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Zhao G, Zeng Y, Cheng W, Karkampouna S, Papadopoulou P, Hu B, Zang S, Wezenberg E, Forn-Cuní G, Lopes-Bastos B, Julio MKD, Kros A, Snaar-Jagalska BE. Peptide-Modified Lipid Nanoparticles Boost the Antitumor Efficacy of RNA Therapeutics. ACS NANO 2025; 19:13685-13704. [PMID: 40176316 PMCID: PMC12004924 DOI: 10.1021/acsnano.4c14625] [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: 10/16/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
RNA therapeutics offer a promising approach to cancer treatment by precisely regulating cancer-related genes. While lipid nanoparticles (LNPs) are currently the most advanced nonviral clinically approved vectors for RNA therapeutics, their antitumor efficacy is limited by their unspecific hepatic accumulation after systemic administration. Thus, there is an urgent need to enhance the delivery efficiency of LNPs to target tumor-residing tissues. Here, we conjugated the cluster of differentiation 44 (CD44)-specific targeting peptide A6 (KPSSPPEE) to the cholesterol of LNPs via PEG, named AKPC-LNP, enabling specific tumor delivery. This modification significantly improved delivery to breast cancer cells both in vitro and in vivo, as shown by flow cytometry and confocal microscopy. We further used AKPC-siYT to codeliver siRNAs targeting the transcriptional coactivators YAP and TAZ, achieving potent gene silencing and increased cell death in both 2D cultures and 3D tumor spheroids, outperforming unmodified LNPs. In a breast tumor cell xenografted zebrafish model, systemically administered AKPC-siYT induced robust silencing of YAP/TAZ and downstream genes and significantly enhanced tumor suppression compared to unmodified LNPs. Additionally, AKPC-siYT effectively reduced proliferation in prostate cancer organoids and tumor growth in a patient-derived xenograft (PDX) model. Overall, we developed highly efficient AKPC-LNPs carrying RNA therapeutics for targeted cancer therapy.
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Affiliation(s)
- Gangyin Zhao
- Department
of Cellular Tumor Biology, Leiden Institute of Biology, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
- Shenzhen
Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 51800, China
| | - Ye Zeng
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Wanli Cheng
- Urology
Research Laboratory, Department for BioMedical Research, University of Bern, Bern 3010, Switzerland
| | - Sofia Karkampouna
- Urology
Research Laboratory, Department for BioMedical Research, University of Bern, Bern 3010, Switzerland
- Department
of Urology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Panagiota Papadopoulou
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Bochuan Hu
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Shuya Zang
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Emma Wezenberg
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Gabriel Forn-Cuní
- Department
of Cellular Tumor Biology, Leiden Institute of Biology, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Bruno Lopes-Bastos
- Department
of Cellular Tumor Biology, Leiden Institute of Biology, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - Marianna Kruithof-de Julio
- Department
of Urology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Alexander Kros
- Department
of Supramolecular & Biomaterials Chemistry, Leiden Institute of
Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
| | - B. Ewa Snaar-Jagalska
- Department
of Cellular Tumor Biology, Leiden Institute of Biology, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
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2
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Xu Q, Jin Z, Yuan Z, Yu Z, Gao J, Zhao R, Li H, Ren H, Cao B, Wei B, Jiang L. YAP Promotes Chemoresistance to 5-FU in Colorectal Cancer Through mTOR/GLUT3 Axis. J Cancer 2024; 15:6784-6797. [PMID: 39668819 PMCID: PMC11632981 DOI: 10.7150/jca.100179] [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: 06/27/2024] [Accepted: 09/28/2024] [Indexed: 12/14/2024] Open
Abstract
Background: Although chemoresistance constitutes a significant barrier to the effectiveness of chemotherapy in colorectal cancer (CRC), its precise mechanisms remain unclear. YAP functions as an oncogene in various malignancies. However, the relationship between YAP and chemoresistance in CRC needs clarification. Methods: The expression level of YAP in CRC tissues was assessed through immunohistochemistry (IHC), and the impact of YAP on CRC cell chemoresistance was evaluated using the Cell Counting Kit-8, EdU, and flow cytometry assays. Meanwhile, tumor proliferation was assessed in vivo by analyzing the expression of PCNA and Ki-67 in subcutaneous tumors via IHC. In addition, the TUNEL assay was employed to evaluate tumor apoptosis levels and western blot was utilized to detect the mTOR/GLUT3 pathway-related protein expression to provide insights into the underlying mechanism. Results: YAP was highly expressed in CRC tissues and correlated with patient prognosis and clinicopathological features. Bioinformatic analysis based on the TCGA database revealed that YAP was associated with DNA replication, glycolysis, and the mTOR pathway. Meanwhile, YAP could enhance chemoresistance and glycolysis in CRC cells both in vitro and in vivo. Additional mechanistic experiments unveiled that YAP promoted CRC cell chemoresistance via the mTOR/GLUT3 axis. Conclusion: This study validated the role of YAP as an oncogene in CRC, as it promoted chemoresistance through the mTOR/GLUT3 axis. These results suggested YAP as a potential target for promoting the efficacy of chemotherapy in patients with CRC.
