WNT5A CREs, as well as enhanced binding affinity within the WNT5A promoter that may promote the differential expression of WNT5A and other WNT pathway effectors associated with SIX1-Q177R tumors.
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Affiliation(s)
- Matthew J. Stevenson
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sabrina K. Phanor
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Urvi Patel
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Stephen S. Gisselbrecht
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Martha L. Bulyk
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Lori L. O'Brien
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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12
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Li X, Qi Q, Li Y, Miao Q, Yin W, Pan J, Zhao Z, Chen X, Yang F, Zhou X, Huang M, Wang C, Deng L, Huang D, Qi M, Fan S, Zhang Y, Qiu S, Deng W, Liu T, Chen M, Ye W, Zhang D. TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302717. [PMID: 37635201 PMCID: PMC10602580 DOI: 10.1002/advs.202302717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/04/2023] [Indexed: 08/29/2023]
Abstract
Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium-based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel-associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease-free survival in CRC patients. Gain- and loss-of-function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial-mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte-conditional Tcaf2-knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro-metastatic effects of TPCs from the perspective of cold-sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.
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Affiliation(s)
- Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Qi Qi
- MOE Key Laboratory of Tumor Molecular BiologyClinical Translational Center for Targeted DrugDepartment of PharmacologySchool of MedicineJinan UniversityGuangzhou510632China
| | - Yong Li
- College of PharmacyJinan UniversityGuangzhou510632China
- School of PharmacyNorth Sichuan Medical CollegeNanchong637100China
| | - Qun Miao
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Wenqian Yin
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Jinghua Pan
- Department of General SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhou510632China
| | - Zhan Zhao
- Department of General SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhou510632China
| | - Xiaoying Chen
- Department of BiophysicsKidney Disease Center of First Affiliated HospitalZhejiang University School of MedicineHangzhou310058China
| | - Fan Yang
- Department of BiophysicsKidney Disease Center of First Affiliated HospitalZhejiang University School of MedicineHangzhou310058China
| | - Xiaofeng Zhou
- MOE Key Laboratory of Tumor Molecular BiologyClinical Translational Center for Targeted DrugDepartment of PharmacologySchool of MedicineJinan UniversityGuangzhou510632China
| | - Maohua Huang
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Chenran Wang
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Lijuan Deng
- Formula‐Pattern Research CenterSchool of Traditional Chinese MedicineJinan UniversityGuangzhou510632China
| | - Dandan Huang
- The Sixth Affiliated Hospital of Sun Yet‐Sen UniversityGuangzhou510655China
| | - Ming Qi
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Shuran Fan
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Yiran Zhang
- Department of General SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhou510632China
| | - Shenghui Qiu
- Department of General SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhou510632China
| | - Weiqing Deng
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Tongzheng Liu
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Minfeng Chen
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Wencai Ye
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
| | - Dongmei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability AssessmentJinan UniversityGuangzhou510632China
- College of PharmacyJinan UniversityGuangzhou510632China
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13
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Li Y, Kong Y, An M, Luo Y, Zheng H, Lin Y, Chen J, Yang J, Liu L, Luo B, Huang J, Lin T, Chen C. ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway. J Exp Clin Cancer Res 2023; 42:191. [PMID: 37528489 PMCID: PMC10394821 DOI: 10.1186/s13046-023-02757-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 07/10/2023] [Indexed: 08/03/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored. METHODS RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues. RESULTS In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2-9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression. CONCLUSIONS Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients.
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Affiliation(s)
- Yuanlong Li
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Yao Kong
- Department of Pancreatic Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P. R. China
| | - Mingjie An
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Yuming Luo
- Department of Pancreatic Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P. R. China
| | - Hanhao Zheng
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Yan Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Jiancheng Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Jin Yang
- Department of Urology, Affiliated Hospital of Chengdu University, Chengdu, Sichuan, P. R. China
| | - Libo Liu
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Baoming Luo
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China.
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China.
| | - Changhao Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong, P. R. China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China.
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14
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Manfreda L, Rampazzo E, Persano L. Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target. BIOLOGY 2023; 12:biology12050729. [PMID: 37237541 DOI: 10.3390/biology12050729] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023]
Abstract
The involvement of Wnt signaling in normal tissue homeostasis and disease has been widely demonstrated over the last 20 years. In particular, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies, playing a role in cancer onset, progression, and response to treatments. In this review, we summarize the current knowledge on the instructions provided by Wnt signaling during organogenesis and, particularly, brain development. Moreover, we recapitulate the most relevant mechanisms through which aberrant Wnt pathway activation may impact on brain tumorigenesis and brain tumor aggressiveness, with a particular focus on the mutual interdependency existing between Wnt signaling components and the brain tumor microenvironment. Finally, the latest anti-cancer therapeutic approaches employing the specific targeting of Wnt signaling are extensively reviewed and discussed. In conclusion, here we provide evidence that Wnt signaling, due to its pleiotropic involvement in several brain tumor features, may represent a relevant target in this context, although additional efforts will be needed to: (i) demonstrate the real clinical impact of Wnt inhibition in these tumors; (ii) overcome some still unsolved concerns about the potential systemic effects of such approaches; (iii) achieve efficient brain penetration.
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Affiliation(s)
- Lorenzo Manfreda
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
| | - Elena Rampazzo
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
| | - Luca Persano
- Department of Women and Children's Health, University of Padova, Via Giustininani, 3, 35128 Padova, Italy
- Pediatric Research Institute, Corso Stati Uniti, 4, 35127 Padova, Italy
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15
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Jasuja H, Solaymani Mohammadi F, Kim J, Gaba A, Katti DR, Katti KS. Patient-Derived Breast Cancer Bone Metastasis In Vitro Model Using Bone-Mimetic Nanoclay Scaffolds. J Tissue Eng Regen Med 2023; 2023:5753666. [PMID: 40226410 PMCID: PMC11919058 DOI: 10.1155/2023/5753666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/21/2023] [Indexed: 04/15/2025]
Abstract
The unavailability of reliable models for studying breast cancer bone metastasis is the major challenge associated with poor prognosis in advanced-stage breast cancer patients. Breast cancer cells tend to preferentially disseminate to bone and colonize within the remodeling bone to cause bone metastasis. To improve the outcome of patients with breast cancer bone metastasis, we have previously developed a 3D in vitro breast cancer bone metastasis model using human mesenchymal stem cells (hMSCs) and primary breast cancer cell lines (MCF-7 and MDAMB231), recapitulating late-stage of breast cancer metastasis to bone. In the present study, we have tested our model using hMSCs and patient-derived breast cancer cell lines (NT013 and NT023) exhibiting different characteristics. We investigated the effect of breast cancer metastasis on bone growth using this 3D in vitro model and compared our results with previous studies. The results showed that NT013 and NT023 cells exhibiting hormone-positive and triple-negative characteristics underwent mesenchymal to epithelial transition (MET) and formed tumors in the presence of bone microenvironment, in line with our previous results with MCF-7 and MDAMB231 cell lines. In addition, the results showed upregulation of Wnt-related genes in hMSCs, cultured in the presence of excessive ET-1 cytokine released by NT013 cells, while downregulation of Wnt-related genes in the presence of excessive DKK-1, released by NT023 cells, leading to stimulation and abrogation of the osteogenic pathway, respectively, ultimately mimicking different types of bone lesions in breast cancer patients.