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Affiliation(s)
- Qixuan Xu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Zhesi Jin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu,China
| | - Zhen Yuan
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Zhiyuan Yu
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Jingwang Gao
- Department of General Surgery, Linfen Central Hospital, Linfen, Shanxi, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Huiguang Ren
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Linhua Jiang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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Zhang H, Yin M, Hu Y, Jiang M, Lu M, Wu Y. Prognostic analysis of Yes-associated protein 1 in patients with colorectal cancer. A systematic review and meta-analysis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:148-156. [PMID: 36177818 DOI: 10.17235/reed.2022.8472/2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
BACKGROUND colorectal cancer (CRC) is the most common carcinoma worldwide, but a lack of effective prognostic markers limits clinical diagnosis and treatment. Yes-associated protein 1 (YAP1) is an effector of the HIPPO-pathway, which plays a critical role in cancer development and prognosis, including CRC. However, previous reports have suggested that it plays a dual role in CRC. METHODS a meta-analysis using RevMan 5.4 and Stata 14.0 was performed to evaluate the relationship between YAP1 and clinical outcomes of CRC, after searching for eligible studies in the PubMed, Web of Science and Embase databases. Online datasets GEPIA and LOGpc were also used to calculate survival results and for comparison with the meta-analysis results. Besides, "DESeq" packages were used for the expression analysis of YAP1 from the TCGA dataset. RESULTS YAP1 was overexpressed in the cancer tissues when compared to normal tissues in patients with CRC from the TCGA database (p = 0.000164) and GEPIA database. A total of 10 studies involving 2305 patients from the literature were selected. Pooled HR indicated that overexpression of YAP1 was associated with poor clinical outcomes (HR = 1.70, 95 % CI: 1.28-2.26, p = 0.0003). Subgroup analysis showed a clear correlation between overexpression of YAP1 and worse survival rate in Chinese patients (HR = 1.94, 95 % CI: 1.40-2.69, p = 0.0001), nuclear YAP1 overexpression (HR = 2.07, 95 % CI: 1.29-3.31, p = 0.003), 60 months of follow-up (HR = 1.89, 95 % CI: 1.30-2.73, p = 0.0008), IHC test (HR = 1.65, 95 % CI: 1.17-2.33, p = 0.005), IHC combined with other tests (HR = 1.77, 95 % CI: 1.13-2.77, p = 0.01) and multivariate analysis (HR = 1.70, 95 % CI: 1.24-2.31, p = 0.0009). Nevertheless, disease-free survival (DFS) showed no significant results in the patients with CRC in our meta-analysis (HR = 1.38, 95 % CI: 0.51-3.75, p = 0.52) as well as in the GEPIA and LOGpc databases. Meanwhile, YAP1 overexpression was also significantly associated with worse overall survival (OS) in GSE17536, GSE40967, GSE29623 and GSE71187. CONCLUSION YAP1 overexpression is common in CRC tissues. Overexpression of YAP1 in CRC patients, particularly in the nucleus, might be related to shorter OS, maybe in the early stages. YAP1 could serve as a potential predictor of poor prognosis in CRC.
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Affiliation(s)
- Hui Zhang
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | | | - Yu Hu
- Wuhan Mental Health Center, Tongji Medical College of Huazhong University,
| | - Mingming Jiang
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | - Mingliang Lu
- Gastroenterology, The Second Affiliated Hospital. Kunming Medical University,
| | - Yajuan Wu
- Radiotherapy, The Second Chest Radiotherapy Ward of Shanxi Cancer Hospital, china
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Ma L, Gao F, Dong W, Song Q, Jia Y. Association Study between SNPs in MST1 and MST2 and H. pylori Infection as well as Noncardia Gastric Carcinogenesis. Dig Dis 2024; 42:230-239. [PMID: 38295774 DOI: 10.1159/000536507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/26/2024] [Indexed: 06/05/2024]
Abstract
INTRODUCTION Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for noncardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in mammalian sterile 20-like kinase 1 (MST1) and MST2, H. pylori (H. pylori) infection, and the risk of noncardia gastric cancer (GC). METHODS A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and TaqMan method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of noncardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. RESULTS The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT + CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of noncardia gastric cancer compared to the AA + AT genotype. None of the SNPs were associated with noncardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of noncardia gastric cancer. CONCLUSIONS The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and noncardia gastric cancer risk, respectively.
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Affiliation(s)
- Licong Ma
- School of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Fang Gao
- School of Medical Technology and Anesthesiology, Baotou Medical College, Baotou, China
| | - Wenjie Dong
- School of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Qiang Song
- School of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Yanbin Jia
- School of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, China
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Doxtater K, Tripathi MK, Sekhri R, Hafeez BB, Khan S, Zafar N, Behrman SW, Yallapu MM, Jaggi M, Chauhan SC. MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway. Life Sci Alliance 2023; 6:e202301975. [PMID: 37793774 PMCID: PMC10551643 DOI: 10.26508/lsa.202301975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
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Affiliation(s)
- Kyle Doxtater
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Radhika Sekhri
- Department of Pathology, Montefiore Medical Center College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Nadeem Zafar
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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Joseph I, Flores J, Farrell V, Davis J, Bianchi‐Smak J, Feng Q, Goswami S, Lin X, Wei Z, Tong K, Feng Z, Verzi MP, Bonder EM, Goldenring JR, Gao N. RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells. EMBO Rep 2023; 24:e56240. [PMID: 37424454 PMCID: PMC10481667 DOI: 10.15252/embr.202256240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/11/2023] Open
Abstract
RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.
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Affiliation(s)
- Ivor Joseph
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - Juan Flores
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | | | - Justin Davis
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | | | - Qiang Feng
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | | | - Xiang Lin
- Department of Computer SciencesNew Jersey Institute of TechnologyNewarkNJUSA
| | - Zhi Wei
- Department of Computer SciencesNew Jersey Institute of TechnologyNewarkNJUSA
| | - Kevin Tong
- Department of GeneticsRutgers UniversityNew BrunswickNJUSA
| | - Zhaohui Feng
- Rutgers Cancer Institute of New JerseyNew BrunswickNJUSA
| | | | - Edward M Bonder
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
| | - James R Goldenring
- Section of Surgical Sciences and Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Nan Gao
- Department of Biological SciencesRutgers UniversityNewarkNJUSA
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Yu H, Qu T, Yang J, Dai Q. Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression. Cell Commun Signal 2023; 21:75. [PMID: 37046308 PMCID: PMC10100184 DOI: 10.1186/s12964-023-01096-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/07/2023] [Indexed: 04/14/2023] Open
Abstract
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a key messenger that mediates several central and peripheral functions in the human body. Emerging evidence indicates that serotonin is critical in tumorigenesis, but its role in colorectal cancer remains elusive. Herein, we report that serotonin transporter (SERT) transports serotonin into colorectal cancer cells, enhancing Yes-associated protein (YAP) expression and promoting in vitro and in vivo colon cancer cell growth. Once within the cells, transglutaminase 2 (TG2) mediates RhoA serotonylated and activates RhoA-ROCK1/2 signalling to upregulate YAP expression in SW480 and SW1116 cells. Blocking SERT with citalopram reversed the serotonin-induced YAP expression and cell proliferation, inhibiting serotonin's effects on tumour formation in mice. Moreover, SERT expression was correlated with YAP in pathological human colorectal cancer samples and the levels of 5-HT were highly significant in the serum of patients with colorectal cancer. Together, our findings suggested that serotonin enters cells via SERT to activate RhoA/ROCK/YAP signalling to promote colon cancer carcinogenesis. Consequently, targeting serotonin-SERT-YAP axis may be a potential therapeutic strategy for colorectal cancer. Video abstract.
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Affiliation(s)
- Huangfei Yu
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
- Clinical Cancer Center of Zunyi, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China.
| | - Tianyin Qu
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Clinical Cancer Center of Zunyi, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
| | - Jinlan Yang
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
| | - Qing Dai
- Department of Oncology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
- Scientific Research Center, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563003, Guizhou, China
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9
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Retraction: Overexpression of YAP and TAZ Is an Independent Predictor of Prognosis in Colorectal Cancer and Related to the Proliferation and Metastasis of Colon Cancer Cells. PLoS One 2023; 18:e0281614. [PMID: 36749756 PMCID: PMC9904481 DOI: 10.1371/journal.pone.0281614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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10
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Wang CH, Baskaran R, Ng SSC, Wang TF, Li CC, Ho TJ, Hsieh DJY, Kuo CH, Chen MC, Huang CY. Platycodin D confers oxaliplatin Resistance in Colorectal Cancer by activating the LATS2/YAP1 axis of the hippo signaling pathway. J Cancer 2023; 14:393-402. [PMID: 36860929 PMCID: PMC9969589 DOI: 10.7150/jca.77322] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/06/2022] [Indexed: 02/04/2023] Open
Abstract
Oxaliplatin-based therapy is used as a first-line drug to treat metastatic colorectal cancer. However, long-term and repeated drug treatment resulted in drug resistance and the failure of chemotherapy. Various natural compounds were previously reported to act as chemosensitizers to reverse drug resistance. In this study, we found that platycodin D (PD), a saponin found in Platycodon grandiflorum, inhibited LoVo and OR-LoVo cells proliferation, invasion, and migration ability. Our results indicated that combined treatment of oxaliplatin with PD dramatically reduced the cellular proliferation in both LoVo and OR-LoVo cells. Furthermore, treatment with PD dose-dependently decreased LATS2/YAP1 hippo signaling and survival marker p-AKT expression, as well as increased cyclin-dependent kinase inhibitor proteins such as p21 and p27 expression. Importantly, PD activates and promotes YAP1 degradation through the ubiquitination and proteasome pathway. The nuclear transactivation of YAP was significantly reduced under PD treatment, leading to transcriptional inhibition of the downstream genes regulating cell proliferation, pro-survival, and metastasis. In conclusion, our results showed that PD is suitable as a promising agent for overcoming oxaliplatin-resistant colorectal cancer.
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Affiliation(s)
- Chien-Hao Wang
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan,Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Shawn Shang-Chuan Ng
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan,Ph.D. Program for Biotechnology Industry, China Medical University, Taichung 406, Taiwan
| | - Tso-Fu Wang
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan,School of Medicine Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien 97004, Taiwan
| | - Chi-Cheng Li
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan,Center of Stem Cell & Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Tsung-Jung Ho
- Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan,Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan,Department of Kinesiology and Health Science, College of William and Mary, Williamsburg, VA, USA
| | - Ming-Cheng Chen
- Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,✉ Corresponding author: Chih-Yang Huang Ph.D., Chair Professor, Cardiovascular and Mitochondria related diseases research center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan; Tel: +886-4-22053366 ext 3313. Fax: +886-4-22032295. E-mail address:
| | - Chih-Yang Huang
- Cardiovascular and Mitochondria related diseases research center, Hualien Tzu Chi Hospital, Hualien 970, Taiwan,Graduate Institute of Biomedicine, China Medical University, Taichung, Taiwan,Department of Biotechnology, Asia University, Taichung 413, Taiwan,Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan,✉ Corresponding author: Chih-Yang Huang Ph.D., Chair Professor, Cardiovascular and Mitochondria related diseases research center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan; Tel: +886-4-22053366 ext 3313. Fax: +886-4-22032295. E-mail address:
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11
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Ma FY, Zhou XH, Liang Q. Advances in understanding of role and mechanism of Hippo signaling pathway in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2023; 31:14-19. [DOI: 10.11569/wcjd.v31.i1.14] [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] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors, and most patients have a poor prognosis. Many studies have shown that the Hippo signaling pathway plays a key role in the occurrence and development of CRC by regulating CRC cell proliferation and apoptosis, tumor invasion and metastasis, autophagy, metabolic reprogramming, drug resistance, and other processes. This article reviews the latest progress in research of the expression of key molecules of the Hippo signaling pathway in CRC as well as the understanding of the mechanism by which this pathway regulates the occurrence and development of CRC.
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Affiliation(s)
- Fu-Yan Ma
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Xi-Han Zhou
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical College Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
| | - Qiao Liang
- Graduate School of Youjiang Medical College for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
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12
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Haji Ghaffari M, Mohammadzadeh M, Simonian M, Hashemi M, Sadeghi N, Negahdari B, Mazloomi M, Rabbani H. An Anti-TAZ Monoclonal Antibody Recognizing Cell Surface Expressed TAZ Protein in Human Tumor Cells. Avicenna J Med Biotechnol 2023; 15:14-20. [PMID: 36789121 PMCID: PMC9895982 DOI: 10.18502/ajmb.v15i1.11420] [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: 06/13/2022] [Accepted: 08/20/2022] [Indexed: 12/27/2022] Open
Abstract
Background WWTR1 or TAZ is a transcriptional co-activator protein expressed in cytoplasm which functions as the main downstream effector of the Hippo signaling pathway. This pathway is an evolutionally conserved signal cascade, which plays a pivotal role in organ size control and tumorigenesis. Ectopic expression of TAZ has already been observed in many malignancies, while the ectopic localization of TAZ is reported for the first time. The aim of this study was to produce a specific monoclonal antibody (mAb) against a synthetic peptide derived from WWTR1 protein to be used as a research tool in human carcinomas. Methods A 21-mer synthetic peptide (derived from human TAZ protein) was used for immunization of BALB/c mice after conjugation with Keyhole Limpet Haemocyanin (KLH) using hybridoma technology. The generated mAb reacted with the immunizing peptide employing ELISA assay. The reactivity of the antibody with native TAZ protein was assessed through Western blot, immunocytochemistry, and flow cytometry using different cancer cell lines. Results The produced mAb could recognize the immunizing peptide in ELISA and Kaff was 0.6×10-9 M. The produced anti-TAZ mAb unlike available commercial anti-TAZ antibody, was capable of specifically recognizing cell surface TAZ in human carcinoma cell lines including MCF-7, Raji, and A431 in Western blot, immunocytochemistry, and flow cytometry assays. As expected, no reactivity was observed using normal Peripheral Blood Mononuclear Cell (PBMC) from healthy donors. Conclusion Based on the results, TAZ is ectopically expressed on the surface of tumor cell lines which is not the case in normal cells. The generated mAb has a potential to be used as a research tool in studying the expression of TAZ in human carcinomas in different applications.