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Affiliation(s)
- Haneesh Jasuja
- Department of Civil Construction and Environmental Engineering, North Dakota State University, Fargo, ND 58108, USA
| | | | - Jiha Kim
- Department of Biological Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - Anu Gaba
- Sanford Roger Maris Cancer Center, Fargo, ND 58102, USA
| | - Dinesh R. Katti
- Department of Civil Construction and Environmental Engineering, North Dakota State University, Fargo, ND 58108, USA
| | - Kalpana S. Katti
- Department of Civil Construction and Environmental Engineering, North Dakota State University, Fargo, ND 58108, USA
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16
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Li M, Zheng Y, Li X, Shen X, Zhang T, Weng B, Mao H, Zhao J. ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer. BMC Cancer 2022; 22:1280. [PMID: 36476423 PMCID: PMC9727999 DOI: 10.1186/s12885-022-10380-2] [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: 08/03/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Histological grade has been demonstrated to be an important factor of breast cancer outcome and is associated with cell differentiation and is currently being evaluated via H&E-stained sections. Molecular biomarkers are essential to improve the accuracy of histological grading. ATBF1, a large transcription factor, has been considered a tumor suppressor gene with frequent mutations or deletions in multiple cancers. In breast cancer, ATBF1 was reported to function in cell differentiation and mammary development. However, its role in the clinic has rarely been reported. METHODS Breast cancer tissues (BCTs) and adjacent noncancerous tissues (ANCTs) were collected to analyze the expression of ATBF1 at the mRNA and protein levels. Three anti-ATBF1 antibodies recognizing independent peptides of ATBF1 (N-terminal end, middle region and C-terminal end) were applied for IHC staining. Small interfering RNA (siRNA) was used to silence ATBF1 expression and to investigate the roles of ATBF1 in MCF7 cells. Microarrays were introduced to analyze the differentially expressed genes, enriched GO terms and KEGG terms regulated by ATBF1 and its potential downstream genes, which were further confirmed in vitro and in clinical samples. RESULTS The expression of ATBF1 was reduced in BCTs at both the mRNA and protein levels compared with that in ANCTs. ATBF1 protein was predominantly localized in the nucleus of ANCTs but in the cytoplasm of BCTs. Both the mRNA and protein levels of ATBF1 were significantly correlated with histological grade. Consistently, knockdown of ATBF1 increased stemness marker expression and reduced differentiation markers in vitro. Further analysis identified WNT5A as an essential downstream gene of ATBF1 in breast cancer cells. Treatment of WNT5A disrupted cell proliferation induced by ATBF1 silencing. In BCTs, a significant correlation was observed between the expression of WNT5A and ATBF1. CONCLUSION The results indicated that ATBF1 expression might be a useful diagnostic marker associated with histological grade and breast cancer malignancy. WNT5A and its signaling pathway are novel mechanisms by which ATBF1 contributes to breast cancer tumorigenesis.
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Affiliation(s)
- Mei Li
- grid.203507.30000 0000 8950 5267Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211 China ,Ningbo Institute of Medical Sciences, Ningbo, Zhejiang China
| | - Yanan Zheng
- grid.203507.30000 0000 8950 5267Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211 China
| | - Xujun Li
- grid.9227.e0000000119573309Department of Breast Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang China
| | - Xiaohan Shen
- Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang China
| | - Tingxia Zhang
- grid.203507.30000 0000 8950 5267Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211 China
| | - Bowen Weng
- grid.203507.30000 0000 8950 5267Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211 China
| | - Haijiao Mao
- grid.203507.30000 0000 8950 5267Department of Orthopaedic Surgery, the Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang China
| | - Jiyuan Zhao
- grid.203507.30000 0000 8950 5267Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211 China
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17
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Kim KB, Kim DW, Kim Y, Tang J, Kirk N, Gan Y, Kim B, Fang B, Park JI, Zheng Y, Park KS. WNT5A-RHOA Signaling Is a Driver of Tumorigenesis and Represents a Therapeutically Actionable Vulnerability in Small Cell Lung Cancer. Cancer Res 2022; 82:4219-4233. [PMID: 36102736 PMCID: PMC9669186 DOI: 10.1158/0008-5472.can-22-1170] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/11/2022] [Accepted: 09/07/2022] [Indexed: 12/14/2022]
Abstract
WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models. β-Catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin-independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, whereas WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity. SIGNIFICANCE The p130-WNT5A-RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment.
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Affiliation(s)
- Kee-Beom Kim
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA
| | - Dong-Wook Kim
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA
| | - Youngchul Kim
- Department of Biostatistics and Bioinformatics, Moffitt
Cancer Research Center, Tampa Bay, FL 33612, USA
| | - Jun Tang
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA
| | - Nicole Kirk
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA
| | - Yongyu Gan
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA
| | - Bongjun Kim
- Department of Experimental Radiation Oncology, MD Anderson
Cancer Center, Houston, TX 77030, USA
| | - Bingliang Fang
- Department of Thoracic and Cardiovascular Surgery, MD
Anderson Cancer Center, Houston, TX 77030, USA
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, MD Anderson
Cancer Center, Houston, TX 77030, USA
| | - Yi Zheng
- Devision of Experimental Hematology and Cancer Biology,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229,
USA
| | - Kwon-Sik Park
- Department of Microbiology, Immunology, and Cancer Biology,
University of Virginia, Charlottesville, VA 22908, USA,Correspondence to Kwon-Sik Park, 1340 Jefferson
Park Avenue, Charlottesville, VA 22908 USA, ,
phone: 434-982-1947
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18
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Bhattacharya A, Wei J, Song W, Gao B, Tian C, Wu SA, Wang J, Chen L, Fang D, Qi L. SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 2022; 25:105183. [PMID: 36238898 PMCID: PMC9550610 DOI: 10.1016/j.isci.2022.105183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/15/2022] [Accepted: 09/20/2022] [Indexed: 11/02/2022] Open
Abstract
Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality control mechanisms in tumorigenesis remains incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen from SEL1L-deficient livers revealed WNT5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent WNT5A was misfolding prone and degraded by SEL1L-HRD1 ERAD in a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.
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Affiliation(s)
- Asmita Bhattacharya
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Graduate Program of Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853, USA
| | - Juncheng Wei
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Wenxin Song
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
| | - Beixue Gao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Chunyan Tian
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
| | - Shuangcheng Alivia Wu
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Ling Qi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA
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19
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Lu Z, Zhou Y, Jing Q. Wnt5a-mediated autophagy promotes radiation resistance of nasopharyngeal carcinoma. J Cancer 2022; 13:2388-2396. [PMID: 35517407 PMCID: PMC9066197 DOI: 10.7150/jca.71526] [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: 01/28/2022] [Accepted: 04/04/2022] [Indexed: 12/24/2022] Open
Abstract
Wnt signaling pathways and autophagy play an essential role in tumor progression. Canonical Wnt signaling pathways in radiation resistance have been studied in the past, but it remains unclear whether the noncanonical Wnt signaling pathways can affect tumor radiation resistance through protective autophagy. Nasopharyngeal carcinoma, a particular subtype of head and neck squamous cell carcinoma, relies on radiation therapy. In this study, we found that radioactive rays could significantly promote the expression of Wnt noncanonical signaling pathways ligands in nasopharyngeal carcinoma, among which Wnt5A was the most markedly altered. We have demonstrated that Wnt5a can reduce the radiation sensitivity of nasopharyngeal carcinoma in vitro and in vitro experiments. Meanwhile, we found much more greater autophagosomes in overexpressed-Wnt5A nasopharyngeal carcinoma cells by electron microscopy. Further mechanism exploration revealed that Beclin1 is the main target of Wnt5A, and knocking down Beclin1 can partially reduce Wnt5a-induced radiation resistance. By studying Wnt5A-mediated protective autophagy in promoting radiation resistance in nasopharyngeal carcinoma cells, we hope that the Wnt5A and Beclin1 can become effective targets for overcoming radiation resistance in the future.
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Affiliation(s)
- Zhaoyi Lu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, People's Republic of China
| | - Yandan Zhou
- Changsha Aier Eye Hospital, Aier Eye Hospital Group, Changsha, Hunan,410000, People's Republic of China
| | - Qiancheng Jing
- The Affiliated Changsha Central Hospital, Department of Otolaryngology Head and Neck Surgery, Hengyang Medical School, University of South China. Changsha, Hunan, 410001, People's Republic of China
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20
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Application of explainable artificial intelligence in the identification of Squamous Cell Carcinoma biomarkers. Comput Biol Med 2022; 146:105505. [DOI: 10.1016/j.compbiomed.2022.105505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022]
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Mondal D, Amin SA, Moinul M, Das K, Jha T, Gayen S. How the structural properties of the indole derivatives are important in kinase targeted drug design?: A case study on tyrosine kinase inhibitors. Bioorg Med Chem 2022; 53:116534. [PMID: 34864496 DOI: 10.1016/j.bmc.2021.116534] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/18/2022]
Abstract
Kinases are considered as important signalling enzymes that illustrate 20% of the druggable genome. Human kinase family comprises >500 protein kinases and about 20 lipid kinases. Protein kinases are responsible for the mechanism of protein phosphorylation. These are necessary for regulation of various cellular activities including proliferation, cell cycle, apoptosis, motility, growth, differentiation, etc. Their deregulation leads to disruption of many cellular processes leading to different diseases most importantly cancer. Thus, kinases are considered as valuable targets in different types of cancer as well as other diseases. Researchers around the world are actively engaged in developing inhibitors based on distinct chemical scaffolds. Indole represents as a versatile scaffold in the naturally occurring and bioactive molecules. It is also used as a privileged scaffold for the target-based drug design against different diseases. This present article aim to review the applications of indole scaffold in the design of inhibitors against different tyrosine kinases such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), etc. Important structure activity relationships (SARs) of indole derivatives were discussed. The present work is an attempt to summarize all the crucial structural information which is essential for the development of indole based tyrosine kinase inhibitors with improved potency.