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Affiliation(s)
- Mozhan Haji Ghaffari
- Department of Medical Biotechnology, School of Advanced Science in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mahsa Mohammadzadeh
- Department of Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran
| | - Miganoosh Simonian
- Department of Medical Biotechnology, School of Advanced Science in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran
| | - Niloufar Sadeghi
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Science in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mohammadali Mazloomi
- Department of Medical Biotechnology, School of Advanced Science in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Hodjattallah Rabbani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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13
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Hu X, Zhang Y, Yu H, Zhao Y, Sun X, Li Q, Wang Y. The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective. Front Immunol 2022; 13:1012173. [PMID: 36479120 PMCID: PMC9719955 DOI: 10.3389/fimmu.2022.1012173] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction Dysregulation of the Hippo signaling pathway has been implicated in multiple pathologies, including cancer, and YAP1 is the major effector of the pathway. In this study, we assessed the role of YAP1 in prognostic value, immunomodulation, and drug response from a pan-cancer perspective. Methods We compared YAP1 expression between normal and cancerous tissues and among different pathologic stages survival analysis and gene set enrichment analysis were performed. Additionally, we performed correlation analyses of YAP1 expression with RNA modification-related gene expression, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint regulator expression, and infiltration of immune cells. Correlations between YAP1 expression and IC50s (half-maximal inhibitory concentrations) of drugs in the CellMiner database were calculated. Results We found that YAP1 was aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications, particularly m6A methylation. High expression of YAP1 was associated with poor survival outcomes in ACC, BLCA, LGG, LUAD, and PAAD. YAP1 expression was negatively correlated with the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, and positively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in pan-cancer. Higher YAP1 expression showed upregulation of TGF-β signaling, Hedgehog signaling, and KRAS signaling. IC50s of FDA-approved chemotherapeutic drugs capable of inhibiting DNA synthesis, including teniposide, dacarbazine, and doxorubicin, as well as inhibitors of hypoxia-inducible factor, MCL-1, ribonucleotide reductase, and FASN in clinical trials were negatively correlated with YAP1 expression. Discussion In conclusion, YAP1 is aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications. High expression of YAP1 is associated with poor survival outcomes in certain cancer types. YAP1 may promote tumor progression through immunosuppression, particularly by suppressing the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, as well as recruiting MDSCs and CAFs in pan-cancer. The tumor-promoting activity of YAP1 is attributed to the activation of TGF-β, Hedgehog, and KRAS signaling pathways. AZD2858 and varlitinib might be effective in cancer patients with high YAP1 expression.
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Affiliation(s)
- Xueqing Hu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingru Zhang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Yu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiyang Zhao
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoting Sun
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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14
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Li Y, Wu T, Peng Z, Tian X, Dai Q, Chen M, Zhu J, Xia S, Sun A, Yang W, Lin Q. ETS1 is a prognostic biomarker of triple-negative breast cancer and promotes the triple-negative breast cancer progression through the YAP signaling. Am J Cancer Res 2022; 12:5074-5084. [PMID: 36504910 PMCID: PMC9729895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/26/2022] [Indexed: 12/15/2022] Open
Abstract
E26 transcription factor-1 (ETS1) is involved in extracellular matrix remodeling, migratory infiltration and angiogenesis in tumors and known to play an important role in tumor progression. However, the mechanism by which ETS1 promotes tumor progression remains elusive. In this report, we show that ETS1 is highly expressed in breast tumor tissues and specifically associated with the tumor metastasis and poor survival in triple negative breast cancer (TNBC) tumors, upon analysis by immunohistochemical (IHC) staining of tumor samples from 240 breast cancer cases. Depletion of ETS1 in TNBC cells by shETS1 significantly inhibited the cell proliferation and migration. Mechanistically, knockdown of ETS1 in TNBC cells dramatically reduced expression of YAP and the YAP target genes, and overexpression of YAP in the ETS1 knockdown cells restored the cell proliferation and migration. These data indicate that YAP is a downstream effector mediating the ETS1-promoted TNBC cell proliferation and migration. Taken together, our results suggest that ETS1 promotes TNBC progression through the YAP signaling.
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Affiliation(s)
- Yanlin Li
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Tiantian Wu
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Ziluo Peng
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Xianyan Tian
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Qian Dai
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical UniversityHefei, Anhui, China
| | - Miao Chen
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China,The First People’s Hospital of ZhenjiangZhenjiang, Jiangsu, China
| | - Jun Zhu
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Song Xia
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Aiqin Sun
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Wannian Yang
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Qiong Lin
- School of Medicine, Jiangsu UniversityZhenjiang, Jiangsu, China
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15
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Koinis F, Chantzara E, Samarinas M, Xagara A, Kratiras Z, Leontopoulou V, Kotsakis A. Emerging Role of YAP and the Hippo Pathway in Prostate Cancer. Biomedicines 2022; 10:2834. [PMID: 36359354 PMCID: PMC9687800 DOI: 10.3390/biomedicines10112834] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/13/2022] [Accepted: 11/02/2022] [Indexed: 09/05/2023] Open
Abstract
The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. YAP overexpression and nuclear localization has been linked to poor prognosis and resistance to treatment, highlighting a therapeutic potential that may suggest innovative strategies to treat cancer. This review aimed to summarize available data on the biological function of the dysregulated Hippo pathway in PCa and identify knowledge gaps that need to be addressed for optimizing the development of YAP-targeted treatment strategies in patients likely to benefit.
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Affiliation(s)
- Filippos Koinis
- Department of Medical Oncology, University General Hospital of Larissa, 41221 Larissa, Greece
- Laboratory of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41500 Larissa, Greece
| | - Evangelia Chantzara
- Department of Medical Oncology, University General Hospital of Larissa, 41221 Larissa, Greece
| | - Michael Samarinas
- Department of Urology, General Hospital “Koutlibanio”, 41221 Larissa, Greece
| | - Anastasia Xagara
- Laboratory of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41500 Larissa, Greece
| | - Zisis Kratiras
- 3rd Urology Department University of Athens, “Attikon” University General Hospital, 12462 Chaidari, Greece
| | - Vasiliki Leontopoulou
- Department of Medical Oncology, University General Hospital of Larissa, 41221 Larissa, Greece
| | - Athanasios Kotsakis
- Department of Medical Oncology, University General Hospital of Larissa, 41221 Larissa, Greece
- Laboratory of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41500 Larissa, Greece
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16
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Wang LL, Zheng W, Liu XL, Yin F. Somatic mutations in FAT cadherin family members constitute an underrecognized subtype of colorectal adenocarcinoma with unique clinicopathologic features. World J Clin Oncol 2022; 13:779-788. [PMID: 36337316 PMCID: PMC9630991 DOI: 10.5306/wjco.v13.i10.779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/25/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The FAT cadherin family members (FAT1, FAT2, FAT3 and FAT4) are conserved tumor suppressors that are recurrently mutated in several types of human cancers, including colorectal carcinoma (CRC). AIM To characterize the clinicopathologic features of CRC patients with somatic mutations in FAT cadherin family members. METHODS We analyzed 526 CRC cases from The Cancer Genome Atlas PanCancer Atlas dataset. CRC samples were subclassified into 2 groups based on the presence or absence of somatic mutations in FAT1, FAT2, FAT3 and FAT4. Individual clinicopathological data were collected after digital slide review. Statistical analysis was performed using t tests and chi-square tests. RESULTS This CRC study cohort had frequent mutations in the FAT1 (10.5%), FAT2 (11.2%), FAT3 (15.4%) and FAT4 (23.4%) genes. Two hundred CRC patients (38.0%) harbored somatic mutations in one or more of the FAT family genes and were grouped into the FAT mutated CRC subtype. The FAT-mutated CRC subtype was more commonly located on the right side of the colon (51.0%) than in the rest of the cohort (30.1%, P < 0.001). It showed favorable clinicopathologic features, including a lower rate of positive lymph nodes (pN1-2: 33.5% vs 46.4%, P = 0.005), a lower rate of metastasis to another site or organ (pM1: 7.5% vs 16.3%, P = 0.006), and a trend toward an early tumor stage (pT1-2: 25.0% vs 18.7%, P = 0.093). FAT somatic mutations were significantly enriched in microsatellite instability CRC (28.0% vs 2.1%, P < 0.001). However, FAT somatic mutations in microsatellite stable CRC demonstrated similar clinicopathologic behaviors, as well as a trend of a better disease-free survival rate (hazard ratio = 0.539; 95% confidence interval: 0.301-0.967; log-rank P = 0.073). CONCLUSION FAT cadherin family genes are frequently mutated in CRC, and their mutation profile defines a subtype of CRC with favorable clinicopathologic characteristics.
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Affiliation(s)
- Liang-Li Wang
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Xiu-Li Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
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17
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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022; 10:biomedicines10102512. [PMID: 36289774 PMCID: PMC9599207 DOI: 10.3390/biomedicines10102512] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.
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18
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HMG-CoA Reductase Inhibitor Statins Activate the Transcriptional Activity of p53 by Regulating the Expression of TAZ. Pharmaceuticals (Basel) 2022; 15:ph15081015. [PMID: 36015162 PMCID: PMC9412369 DOI: 10.3390/ph15081015] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 12/18/2022] Open
Abstract
Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy.
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Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3798694. [PMID: 35911146 PMCID: PMC9325623 DOI: 10.1155/2022/3798694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/07/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
Yes-associated protein 1 (YAP1) is involved in the development of a variety of malignancies. However, the prognosis of malignant digestive tumors with YAP1 expression is still controversial. This study searched 31 articles with 36 data sets of 4023 patients to explore the role of YAP1 expression on the prognosis of digestive malignant tumors by searching the PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library databases. Specifically, relevant cancer expression matrix data were downloaded from The Cancer Genome Atlas (TCGA) database. In this meta-analysis, quantitative analysis showed that the overexpression of YAP1 was not conducive to OS (1.62, 95% CI (1.38, 1.90), P=0.001) and DFS (1.59, 95% CI (1.31, 1.93), P=0.001) in patients with digestive malignant tumors. In addition, TCGA database analysis showed that YAP1 was overexpressed in gastric cancer, cholangiocarcinoma, and colorectal cancer. Survival analysis showed that the patients with high expression of YAP1 in pancreatic cancer have a poor OS (MST: 394 vs. 691 days, P < 0.0001) and DFS (MST: 371 vs. 542 days, P=0.026) prognosis. YAP1 may be a molecular marker that effectively predicts the survival of malignant digestive tumors, especially pancreatic cancer, and is a potential therapeutic target for malignant digestive tumors.
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20
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ENO2 Promotes Colorectal Cancer Metastasis by Interacting with the LncRNA CYTOR and Activating YAP1-Induced EMT. Cells 2022; 11:cells11152363. [PMID: 35954207 PMCID: PMC9367517 DOI: 10.3390/cells11152363] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/24/2022] [Accepted: 07/29/2022] [Indexed: 01/27/2023] Open
Abstract
The glycolytic enzyme enolase 2 (ENO2) is dysregulated in many types of cancer. However, the roles and detailed molecular mechanism of ENO2 in colorectal cancer (CRC) metastasis remain unclear. Here, we performed a comprehensive analysis of ENO2 expression in 184 local CRC samples and samples from the TCGA and GEO databases and found that ENO2 upregulation in CRC samples was negatively associated with prognosis. By knocking down and overexpressing ENO2, we found that ENO2 promoted CRC cell migration and invasion, which is dependent on its interaction with the long noncoding RNA (lncRNA) CYTOR, but did not depend on glycolysis regulation. Furthermore, CYTOR mediated ENO2 binding to large tumor suppressor 1 (LATS1) and competitively inhibited the phosphorylation of Yes-associated protein 1 (YAP1), which ultimately triggered epithelial–mesenchymal transition (EMT). Collectively, these findings highlight the molecular mechanism of the ENO2–CYTOR interaction, and ENO2 could be considered a potential therapeutic target for CRC.
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21
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Wang Y, Nie H, Li H, Liao Z, Yang X, He X, Ma J, Zhou J, Ou C. The Hippo Pathway Effector Transcriptional Co-activator With PDZ-Binding Motif Correlates With Clinical Prognosis and Immune Infiltration in Colorectal Cancer. Front Med (Lausanne) 2022; 9:888093. [PMID: 35865173 PMCID: PMC9295930 DOI: 10.3389/fmed.2022.888093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
The transcriptional co-activator with PDZ-binding motif (TAZ) is a downstream effector of the Hippo pathway. It has been identified as an oncogene in certain tumor types; however, the function and role of TAZ in colorectal cancer (CRC) has not been illustrated. Here, we aimed to analyze the expression and role of TAZ in CRC. In this study, we investigated the expression level of TAZ in 127 CRC and matched adjacent normal tissues by immunohistochemistry (IHC) and analyzed its correlation with clinicopathological characteristics in CRC. Moreover, we further analyzed the role of TAZ in the CRC-associated immunology using integrative bioinformatic analyses. The cBioPortal and WebGestalt database were used to analyze the co-expressed genes and related pathways of TAZ in CRC by gene ontology (GO) and KEGG enrichment analyses. Meanwhile, the correlations between TAZ and the infiltrating immune cells and gene markers were analyzed by TIMER database. Our study revealed that TAZ expression is higher in CRC tissues than in matched adjacent non-tumor tissues. In addition, CRC patients with higher TAZ expression demonstrated poor overall survival (OS) and recurrent-free survival rates as compared to CRC patients with lower expression of TAZ. Furthermore, the TAZ expression was identified to closely associate with the immune infiltration of CD4 + T, CD8 + T, and B cells. Taken together, our findings suggest that TAZ may serve as a promising prognostic biomarker and therapeutic target in CRC.