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Affiliation(s)
- Dipayan Mondal
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, MP, India
| | - Sk Abdul Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, P. O. Box 17020, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Md Moinul
- Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Kalpataru Das
- Advanced Organic Synthesis Laboratory, Department of Chemistry, Dr. Harisingh Gour University, Sagar 470003, MP, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, P. O. Box 17020, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
| | - Shovanlal Gayen
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, MP, India; Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
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22
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Wang Y, Zhou J, Zhang J, Cao H, Han F, Zhang H, Xu E. The expression of ADAMTS14 is regulated by promoter DNA methylation and is associated with poor prognosis in colorectal cancer. Exp Cell Res 2022; 410:112953. [PMID: 34856162 DOI: 10.1016/j.yexcr.2021.112953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 11/01/2021] [Accepted: 11/28/2021] [Indexed: 12/23/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors of digestive system, and its main cause of death is tumor metastasis. The occurrence of CRC is a polygenic and multi-step complex process involving genetic and epigenetic alterations. It has been demonstrated that ADAMTS14 (A disintegrin and metalloproteinase with thrombospondin motifs 14) was hypermethylated in esophageal cancer using whole-genome methylation microarray in our previous report. The present study revealed that ADAMTS14 was highly methylated accompanied with low expression in CRC. In addition, demethylation agent 5-Aza-dC could demethylate ADAMTS14 promoter region and reactivate ADAMTS14 expression effectively in vitro. Therefore, promoter hypermethylation was probably contributed to ADAMTS14 epigenetic silencing in CRC. Furthermore, ADAMTS14 protein expression was higher at invasive tumor front than at the tumor center or other areas of tumor. Kaplan-meier survival analysis indicated that the high ADAMTS14 expression was correlated with poor prognosis in CRC patients, suggesting the possibility that ADAMTS14 is a promising indicator in the evaluation of CRC prognosis.
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Affiliation(s)
- Yan Wang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jing Zhou
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jing Zhang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; The First Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Hui Cao
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Pathology and Pathophysiology, Cheng Du Medical College, Chengdu, China.
| | - Fengyan Han
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Honghe Zhang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Enping Xu
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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23
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Castro MV, Barbero GA, Villanueva MB, Grumolato L, Nsengimana J, Newton-Bishop J, Illescas E, Quezada MJ, Lopez-Bergami P. ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation. J Biomed Sci 2021; 28:76. [PMID: 34774050 PMCID: PMC8590781 DOI: 10.1186/s12929-021-00776-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/07/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. METHODS Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. RESULTS Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. CONCLUSION We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.
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Affiliation(s)
- María Victoria Castro
- grid.440480.c0000 0000 9361 4204Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405 Buenos Aires, Argentina ,grid.423606.50000 0001 1945 2152Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425 Buenos Aires, Argentina
| | - Gastón Alexis Barbero
- grid.440480.c0000 0000 9361 4204Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405 Buenos Aires, Argentina ,grid.423606.50000 0001 1945 2152Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425 Buenos Aires, Argentina
| | - María Belén Villanueva
- grid.440480.c0000 0000 9361 4204Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405 Buenos Aires, Argentina ,grid.423606.50000 0001 1945 2152Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425 Buenos Aires, Argentina
| | - Luca Grumolato
- grid.10400.350000 0001 2108 3034INSERM U982, Institute for Research and Innovation in Biomedicine, University of Rouen, 76183 Rouen, France
| | - Jérémie Nsengimana
- grid.1006.70000 0001 0462 7212Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH UK
| | | | - Edith Illescas
- grid.440480.c0000 0000 9361 4204Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405 Buenos Aires, Argentina
| | - María Josefina Quezada
- grid.440480.c0000 0000 9361 4204Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405 Buenos Aires, Argentina ,grid.423606.50000 0001 1945 2152Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425 Buenos Aires, Argentina
| | - Pablo Lopez-Bergami
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425, Buenos Aires, Argentina. .,Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimonides, Hidalgo 775, 6th Floor, Lab 602., 1405, Buenos Aires, Argentina.
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24
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Astudillo P. An emergent Wnt5a/YAP/TAZ regulatory circuit and its possible role in cancer. Semin Cell Dev Biol 2021; 125:45-54. [PMID: 34764023 DOI: 10.1016/j.semcdb.2021.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/29/2022]
Abstract
Wnt5a is a ligand that plays several roles in development, homeostasis, and disease. A growing body of evidence indicates that Wnt5a is involved in cancer progression. Despite extensive research in this field, our knowledge about how Wnt5a is precisely involved in cancer is still incomplete. It is usually thought that certain combinations of Frizzled receptors and co-receptors might explain the observed effects of Wnt5a either as a tumor suppressor or by promoting migration and invasion. While accepting this 'receptor context' model, this review proposes that Wnt5a is integrated within a larger regulatory circuit involving β-catenin, YAP/TAZ, and LATS1/2. Remarkably, WNT5A and YAP1 are transcriptionally regulated by the Hippo and Wnt pathways, respectively, and might form a regulatory circuit acting through LATS kinases and secreted Wnt/β-catenin inhibitors, including Wnt5a itself. Therefore, understanding the precise role of Wnt5a and YAP in cancer requires a systems biology perspective.
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Affiliation(s)
- Pablo Astudillo
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile.
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25
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Zougros A, Michelli M, Chatziandreou I, Nonni A, Gakiopoulou H, Michalopoulos NV, Lazaris AC, Saetta AA. mRNA coexpression patterns of Wnt pathway components and their clinicopathological associations in breast and colorectal cancer. Pathol Res Pract 2021; 227:153649. [PMID: 34656913 DOI: 10.1016/j.prp.2021.153649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 11/24/2022]
Abstract
Aberrant Wnt signaling is implicated in carcinogenesis triggering efforts for the development of new therapeutic agents, many of which have entered clinical trials. We extend our previous analysis of WNT3, FZD7, LEF1 expression levels in breast and colorectal cancer including WNT2, FZD4 and β-catenin expression, in an effort to delineate their relative expression levels along with concurrent expression patterns and possible prognostic value. We analyzed 82 breast and 102 colorectal carcinomas for relative mRNA expression levels of the investigated genes by RT-PCR relative quantification with the ΔΔCt method. Statistical analysis was performed in order to determine associations of relative mRNA expression and linear correlations. β-catenin expression was determined by immunochemistry. Regarding breast carcinomas, decreased relative mRNA expression levels of WNT2, FZD4 were found frequently and WNT2 expression was correlated with ER/ PR status (p = 0.045/p = 0.028), whereas β-catenin with grade (p = 0.026). In colorectal carcinomas, increased relative mRNA expression levels of WNT2 and FZD4 were found in 59% and 32% of cases respectively, whereas β-catenin showed decreased mRNA expression levels in 57% of cases and a correlation with pN-category (p = 0.037). Linear correlations were observed between WNT2/FZD4 (R=0.542, p < 0.001), WNT2/β-catenin (R=0.254, p = 0.010), FZD4/β-catenin (R=0.406, p < 0.001) expression and a correlation between mRNA expression and membranous/cytoplasmic β-catenin emerged (p = 0.039/0.046). Our results suggest a possible clinical significance for Wnt pathway gene expression levels in both tumour types. The concurrent expression of the investigated genes as well as the different expression profiles, underlines the complexity of this pathway and the necessity of patient selection in order to maximize the efficacy of drugs targeting Wnt pathway.
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Affiliation(s)
- Alexandros Zougros
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Maria Michelli
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Ilenia Chatziandreou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Afroditi Nonni
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Harikleia Gakiopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Nikolaos V Michalopoulos
- Fourth Department of Surgery, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Haidari, Athens, Greece
| | - Andreas C Lazaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Angelica A Saetta
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece.
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Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells. Pharmaceuticals (Basel) 2021; 14:ph14090871. [PMID: 34577571 PMCID: PMC8465904 DOI: 10.3390/ph14090871] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context. This review summarizes the available information on the role of the Wnt/β-catenin pathway and its crosstalk with other signaling pathways in apoptosis induction in cancer cells and presents a modified dual-signal model for the function of β-catenin. Understanding the proapoptotic mechanisms induced by the Wnt/β-catenin pathway could open new therapeutic opportunities.
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Affiliation(s)
- Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
- Correspondence:
| | - Angel Escamilla-Ramirez
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
| | - Dolores Jimenez-Farfan
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | | | - Athenea Flores-Najera
- Centro Médico Nacional 20 de Noviembre, Departamento de Cirugía General, Ciudad de Mexico 03229, Mexico;
| | - Arturo Cruz-Salgado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico 14269, Mexico; (A.E.-R.); (A.C.-S.)
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27
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Khan W, Haragannavar VC, Rao RS, Prasad K, Sowmya SV, Augustine D, Patil S. P-Cadherin and WNT5A expression in assessment of lymph node metastasis in oral squamous cell carcinoma. Clin Oral Investig 2021; 26:259-273. [PMID: 34216280 DOI: 10.1007/s00784-021-03996-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 05/19/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Oral cancer progression is a multi-step process in which adhesion molecules play a pivotal role in the development of recurrent, invasive, and distant metastasis. The aim of this study was to adopt prognostic biomarkers to assess the lymph node metastasis of OSCC that will facilitate in deciding the treatment modality by the surgeons. OBJECTIVES The objectives of the study were to assess the biological behaviour of OSCC by correlating the expression levels of P-Cadherin and WNT5A immunohistochemically. METHODS A total of 60 selected OSCCs cases (lymph node metastasis n = 30, non-metastatic n = 30) and 10 normal healthy controls were quantitatively and qualitatively analysed by immunohistochemistry for P-Cadherin and WNT5A. A survival analysis was also performed. RESULTS The expression levels of P-Cadherin and WNT5A in OSCC groups were statistically significant between metastatic and non-metastatic groups (p < 0.001). P-Cadherin and WNT5A expression in metastatic (lymph node metastasis) and non-metastatic cases showed a significant correlation coefficient of 0.753 at (p < 0.01). The present study also found that the aberrant expression (high) of P-Cadherin was associated with diminished survival of patients with metastatic OSCC. CONCLUSION The present study demonstrated the aberrant expression of P-Cadherin and WNT5A could serve as important prognosticator in OSCC. CLINICAL RELEVANCE P-Cadherin and WNT5A could be used as significant predictors of disease outcome.
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Affiliation(s)
- Wafa Khan
- Department of Oral Pathology & Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Vanishri C Haragannavar
- Department of Oral Pathology & Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Roopa S Rao
- Department of Oral Pathology & Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Kavitha Prasad
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Samudrala Venkatesiah Sowmya
- Department of Oral Pathology & Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Dominic Augustine
- Department of Oral Pathology & Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia.
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28
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Molecular Landscape of the Epithelial-Mesenchymal Transition in Endometrioid Endometrial Cancer. J Clin Med 2021; 10:jcm10071520. [PMID: 33917330 PMCID: PMC8038735 DOI: 10.3390/jcm10071520] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/02/2021] [Indexed: 12/25/2022] Open
Abstract
Modern diagnostics are based on molecular analysis and have been focused on searching for new molecular markers to use in diagnostics. Included in this has been the search for the correlation between gene expression in tissue samples and liquid biological materials. The aim of this study was to evaluate the differences in the expression profile of messenger RNA (mRNA) and micro-RNA (miRNA) related to the epithelial-mesenchymal transition (EMT) in different grades of endometrial cancer (G1-G3), in order to select the most promising molecular markers. The study material consisted of tissue samples and whole blood collected from 30 patients with endometrial cancer (study group; G1 = 15; G2 = 8; G3 = 7) and 30 without neoplastic changes (control group). The molecular analysis included the use of the microarray technique and RTqPCR. Microarray analysis indicated the following number of mRNA differentiating the endometrial cancer samples from the control (tissue/blood): G1 vs. C = 21/18 mRNAs, G2 vs. C = 19/14 mRNAs, and G3 vs. C = 10/9 mRNAs. The common genes for the tissue and blood samples (Fold Change; FC > 3.0) were G1 vs. C: TGFB1, WNT5A, TGFB2, and NOTCH1; G2 vs. C: BCL2L, SOX9, BAMBI, and SMAD4; G3 vs. C STAT1 and TGFB1. In addition, mRNA TGFB1, NOTCH1, and BCL2L are common for all grades of endometrial cancer. The analysis showed that miR-144, miR-106a, and miR-30d are most strongly associated with EMT, making them potential diagnostic markers.
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Sun G, Wu L, Sun G, Shi X, Cao H, Tang W. WNT5a in Colorectal Cancer: Research Progress and Challenges. Cancer Manag Res 2021; 13:2483-2498. [PMID: 33758546 PMCID: PMC7981155 DOI: 10.2147/cmar.s289819] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/17/2021] [Indexed: 12/31/2022] Open
Abstract
Despite the clinical development of new adjuvant and neoadjuvant chemotherapy drugs, colorectal cancer is still one of the leading causes of cancer-related death in human beings. WNT5a, an autocrine and paracrine β-catenin independent ligand, has been shown to induce tumor inhibition and carcinogenic signals, depending on the type of cancer. In patients with colorectal cancer, WNT5a triggers a variety of downstream signaling pathways, which mainly affect the migration and invasion of tumor cells. This article reviews the mechanism and therapeutic potential of WNT5a in colorectal cancer. In short, an in-depth understanding of the role of WNT5a in colorectal cancer is very helpful to better deal with this disease.
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Affiliation(s)
- Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Liangliang Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Xuesong Shi
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China
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30
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Wan J, Liu Y, Long F, Tian J, Zhang C. circPVT1 promotes osteosarcoma glycolysis and metastasis by sponging miR-423-5p to activate Wnt5a/Ror2 signaling. Cancer Sci 2021; 112:1707-1722. [PMID: 33369809 PMCID: PMC8088910 DOI: 10.1111/cas.14787] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Osteosarcoma (OS) is the most prevalent form of bone cancer. It has a high metastatic potential and progresses rapidly. The molecular mechanisms of OS remain unclear and this study aims to examine the functional role of circPVT1 and miR‐423‐5p in OS. Quantitative RT‐PCR (qRT‐PCR) and western blotting were used to examine levels of miR‐423‐5p, circPVT1, Wnt5a, Ror2, and glycolysis‐related proteins, including HK2, PKM2, GLUT1, and LDHA. Colony formation and transwell assays were used to test the roles of miR‐423‐5p, circPVT1, and Wnt5a/Ror2 in OS cell proliferation, migration, and invasion. Dual luciferase assay and Ago2‐RIP were used to validate the interactions of miR‐423‐5p/Wnt5a, miR‐423‐5p/Ror2, and circPVT1/miR‐423‐5p. Glucose uptake assay and measurement of lactate production were performed to assess the glycolysis process. A nude mouse xenograft model was used to evaluate the effects of sh‐circPVT1 and miR‐423‐5p mimics on tumor growth and metastasis in vivo. miR‐423‐5p was reduced in both OS tissues and OS cell lines, while Wnt5a/Ror2 and circPVT1 were elevated. miR‐423‐5p bound to 3′‐UTR of Wnt5a and Ror2 mRNA, and inhibited glycolysis and OS cell proliferation, migration, and invasion by targeting Wnt5a and Ror2. circPVT1 interacted with miR‐423‐5p and activated Wnt5a/Ror2 signaling by sponging miR‐423‐5p. Knockdown of circPVT1 or overexpression of miR‐423‐5p suppressed OS tumor growth and metastasis in vivo. miR‐423‐5p inhibited OS glycolysis, proliferation, migration, and metastasis by targeting and suppressing Wnt5a/Ror2 signaling pathway, while circPVT1 promoted those processes by acting as a sponge of miR‐423‐5p.