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Affiliation(s)
- Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Huiling Li
- Department of Pathology, Rizhao City People’s Hospital, Rizhao, China
| | - Zhiming Liao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xuejie Yang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Jian Ma
- Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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22
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O-GlcNAcylation: An Emerging Protein Modification Regulating the Hippo Pathway. Cancers (Basel) 2022; 14:cancers14123013. [PMID: 35740678 PMCID: PMC9221189 DOI: 10.3390/cancers14123013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/16/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The contact point between the Hippo pathway, which serves as a central hub for various external environments, and O-GlcNAcylation, which is a non-canonical glycosylation process acting as a dynamic regulator in various signal transduction pathways, has recently been identified. This review aims to summarize the function of O-GlcNAcylation as an intrinsic and extrinsic regulator of the Hippo pathway. Abstract The balance between cellular proliferation and apoptosis and the regulation of cell differentiation must be established to maintain tissue homeostasis. These cellular responses involve the kinase cascade-mediated Hippo pathway as a crucial regulator. Hence, Hippo pathway dysregulation is implicated in diverse diseases, including cancer. O-GlcNAcylation is a non-canonical glycosylation that affects multiple signaling pathways through its interplay with phosphorylation in the nucleus and cytoplasm. An abnormal increase in the O-GlcNAcylation levels in various cancer cells is a potent factor in Hippo pathway dysregulation. Intriguingly, Hippo pathway dysregulation also disrupts O-GlcNAc homeostasis, leading to a persistent elevation of O-GlcNAcylation levels, which is potentially pathogenic in several diseases. Therefore, O-GlcNAcylation is gaining attention as a protein modification that regulates the Hippo pathway. This review presents a framework on how O-GlcNAcylation regulates the Hippo pathway and forms a self-perpetuating cycle with it. The pathological significance of this self-perpetuating cycle and clinical strategies for targeting O-GlcNAcylation that causes Hippo pathway dysregulation are also discussed.
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Role of Yes-Associated Protein in Psoriasis and Skin Tumor Pathogenesis. J Pers Med 2022; 12:jpm12060978. [PMID: 35743763 PMCID: PMC9225571 DOI: 10.3390/jpm12060978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022] Open
Abstract
Psoriasis and skin tumors (such as basal cell carcinoma, squamous cell carcinoma, and melanoma) are chronic diseases that endanger physical and mental health, and yet the causes are largely unknown and treatment options limited. The development of targeted drugs requires a better understanding of the exact pathogenesis of these diseases, and Yes-associated protein (YAP), a member of the Hippo signaling pathway, is believed to play an important role. Psoriasis and skin tumors are characterized by excessive cell proliferation, abnormal differentiation, vasodilation, and proliferation. Here, we review the literature related to YAP-associated disease mechanisms and discuss the latest research. YAP regulates cell apoptosis, proliferation, and differentiation; inhibits cell density and intercellular contacts and angiogenesis; and maintains the three-dimensional structure of the skin. These mechanisms may be associated with the occurrence and development of psoriasis and skin tumors. The results of recent studies have shown that YAP expression is increased in psoriasis and skin tumors. High expression of YAP in psoriasis and skin tumors may indicate its positive functions in skin inflammation and malignancies and may play an important role in disease pathogenesis. The study of new drugs targeting YAP can provide novel approaches for the treatment of skin diseases.
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He J, Chen S, Yu T, Chen W, Huang J, Peng C, Ding Y. Harmine suppresses breast cancer cell migration and invasion by regulating TAZ-mediated epithelial-mesenchymal transition. Am J Cancer Res 2022; 12:2612-2626. [PMID: 35812064 PMCID: PMC9251681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 05/27/2022] [Indexed: 06/15/2023] Open
Abstract
Breast cancer is a highly lethal disease due to cancer metastasis. Harmine (HM), a β-carboline alkaloid, is present in various medicinal plants. Our previous study demonstrated that HM suppresses cell proliferation and migration by regulating TAZ in breast cancer cells and accelerates apoptosis. Epithelial-mesenchymal transition (EMT) plays an important role in the development of breast cancer by inducing the characteristics of cancer stem cells, cancer metastasis and recurrence. Overexpression of TAZ was shown to mediate EMT in breast cancer cells. We aimed to investigate whether HM inhibits EMT and metastasis of breast cancer cells by targeting TAZ. In this study, the cells treated with HM or with downregulated expression of TAZ showed an increase in epithelial markers and decrease in mesenchymal markers in breast cancer cells. Consistently, the breast cancer cells treated with HM or with downregulated expression of TAZ showed suppressed migration and proliferation. Moreover, TAZ overexpression reversed EMT and metastasis induced by HM in breast cancer cells. Thus, HM suppresses EMT and metastasis and invasion by targeting TAZ in breast cancer cells. HM can be used as an anticancer drug for breast cancer treatment and chemoprevention.
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Affiliation(s)
- Jinrong He
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
| | - Shanshan Chen
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
| | - Tong Yu
- Department of Traditional Chinese Medicine, Humanwell Healthcare (Group) Co., Ltd.Wuhan 430075, Hubei, China
| | - Weiqun Chen
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
| | - Jin Huang
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
| | - Caixia Peng
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
| | - Yu Ding
- Key Laboratory for Molecular Diagnosis of Hubei ProvinceHubei, China
- Central Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430014, Hubei, China
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Fallah S, Beaulieu JF. Differential influence of YAP1 and TAZ on differentiation of intestinal epithelial cell: A review. Anat Rec (Hoboken) 2022; 306:1054-1061. [PMID: 35648375 DOI: 10.1002/ar.24996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/30/2022] [Accepted: 04/27/2022] [Indexed: 11/06/2022]
Abstract
Intestinal cell stemness, proliferation and differentiation are complex processes all occurring in distinct compartments of the crypt that need to be closely regulated to ensure proper epithelial renewal. The involvement of the Hippo pathway in intestinal epithelial proliferation and regeneration after injury via the regulation of its effectors YAP1 and TAZ has been well-documented over the last decade. The implication of YAP1 and TAZ on intestinal epithelial cell differentiation is less clear. Using intestinal cell models in which the expression of YAP1 and TAZ can be modulated, our group showed that YAP1 inhibits differentiation of the two main intestinal epithelial cell types, goblet and absorptive cells through a specific mechanism involving the repression of prodifferentiation transcription factor CDX2 expression. Further analysis provided evidence that the repressive effect of YAP1 on intestinal differentiation is mediated by regulation of the Hippo pathway by Src family kinase activity. Interestingly, the TAZ paralog does not seem to be involved in this process, which provides another example of the lack of perfect complementarity of the two main Hippo effectors.