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Affiliation(s)
- Jun Wan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Yupeng Liu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Feng Long
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Jian Tian
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Can Zhang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
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31
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Wan X, Guan S, Hou Y, Qin Y, Zeng H, Yang L, Qiao Y, Liu S, Li Q, Jin T, Qiu Y, Liu M. FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts. Am J Cancer Res 2021; 11:4975-4991. [PMID: 33754039 PMCID: PMC7978317 DOI: 10.7150/thno.55074] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/24/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs), a predominant component of the tumor microenvironment, contribute to aggressive angiogenesis progression. In clinical practice, traditional anti-angiogenic therapy, mainly anti-VEGF, provides extremely limited beneficial effects to breast cancer. Here, we reveal that FOS-like 2 (FOSL2), a transcription factor in breast CAFs, plays a critical role in VEGF-independent angiogenesis in stromal fibroblasts. Methods: FOSL2 and Wnt5a expression was assessed by qRT-PCR, western blotting and immunohistochemistry in primary and immortalized CAFs and clinical samples. FOSL2- or Wnt5a-silenced CAFs and FOSL2-overexpressing NFs were established to explore their proangiogenic effects. Invasion, tubule formation, three-dimensional sprouting assays, and orthotopic xenografts were conducted as angiogenesis experiments. FZD5/NF-κB/ERK signaling activation was evaluated by western blotting after blocking VEGF/VEGFR with an anti-VEGF antibody and axitinib. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to test the role of FOSL2 in regulating Wnt5a expression, and Wnt5a in the serum of the patients was measured to assess its clinical diagnostic value for breast cancer patients. Results: Enhanced FOSL2 in breast CAFs was significantly associated with angiogenesis and clinical progression in patients. The supernatant from CAFs highly expressing FOSL2 strongly promoted tube formation and sprouting of human umbilical vein endothelial cells (HUVECs) in a VEGF-independent manner and angiogenesis as well as tumor growth in vivo. Mechanistically, the enhanced FOSL2 in CAFs was regulated by estrogen/cAMP/PKA signaling. Wnt5a, a direct target of FOSL2, specifically activated FZD5/NF-κB/ERK signaling in HUVECs to promote VEGF-independent angiogenesis. In addition, a high level of Wnt5a was commonly detected in the serum of breast cancer patients and closely correlated with microvessel density in breast tumor tissues, suggesting a promising clinical value of Wnt5a for breast cancer diagnostics. Conclusion: FOSL2/Wnt5a signaling plays an essential role in breast cancer angiogenesis in a VEGF-independent manner, and targeting the FOSL2/Wnt5a signaling axis in CAFs may offer a potential option for antiangiogenesis therapy.
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Li H, Tong F, Meng R, Peng L, Wang J, Zhang R, Dong X. E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer. Cell Mol Life Sci 2021; 78:2877-2891. [PMID: 33078208 PMCID: PMC11072416 DOI: 10.1007/s00018-020-03678-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/30/2020] [Accepted: 10/06/2020] [Indexed: 12/11/2022]
Abstract
Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. Herein, we found the protein WNT5A, was significantly downregulated in BM tissues and EGFR-mutant samples. In addition, the overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared with the EGFR wide-type cells. We demonstrated a molecular mechanism whereby WNT5A be negatively regulated by transcription factor E2F1, and ERK1/2 inhibitor (U0126) suppressed E2F1's regulation of WNT5A expression in EGFR-mutant cells. Furthermore, WNT5A inhibited β-catenin activity and the transcriptional levels of its downstream genes in cancer progression. Our research revealed the role of WNT5A in NSCLC BM with EGFR mutation, and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, supporting the notion that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFR-mutant NSCLC.
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Affiliation(s)
- Huanhuan Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Fan Tong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Ling Peng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Jiaojiao Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Ruiguang Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People's Republic of China.
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Xing F, Liu Y, Dong R, Cheng Y. miR-374 improves cerebral ischemia reperfusion injury by targeting Wnt5a. Exp Anim 2021; 70:126-136. [PMID: 33116025 PMCID: PMC7887619 DOI: 10.1538/expanim.20-0034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022] Open
Abstract
To date, studies have demonstrated the potential functions of microRNAs in cerebral ischemia reperfusion (IR) injury. Herein, we established a middle cerebral artery occlusion (MCAO) model in rats and then subjected them to reperfusion to explore the role of microRNA-374 (miR-374) in cerebral IR injury. After reperfusion, the endogenous miR-374 level decreased, and the expression of its target gene, Wnt5a, increased in brain tissues. Intracerebral pretreatment of miR-374 agomir attenuated cerebral damage induced by IR, including neurobehavioral deficits, infarction, cerebral edema and blood-brain barrier disruption. Moreover, rats pretreated with miR-374 agomir showed a remarkable decrease in apoptotic neurons, which was further confirmed by reduced BAX expression as well as increased BCL-2 and BCL-XL expression. A dual-luciferase reporter assay substantiated that Wnt5a was the target gene of miR-374. miR-374 might protect against brain injury by downregulating Wnt5a in rats after IR. Thus, our study provided a novel mechanism of cerebral IR injury from the perspective of miRNA regulation.
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Affiliation(s)
- Fangyuan Xing
- Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, People's Republic of China
| | - Yongrong Liu
- Department of Ultrasound, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, People's Republic of China
| | - Ruifang Dong
- Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, People's Republic of China
| | - Ye Cheng
- Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou, Hebei 061000, People's Republic of China
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34
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Lopez-Bergami P, Barbero G. The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment. Cancer Metastasis Rev 2021; 39:933-952. [PMID: 32435939 DOI: 10.1007/s10555-020-09878-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.
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Affiliation(s)
- Pablo Lopez-Bergami
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
| | - Gastón Barbero
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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35
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Zhu GX, Gao D, Shao ZZ, Chen L, Ding WJ, Yu QF. Wnt/β‑catenin signaling: Causes and treatment targets of drug resistance in colorectal cancer (Review). Mol Med Rep 2020; 23:105. [PMID: 33300082 PMCID: PMC7723170 DOI: 10.3892/mmr.2020.11744] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor in humans. Chemotherapy is used for the treatment of CRC. However, the effect of chemotherapy remains unsatisfactory due to drug resistance. Growing evidence has shown that the presence of highly metastatic tumor stem cells, regulation of non-coding RNAs and the tumor microenvironment contributes to drug resistance mechanisms in CRC. Wnt/β-catenin signaling mediates the chemoresistance of CRC in these three aspects. Therefore, the present study analyzed the abundant evidence of the contribution of Wnt/β-catenin signaling to the development of drug resistance in CRC and discussed its possible role in improving the chemosensitivity of CRC, which may provide guidelines for its clinical treatment.
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Affiliation(s)
- Gui-Xian Zhu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Dian Gao
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhao-Zhao Shao
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li Chen
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wen-Jie Ding
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Qiong-Fang Yu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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36
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Chen Y, Chen Z, Tang Y, Xiao Q. The involvement of noncanonical Wnt signaling in cancers. Biomed Pharmacother 2020; 133:110946. [PMID: 33212376 DOI: 10.1016/j.biopha.2020.110946] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/12/2020] [Accepted: 10/25/2020] [Indexed: 12/18/2022] Open
Abstract
Wnt signaling is one of the key cascades regulating normal tissue development and has been tightly associated with cancer. The Wnt signaling can be subdivided into two categories: canonical & noncanonical. Noncanonical Wnt signaling pathways mainly include Wnt/PCP (planar cell polarity) signaling and Wnt-cGMP (cyclic guanosine monophosphate) /Ca2+ signaling. It has been well studied by previous researches that noncanonical Wnt signaling regulates multiple cell functions including proliferation, differentiation, adhesion, polarity, motility, and migration. The aberrant activation or inhibition of noncanonical Wnt signaling is crucial in cancer progression, exerting both oncogenic and tumor-suppressive effects. Recent studies show the involvement of noncanonical Wnt in regulating cancer cell invasion, metastasis, metabolism, and inflammation. Here, we review current insights into novel components of non-canonical signalings and describe their involvement in various cancer types. We also summarize recent biological and clinical discoveries that outline non-canonical Wnt signaling in tumorigenesis. Finally, we provide an overview of current strategies to target non-canonical Wnt signaling in cancer and challenges that are associated with such approaches.
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Affiliation(s)
- Yongfeng Chen
- Department of General Surgery, Zhejiang Yuhuan People's Hospital, Taizhou, Zhejiang, China
| | - Zhengxi Chen
- Department of Orthodontics, Shanghai Ninth People׳s Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China; Department of Cell Biology, Yale School of Medicine, New Haven, CT, United States
| | - Yin Tang
- Omni Family Health, Bakersfield, CA, United States
| | - Qian Xiao
- Department of Cell Biology, Yale School of Medicine, New Haven, CT, United States.
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37
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Gajos-Michniewicz A, Czyz M. WNT Signaling in Melanoma. Int J Mol Sci 2020; 21:E4852. [PMID: 32659938 PMCID: PMC7402324 DOI: 10.3390/ijms21144852] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided.
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Affiliation(s)
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92–215 Lodz, Poland;
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38
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Porru M, Zizza P, Panera N, Alisi A, Biroccio A, Leonetti C. Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12071830. [PMID: 32650388 PMCID: PMC7408740 DOI: 10.3390/cancers12071830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/24/2022] Open
Abstract
Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients’ outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients. In particular, organoids and patient-derived-xenografts (PDXs), as well as genetically engineered mouse models (GEMMs) and patient-derived orthotopic xenografts (PDOXs), should be considered for translational purposes. Overall, omics and advanced mouse models of cancer represent a portfolio of sophisticated biological tools that, if optimized for use in concert with accurate data analysis, could accelerate the anticancer discovery process and provide new weapons against cancer. In this review, we highlight success reached following the integration of omics and experimental models; moreover, results produced by our group in the field of mCRC are also presented.
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Affiliation(s)
- Manuela Porru
- UOSD SAFU, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCSS-Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Pasquale Zizza
- UOSD Oncogenomic and Epigenetic Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCSS-Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Nadia Panera
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.P.); (A.A.)
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.P.); (A.A.)
| | - Annamaria Biroccio
- UOSD Oncogenomic and Epigenetic Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCSS-Regina Elena National Cancer Institute, 00144 Rome, Italy;
- Correspondence: (A.B.); (C.L.)
| | - Carlo Leonetti
- UOSD SAFU, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCSS-Regina Elena National Cancer Institute, 00144 Rome, Italy;
- Correspondence: (A.B.); (C.L.)
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39
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Michelli M, Zougros A, Chatziandreou I, Michalopoulos NV, Lazaris AC, Saetta AA. Concurrent Wnt pathway component expression in breast and colorectal cancer. Pathol Res Pract 2020; 216:153005. [PMID: 32534708 DOI: 10.1016/j.prp.2020.153005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/27/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023]
Abstract
Wnt signaling pathway regulates important cell functions such as proliferation and migration and is frequently deregulated in colorectal and breast cancer. Thus, it constitutes an attractive therapeutic target with many drugs being investigated in clinical trials. Eighty-two breast and 102 colorectal carcinomas were analyzed for: relative mRNA expression levels of Wnt pathway components namely Wnt3 ligand, Frizzled 7 receptor and LEF1 transcriptional factor, their concurrent expression patterns and their correlation with clinicopathological features. Regarding breast carcinomas, increased relative mRNA expression levels of WNT3 were found in 54 % of cases whereas decreased relative mRNA expression levels were observed in FZD7 and LEF1 in 82 % and 43 % of cases, respectively. Expression levels of WNT3 were significantly correlated with tumour grade (p = 0.021) in breast cancer. As far as colorectal carcinomas are concerned, increased relative mRNA expression levels of WNT3, FZD7 and LEF1 were found in 60 %, 37 % and 48 % of cases respectively. A statistically significant correlation emerged between LEF1expression levels and pT-category (p = 0.027), suggesting a possible association with tumour aggressiveness in colorectal carcinomas. Statistically significant linear correlations were observed between the expression of WNT3/LEF1 (R = 0.233, p = 0.035) and FZD7/LEF1 (R = 0.359, p = 0.001) in breast carcinomas as well as in colorectal carcinomas (R = 0.536, p < 0.01 and R = 0.210, p = 0.034) respectively. Our results demonstrate a possible clinical significance of Wnt pathway gene expression levels in both tumour types. The distinct expression patterns and simultaneous expression of the investigated genes underscore the complexity of this pathway in breast and colorectal carcinogenesis and highlights the necessity of patient selection with regard to the effectiveness of Wnt pathway inhibitors.
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Affiliation(s)
- Maria Michelli
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Alexandros Zougros
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Ilenia Chatziandreou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Nikolaos V Michalopoulos
- Fourth Department of Surgery, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Haidari, Athens, Greece
| | - Andreas C Lazaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece
| | - Angelica A Saetta
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, Athens, Greece.
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40
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Huo LW, Wang YF, Bai XB, Zheng HL, Wang MD. circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling. Mol Med 2020; 26:29. [PMID: 32268875 PMCID: PMC7144061 DOI: 10.1186/s10020-020-00159-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/19/2020] [Indexed: 01/09/2023] Open
Abstract
Background Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. Circular RNAs (circRNAs) have been reported to play vital roles in progression of cancer including glioma, and circKIF4A is up-regulated in glioma tissues. However, its role and mechanisms in gliomas are unclear. Methods circKIF4A and miR-139-3p were determined by qRT-PCR. Transwell assay, wound-healing assay, cell colony formation and flow cytometry were performed to measure cell invasion, migration, proliferation and apoptosis. Western blotting was used to evaluate Wnt/β-catenin pathway-related protein. Luciferase reporter assays confirmed the relationship among circKIF4A, miR-139-3p and Wnt5a. Sphere formation was performed to measure the ability of glioma-initiating cells (GICs) spheroid formation. A nude mouse xenograft model was established and immunohistochemical staining was used to detect Ki-67 and Wnt5a levels. Results circKIF4A and Wnt5a were up-regulated and miR-139-3p was down-regulated in both glioma cells and tissues. circKIF4A promoted Wnt5a expression by sponging miR-139-3p. Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p. Knockdown of circKIF4A inhibited Wnt/β-catenin signaling pathway and proliferation-related signal via miR-139-3p. Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/β-catenin signaling pathway and proliferation-related signal in GICs. Additionally, depletion of circKIF4A decreased the expression level of Wnt5a and Ki-67, inhibited tumorigenesis in xenograft modes. Conclusion circKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis. The results indicated that circKIF4A may be a potential target for clinical treatment of glioma.
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Affiliation(s)
- Long-Wei Huo
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiao Tong University, No. 277 Yanta Xi Road, Xi'an, 710061, Shaanxi Province, People's Republic of China.,Department of Neurosurgery, Yulin First Hospital Affiliated to Xi'an Jiao Tong University, Yulin, 719000, People's Republic of China
| | - Ya-Fei Wang
- Department of Neurosurgery, Yulin First Hospital Affiliated to Xi'an Jiao Tong University, Yulin, 719000, People's Republic of China
| | - Xiao-Bin Bai
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiao Tong University, No. 277 Yanta Xi Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Hu-Lin Zheng
- Department of Neurosurgery, Yulin First Hospital Affiliated to Xi'an Jiao Tong University, Yulin, 719000, People's Republic of China
| | - Mao-De Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiao Tong University, No. 277 Yanta Xi Road, Xi'an, 710061, Shaanxi Province, People's Republic of China.
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Astudillo P. Wnt5a Signaling in Gastric Cancer. Front Cell Dev Biol 2020; 8:110. [PMID: 32195251 PMCID: PMC7064718 DOI: 10.3389/fcell.2020.00110] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer remains an important health challenge, accounting for a significant number of cancer-related deaths worldwide. Therefore, a deeper understanding of the molecular mechanisms involved in gastric cancer establishment and progression is highly desirable. The Wnt pathway plays a fundamental role in development, homeostasis, and disease, and abnormal Wnt signaling is commonly observed in several cancer types. Wnt5a, a ligand that activates the non-canonical branch of the Wnt pathway, can play a role as a tumor suppressor or by promoting cancer cell invasion and migration, although the molecular mechanisms explaining these roles have not been fully elucidated. Wnt5a is increased in gastric cancer samples; however, most gastric cancer cell lines seem to exhibit little expression of this ligand, thus raising the question about the source of this ligand in vivo. This review summarizes available research about Wnt5a expression and signaling in gastric cancer. In gastric cancer, Wnt5a promotes invasion and migration by modulating integrin adhesion turnover. Disheveled, a scaffolding protein with crucial roles in Wnt signaling, mediates the adhesion-related effects of Wnt5a in gastric cancer cells, and several studies provide growing support for a model whereby Disheveled-interacting proteins mediates Wnt5a signaling to modulate cytoskeleton dynamics. However, Wnt5a might induce other effects in gastric cancer cells, such as cell survival and induction of gene expression. On the other hand, the available evidence suggests that Wnt5a might be expressed by cells residing in the tumor microenvironment, where feedback mechanisms sustaining Wnt5a secretion and signaling might be established. This review analyzes the possible functions of Wnt5a in this pathological context and discusses potential links to mechanosensing and YAP/TAZ signaling.