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Affiliation(s)
- Sepideh Fallah
- Laboratory of Intestinal Physiopathology, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jean-François Beaulieu
- Laboratory of Intestinal Physiopathology, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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Zhang Y, Wang X, Zhou X. Functions of Yes-association protein (YAP) in cancer progression and anticancer therapy resistance. BRAIN SCIENCE ADVANCES 2022. [DOI: 10.26599/bsa.2022.9050008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The Hippo pathway, a highly conserved kinase cascade, regulates cell proliferation, apoptosis, organ size, and tissue homeostasis. Dysregulation of this pathway reportedly plays an important role in the progression of various human cancers. Yes-association protein (YAP), the Hippo pathway’s core effector, is considered a marker for cancer therapy and patient prognosis. In addition, studies have indicated that YAP is involved in promoting anticancer drug resistance. This review summarizes current knowledge on YAP’s role in cancer progression, anticancer drug resistance, and advances in the development of YAP-targeting drugs. A thorough understanding of the complex interactions among molecular, cellular, and environmental factors concerning YAP function in cancer progression may provide new insight into the underlying mechanism of anticancer drug resistance. It might lead to improved prognosis through novel combined therapies.
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Affiliation(s)
- Yu Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiang Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiuping Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
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Zhao X, Wang L, Lin H, Wang J, Fu J, Zhu D, Xu W. Inhibition of MAT2A-Related Methionine Metabolism Enhances The Efficacy of Cisplatin on Cisplatin-Resistant Cells in Lung Cancer. CELL JOURNAL 2022; 24:204-211. [PMID: 35674024 PMCID: PMC9124450 DOI: 10.22074/cellj.2022.7907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/10/2021] [Indexed: 11/20/2022]
Abstract
Objective Tumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase 2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance. Materials and Methods In this experimental study, we assessed the half maximal inhibitory concentration (IC50) of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung cancer cells via RNA-seq. Results We found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366 treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366. Conclusion Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer cells to cisplatin.
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Affiliation(s)
- Xiaoya Zhao
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China,Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China
| | - Lude Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China,Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China
| | - Haiping Lin
- Department of General Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Jing Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China,Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China
| | - Dan Zhu
- Department of Respiratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China,Department of RespiratoryAffiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiang
ProvinceChina
Central LaboratoryAffiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiang ProvinceChina
;
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China,Precision Diagnosis and Treatment Center of Jinhua City, Jinhua, Zhejiang Province, China,Department of RespiratoryAffiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiang
ProvinceChina
Central LaboratoryAffiliated Jinhua HospitalZhejiang University School of MedicineJinhuaZhejiang ProvinceChina
;
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Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library. Pharmaceutics 2022; 14:pharmaceutics14020391. [PMID: 35214125 PMCID: PMC8878929 DOI: 10.3390/pharmaceutics14020391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 01/25/2023] Open
Abstract
The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.
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29
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Takeda T, Yamamoto Y, Tsubaki M, Matsuda T, Kimura A, Shimo N, Nishida S. PI3K/Akt/YAP signaling promotes migration and invasion of DLD‑1 colorectal cancer cells. Oncol Lett 2022; 23:106. [DOI: 10.3892/ol.2022.13226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/25/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Tomoya Takeda
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Yuuta Yamamoto
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Masanobu Tsubaki
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Takuya Matsuda
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Akihiro Kimura
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Natsumi Shimo
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
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Niu JB, Hua CQ, Liu Y, Yu GX, Yang JJ, Li YR, Zhang YB, Qi YQ, Song J, Jin CY, Zhang SY. Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway. J Enzyme Inhib Med Chem 2021; 36:1715-1731. [PMID: 34425716 PMCID: PMC8386742 DOI: 10.1080/14756366.2021.1958211] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/17/2021] [Accepted: 07/16/2021] [Indexed: 01/07/2023] Open
Abstract
Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.
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Affiliation(s)
- Jin-Bo Niu
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chun-Quan Hua
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, China
| | - Yuan Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, China
| | - Guang-Xi Yu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jia-Jia Yang
- Department of Pharmacy, Zhengzhou People's Hospital, Zhengzhou, China
| | - Yin-Ru Li
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan-Bing Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ying-Qiu Qi
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jian Song
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, China
| | - Cheng-Yun Jin
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, China
| | - Sai-Yang Zhang
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, China
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Li X, Lin YY, Tan JY, Liu KL, Shen XL, Hu YJ, Yang RY. Lappaol F, an anticancer agent, inhibits YAP via transcriptional and post-translational regulation. PHARMACEUTICAL BIOLOGY 2021; 59:619-628. [PMID: 34010589 PMCID: PMC8143639 DOI: 10.1080/13880209.2021.1923759] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/09/2021] [Accepted: 04/24/2021] [Indexed: 06/12/2023]
Abstract
CONTEXT Lappaol F (LAF), a natural lignan from Arctium lappa Linné (Asteraceae), inhibits tumour cell growth by inducing cell cycle arrest. However, its underlying anticancer mechanism remains unclear. OBJECTIVE The effects of LAF on the Hippo-Yes-associated protein (YAP) signalling pathway, which plays an important role in cancer progression, were explored in this study. MATERIALS AND METHODS Cervical (HeLa), colorectal (SW480), breast (MDA-MB-231) and prostate (PC3) cancer cell lines were treated with LAF at different concentrations and different durations. BALB/c nude mice bearing colon xenografts were intravenously injected with vehicle, LAF (10 or 20 mg/kg) or paclitaxel (10 mg/kg) for 15 days. The expression and nuclear localisation of YAP were analysed using transcriptome sequencing, quantitative PCR, western blotting and immunofluorescence. RESULTS LAF suppressed the proliferation of HeLa, MDA-MB-231, SW480 and PC3 cells (IC50 values of 41.5, 26.0, 45.3 and 42.9 μmol/L, respectively, at 72 h), and this was accompanied by significant downregulation in the expression of YAP and its downstream target genes at both the mRNA and protein levels. The expression of 14-3-3σ, a protein that causes YAP cytoplasmic retention and degradation, was remarkably increased, resulting in a decrease in YAP nuclear localisation. Knockdown of 14-3-3σ with small interfering RNA partially blocked LAF-induced YAP inhibition and anti-proliferation effects. In colon xenografts, treatment with LAF led to reduced YAP expression, increased tumour cell apoptosis and tumour growth inhibition. CONCLUSION LAF was shown to be an inhibitor of YAP. It exerts anticancer activity by inhibiting YAP at the transcriptional and post-translational levels.