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Affiliation(s)
- Pablo Astudillo
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
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Tyrosine-Based Signals Regulate the Assembly of Daple⋅PARD3 Complex at Cell-Cell Junctions. iScience 2020; 23:100859. [PMID: 32058970 PMCID: PMC7005484 DOI: 10.1016/j.isci.2020.100859] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/27/2019] [Accepted: 01/16/2020] [Indexed: 01/06/2023] Open
Abstract
Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. We demonstrate that the protein Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular “compass” for establishing and maintaining contact-triggered planar polarity. Furthermore, these processes may be mediated through interaction with the polarity regulator PARD3. This interaction, mediated by Daple's PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by tyrosine phosphorylation on Daple's PBM by receptor and non-receptor tyrosine kinases, such as Src. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it, thereby revealing an unexpected role of Daple as a platform for signal integration and gradient sensing for tyrosine-based signals within the planar cell polarity pathway.
Daple localizes to cell junction, regulates planar cell migration Localization requires Daple's C-terminal PDZ-binding motif (PBM) The PBM binds a PDZ module of the polarity determinant PARD3 The Daple⋅PARD3 interaction is regulated by tyrosine-based signals
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Carneiro I, Quintela-Vieira F, Lobo J, Moreira-Barbosa C, Menezes FD, Martins AT, Oliveira J, Silva R, Jerónimo C, Henrique R. Expression of EMT-Related Genes CAMK2N1 and WNT5A is increased in Locally Invasive and Metastatic Prostate Cancer. J Cancer 2019; 10:5915-5925. [PMID: 31762801 PMCID: PMC6856586 DOI: 10.7150/jca.34564] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 07/16/2019] [Indexed: 12/20/2022] Open
Abstract
Purpose: Prostate cancer (PCa) varies clinically from very indolent, not requiring therapeutic intervention, to highly aggressive, entailing radical treatment. Currently, stratification of PCa aggressiveness is mostly based on Gleason score, serum PSA and TNM stage, but outcome prediction in an individual basis is suboptimal. Thus, perfecting pre-therapeutic discrimination between indolent and aggressive PCa, avoiding overtreatment is a major challenge. Epithelial to mesenchymal transition (EMT) allows epithelial cells to acquire mesenchymal properties, constituting a critical step in tumor invasion and metastization. Thus, we hypothesized that EMT-related markers might allow for improved assessment of PCa aggressiveness. Methods and Results: Using RealTime ready Custom Panel 384 assay, 93 EMT-related genes were assessed in normal prostate tissues (NPT, n=5), stage pT2a+b-PCa (n=5) and stage pT3b-PCa (n=5), from which CAMK2N1, CD44, KRT14, TGFβ3 and WNT5A genes emerged as the most significantly altered. Expression levels were then evaluated in a larger series (16 NPT and 94 PCa) of frozen tissues using quantitative RT-PCR. Globally, CAMK2N1, CD44 and WNT5A displayed higher expression levels at higher stages and less differentiated PCa. CAMK2N1 and WNT5A immunoexpression analysis disclosed significantly lower expression in NPT and increasing proportion of high-expression cases from pT2a+b to pT3b and metastatic PCa. Furthermore, higher CAMK2N1 and WNT5A transcript levels associated with shorter disease-free and disease-specific survival. In multivariable analysis, a trend for WNT5A expression levels to independently predict DFS was disclosed (p=0.056). Conclusions: Globally, our findings suggest an association between PCa aggressiveness and increased expression of CAMK2N1 and WNT5A, reflecting the acquisition of effective EMT characteristics by PCa cells.
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Affiliation(s)
- Isa Carneiro
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Filipa Quintela-Vieira
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,School of Health, Polytechnic of Porto (ESS), R. Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal
| | - João Lobo
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal
| | - Catarina Moreira-Barbosa
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Francisco Duarte Menezes
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Ana Teresa Martins
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Jorge Oliveira
- Department of Urology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Regina Silva
- School of Health, Polytechnic of Porto (ESS), R. Dr. António Bernardino de Almeida 400, 4200-072 Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center of Portuguese Oncology Institute of Porto (GEBC CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal
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An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma. Cells 2019; 8:cells8091060. [PMID: 31510045 PMCID: PMC6770184 DOI: 10.3390/cells8091060] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/29/2019] [Accepted: 09/05/2019] [Indexed: 12/19/2022] Open
Abstract
Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines.
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Shi D, Wang H, Ding M, Yang M, Li C, Yang W, Chen L. MicroRNA-26a-5p inhibits proliferation, invasion and metastasis by repressing the expression of Wnt5a in papillary thyroid carcinoma. Onco Targets Ther 2019; 12:6605-6616. [PMID: 31496749 PMCID: PMC6701645 DOI: 10.2147/ott.s205994] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 07/17/2019] [Indexed: 01/10/2023] Open
Abstract
Background Thyroid cancer (TC) is considered as the fastest growing malignancy in the human endocrine system, particularly papillary thyroid cancer (PTC). MicroRNAs (miRs) serve as a role in promoting or suppressing tumors in various types of malignant tumor including PTC. This study aims to explore whether microRNA-26a-5p (miR-26a-5p) could affect the proliferation, invasion and metastasis ability of PTC cells by regulating Wnt5a. Materials and methods The expression of miR-26a-5p was examined by qRT-PCR in PTC tissue samples (58 cases, mean age 53 years old) and PTC cell lines (K1 and BCPAP). Cell proliferation, invasion and migration were tested with CCK8 assay, colony formation assay, transwell invasion assay and wound healing assay, respectively. Luciferase reporting experiment was used to verify that Wnt5a is a molecular target of miR-26a-5p. The relationship between miR-26a-5p and Wnt5a was analyzed by qRT-PCR and Western blot and was further proved by Pearson's correlation analysis. Animal (24 nude mice) experiments were used to demonstrate that miR-26a-5p inhibits tumor growth by targeting Wnt5a. Results The expression of miR-26a-5p declined in PTC tissues (P<0.01). The expression of miR-26a-5 was also significantly down-regulated in PTC tissues with advanced TNM stages (P<0.01) and lymph node metastasis (P<0.01) compared with normal thyroid tissues. Compared with normal human thyroid cell line Nthy-ori 3-1, the expression of miR-26a-5p in K1 cells and BCPAP cells were nearly 4.02-fold (P<0.01) and 2.51-fold (P<0.01) reduced. Up regulation of miR-26a-5p inhibited proliferation, colony formation, invasion and migration of PTC cells. MiR-26a-5p negatively regulated Wnt5a expression (r=-0.887, P<0.01), yet Wnt5a overexpression reversed the tumor-suppressive effect of miR-26a-5p in PTC. Animal experiments further verified that miR-26a-5p inhibited PTC growth by targeting Wnt5a. Conclusion Overexpression of miR-26a-5p depresses proliferation, invasion, metastasis of PTC via Wnt5a. Therefore, miR-26a-5p may represent a potentially effective target gene for PTC.
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Affiliation(s)
- Dongliang Shi
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Haiyan Wang
- Department of Radiation Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Mingjian Ding
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Meng Yang
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Chenhao Li
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Wenhua Yang
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
| | - Liang Chen
- Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061000, People's Republic of China
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Abstract
Despite the clinical development of novel adjuvant and neoadjuvant chemotherapeutic drugs, metastatic breast cancer is one of the leading causes of cancer-related death among women. The present review focuses on the relevance, mechanisms, and therapeutic potential of targeting WNT5A as a future anti-metastatic treatment strategy for breast cancer patients by restoring WNT5A signaling as an innovative therapeutic option. WNT5A is an auto- and paracrine β-catenin-independent ligand that has been shown to induce tumor suppression as well as oncogenic signaling, depending upon cancer type. In breast cancer patients, WNT5A protein expression has been observed to be significantly reduced in between 45 and 75% of the cases and associated with early relapse and reduced disease-free survival. WNT5A triggers various downstream signaling pathways in breast cancer that primarily affect tumor cell migration and invasion. The accumulated in vitro results reveal that treatment of WNT5A-negative breast cancer cells with recombinant WNT5A caused different tumor-suppressive responses and in particular it impaired migration and invasion. The anti-migratory/invasive and anti-metastatic effects of reconstituting WNT5A signaling by the small WNT5A mimicking peptide Foxy5 form the basis for two successful clinical phase 1-studies aiming at determining safety and pharmacokinetics as well as defining dose-level for a subsequent phase 2-study. We conclude that re-installation of WNT5A signaling is an attractive and promising anti-metastatic therapeutic approach for future treatment of WNT5A-negative breast cancer patients.
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Pavlidis ET, Pavlidis TE. A Review of Primary Thyroid Lymphoma: Molecular Factors, Diagnosis and Management. J INVEST SURG 2019; 32:137-142. [PMID: 29058491 DOI: 10.1080/08941939.2017.1383536] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/19/2017] [Indexed: 02/08/2023]
Abstract
UNLABELLED Purpose/aim: To focus on current aspects of primary thyroid lymphoma (PTL), which is a rare clinical entity usually manifested by a rapidly growing mass in the neck that can cause pressure symptoms. MATERIALS AND METHODS Relevant papers in PubMed published through June 2017 were selected to track updated information about PTL with an emphasis on diagnosis and novel therapeutic management. RESULTS The most frequent cases include non-Hodgkin lymphoma derived from B-cells, mainly diffuse large B-cell lymphoma (DLBCL) followed by mucosa-associated lymphoid tissue (MALT) lymphoma or a mixed type. Other subtypes are less common. Lymphomas derived from T-cells and Hodgkin lymphomas are extremely rare. Hashimoto's autoimmune thyroiditis has been implicated as a risk factor for lymphoma. At the molecular level, the Wnt5a protein and its receptor Ror2 are involved in the course of the disease. Ultrasonography, fine needle aspiration (FNA) biopsy, and core or open biopsy combined with new diagnostic facilities contribute to an accurate diagnosis. An increased potential exists for a cure without the need for a radical surgical procedure. Modern chemoradiation therapy plus the monoclonal antibody rituximab, which acts against CD20, have limited the need for surgical interventions and provide an excellent outcome in most cases. However, some cases have resulted in treatment failure or recurrence. CONCLUSIONS A multidisciplinary approach must be used to define the management policy in each case. Future efforts by researchers are likely to be focused on the molecular level.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biopsy
- Chemoradiotherapy/methods
- Clinical Trials as Topic
- Disease-Free Survival
- Humans
- Lymphoma, B-Cell, Marginal Zone/diagnosis
- Lymphoma, B-Cell, Marginal Zone/mortality
- Lymphoma, B-Cell, Marginal Zone/therapy
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/prevention & control
- Patient Care Team
- Prognosis
- Receptor Tyrosine Kinase-like Orphan Receptors/metabolism
- Rituximab/therapeutic use
- Thyroid Gland/diagnostic imaging
- Thyroid Gland/pathology
- Thyroid Neoplasms/diagnosis
- Thyroid Neoplasms/mortality
- Thyroid Neoplasms/therapy
- Thyroidectomy
- Wnt-5a Protein/metabolism
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Affiliation(s)
- Efstathios T Pavlidis
- a Second Surgical Propedeutic Department , Aristotle University of Thessaloniki, Medical School, Prof. Theodoros E Pavlidis (Department Head), Hippocration Hospital , Konstantinoupoleos 49, Thessaloniki , Greece
| | - Theodoros E Pavlidis
- a Second Surgical Propedeutic Department , Aristotle University of Thessaloniki, Medical School, Prof. Theodoros E Pavlidis (Department Head), Hippocration Hospital , Konstantinoupoleos 49, Thessaloniki , Greece
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Peng KY, Chang HM, Lin YF, Chan CK, Chang CH, Chueh SCJ, Yang SY, Huang KH, Lin YH, Wu VC, Wu KD. miRNA-203 Modulates Aldosterone Levels and Cell Proliferation by Targeting Wnt5a in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab 2018; 103:3737-3747. [PMID: 30085132 DOI: 10.1210/jc.2018-00746] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/27/2018] [Indexed: 02/13/2023]
Abstract
CONTEXT The aberrant expression or alternation of miRNA in the pathogenesis of aldosterone-producing adenomas (APAs) is still largely unknown. OBJECTIVE We investigated the role of miRNA-203 (screened from miRNA microarrays) and elucidated its effects on the Wnt/β-catenin pathway regarding aldosterone production and cell proliferation in APAs. METHODS miR-203 expression was upregulated or downregulated by transfecting miR-203 mimics or inhibitors into primary APA cells, the human adrenocortical cell line HAC15, and C57BL/6 mice. In vitro and biochemical data were correlated with the respective clinical parameters of APAs to evaluate their clinical importance. RESULTS The expression of miR-203 in human APA samples was significantly lower than that of peritumor adrenal samples. Tumoral miR-203 abundance correlated negatively with both plasma aldosterone level and tumor size in patients with APAs. miR-203 inhibitors increased aldosterone production and cell proliferation in HAC15 cells, and restoration of expression via miR-203 mimics showed decreased cell proliferation and aldosterone hypersecretion in APA cell cultures. In vivo selective inhibition of miR-203 via intra-adrenal injection of miR-203 inhibitors in mice led to a substantial increase in systolic blood pressure and plasma aldosterone levels. Additionally, the dual-luciferase reporter assay demonstrated that WNT5A is a direct target of miR-203. Furthermore, plasma Wnt5a levels in adrenal vein sampling were helpful in differentiating tumor localization, and preoperative plasma Wnt5a levels predicted the cure of hypertension after adrenalectomy. CONCLUSION We have demonstrated that attenuated miR-203 expression in APAs increases aldosterone production and the tumorigenesis of adrenal cells by activating the Wnt5a/β-catenin pathway.
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Affiliation(s)
- Kang-Yung Peng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Huang-Ming Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Feng Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chieh-Kai Chan
- Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin Chu, Taiwan
| | - Chia-Hui Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, Hualien, Taiwan
| | - Shih-Chieh Jeff Chueh
- Cleveland Clinic Lerner College of Medicine and Glickman Urological and Kidney Institute, Cleveland Clinic, Ohio
| | - Shao-Yu Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kuo-How Huang
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hung Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- TAIPAI (Taiwan Primary Aldosteronism Investigation), Taipei, Taiwan
| | - Vin-Cent Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- TAIPAI (Taiwan Primary Aldosteronism Investigation), Taipei, Taiwan
| | - Kwan-Dun Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- TAIPAI (Taiwan Primary Aldosteronism Investigation), Taipei, Taiwan
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miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a. Int Urol Nephrol 2018; 50:1811-1819. [DOI: 10.1007/s11255-018-1959-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 08/07/2018] [Indexed: 10/28/2022]
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Coopes A, Henry CE, Llamosas E, Ford CE. An update of Wnt signalling in endometrial cancer and its potential as a therapeutic target. Endocr Relat Cancer 2018; 25:ERC-18-0112. [PMID: 30093601 DOI: 10.1530/erc-18-0112] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 12/20/2022]
Abstract
Endometrial cancer is the most common gynaecological malignancy in developed nations, and its prevalence is rising as women defer or decide not to have children and as obesity rises, both key risk factors. Despite this, treatment options remain limited, particularly for advanced or refractory disease. New genomic analyses have revealed distinct mutational profiles with therapeutic and prognostic potential. Wnt signalling, which is pivotal in embryogenesis, healing and homeostasis, is of importance in the endometrium and has been linked to carcinogenesis. This review aims to update and discuss the current evidence for the role of β-catenin dependent and independent Wnt signalling, including the ROR receptors in the endometrium and its potential as a therapeutic target, in light of recent trials of Wnt-targeted therapy in multiple tumour types.
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Affiliation(s)
- Amy Coopes
- A Coopes, School of Women's and Children's Health, University of New South Wales Adult Cancer Program, Sydney, Australia
| | - Claire E Henry
- C Henry, School of Women's and Children's Health, University of New South Wales Adult Cancer Program, Sydney, Australia
| | - Estelle Llamosas
- E Llamosas, School of Women's and Children's Health, University of New South Wales Adult Cancer Program, Sydney, Australia
| | - Caroline Elizabeth Ford
- C Ford, School of Women's and Children's Health, University of New South Wales Adult Cancer Program, Sydney, Australia
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