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Affiliation(s)
- Xiao Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Ying Lin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia-Yi Tan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kang-Lun Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Ling Shen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying-Jie Hu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui-Yi Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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Chang TY, Wu CT, Sheu ML, Yang RS, Liu SH. CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation. Cancers (Basel) 2021; 13:cancers13235946. [PMID: 34885061 PMCID: PMC8657120 DOI: 10.3390/cancers13235946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/13/2021] [Accepted: 11/23/2021] [Indexed: 12/03/2022] Open
Abstract
Simple Summary CARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC. Abstract CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.
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Affiliation(s)
- Ting-Yu Chang
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan;
| | - Cheng-Tien Wu
- Department of Nutrition, China Medical University, Taichung 406040, Taiwan;
- Master Program for Food and Drug Safety, China Medical University, Taichung 406040, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan;
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Rong-Sen Yang
- Department of Orthopedics, National Taiwan University Hospital, Taipei 10051, Taiwan
- Correspondence: (R.-S.Y.); (S.-H.L.)
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan;
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 406040, Taiwan
- Department of Pediatrics, College of Medicine, National Taiwan University & Hospital, Taipei 10051, Taiwan
- Correspondence: (R.-S.Y.); (S.-H.L.)
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Kim SY, Park SY, Jang HS, Park YD, Kee SH. Yes-Associated Protein Is Required for ZO-1-Mediated Tight-Junction Integrity and Cell Migration in E-Cadherin-Restored AGS Gastric Cancer Cells. Biomedicines 2021; 9:biomedicines9091264. [PMID: 34572450 PMCID: PMC8467433 DOI: 10.3390/biomedicines9091264] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 01/04/2023] Open
Abstract
Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering movement of parental AGS cells. In EC96 cells, YAP and ZO-1 expression increased but nuclear YAP levels and activity were reduced. Nuclear factor-κB (NF-κB) mediated the increase in ZO-1 expression, possibly stabilizing cytoplasmic YAP post-translationally. Downregulation of YAP expression using siYAP RNA or stable knock-down inhibited straightforward cell migration by fragmenting ZO-1 containing tight junctions (TJs) but not adherens junctions, implying involvement of YAP in ZO-1-mediated cell migration. The association of YAP with ZO-1 was mediated by angiomotin (AMOT) because downregulation of AMOT dissociated YAP from ZO-1 and reduced cell migration. E-cadherin restoration in malignant cancer cells induced NF-κB signaling to enhance ZO-1 expression and subsequently stabilize YAP. At high expression levels, YAP associates with ZO-1 via AMOT at TJs, influencing ZO-1-mediated cell migration and maintaining TJ integrity.
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Affiliation(s)
- Seon-Young Kim
- Department of Microbiology, College of Medicine, Korea University, Seoul 02841, Korea; (S.-Y.K.); (S.-Y.P.)
| | - Song-Yi Park
- Department of Microbiology, College of Medicine, Korea University, Seoul 02841, Korea; (S.-Y.K.); (S.-Y.P.)
| | - Hwan-Seok Jang
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Korea; (H.-S.J.); (Y.-D.P.)
| | - Yong-Doo Park
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Korea; (H.-S.J.); (Y.-D.P.)
| | - Sun-Ho Kee
- Department of Microbiology, College of Medicine, Korea University, Seoul 02841, Korea; (S.-Y.K.); (S.-Y.P.)
- Correspondence: ; Tel.: +82-2-2286-1460
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Kim J, Jang J, Cho DW. Recapitulating the Cancer Microenvironment Using Bioprinting Technology for Precision Medicine. MICROMACHINES 2021; 12:1122. [PMID: 34577765 PMCID: PMC8472267 DOI: 10.3390/mi12091122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/09/2021] [Accepted: 09/15/2021] [Indexed: 12/20/2022]
Abstract
The complex and heterogenous nature of cancer contributes to the development of cancer cell drug resistance. The construction of the cancer microenvironment, including the cell-cell interactions and extracellular matrix (ECM), plays a significant role in the development of drug resistance. Traditional animal models used in drug discovery studies have been associated with feasibility issues that limit the recapitulation of human functions; thus, in vitro models have been developed to reconstruct the human cancer system. However, conventional two-dimensional and three-dimensional (3D) in vitro cancer models are limited in their ability to emulate complex cancer microenvironments. Advances in technologies, including bioprinting and cancer microenvironment reconstruction, have demonstrated the potential to overcome some of the limitations of conventional models. This study reviews some representative bioprinted in vitro models used in cancer research, particularly fabrication strategies for modeling and consideration of essential factors needed for the reconstruction of the cancer microenvironment. In addition, we highlight recent studies that applied such models, including application in precision medicine using advanced bioprinting technologies to fabricate biomimetic cancer models. Furthermore, we discuss current challenges in 3D bioprinting and suggest possible strategies to construct in vitro models that better mimic the pathophysiology of the cancer microenvironment for application in clinical settings.
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Affiliation(s)
- Jisoo Kim
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
| | - Jinah Jang
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Department of Creative IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, Korea
| | - Dong-Woo Cho
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, Korea
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Strepkos D, Markouli M, Papavassiliou KA, Papavassiliou AG, Piperi C. Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options. Neuropathol Appl Neurobiol 2021; 48:e12762. [PMID: 34409639 DOI: 10.1111/nan.12762] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/08/2021] [Accepted: 08/09/2021] [Indexed: 12/23/2022]
Abstract
The transcriptional co-activators Yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) have emerged as significant regulators of a wide variety of cellular and organ functions with impact in early embryonic development, especially during the expansion of the neural progenitor cell pool. YAP/TAZ signalling regulates organ size development, tissue homeostasis, wound healing and angiogenesis by participating in a complex network of various pathways. However, recent evidence suggests an association of these physiologic regulatory effects of YAP/TAZ with pro-oncogenic activities. Herein, we discuss the physiological functions of YAP/TAZ as well as the extensive network of signalling pathways that control their expression and activity, leading to brain tumour development and progression. Furthermore, we describe current targeting approaches and drug options including direct YAP/TAZ and YAP-TEA domain transcription factor (TEAD) interaction inhibitors, G-protein coupled receptors (GPCR) signalling modulators and kinase inhibitors, which may be used to successfully attack YAP/TAZ-dependent tumours.
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Affiliation(s)
- Dimitrios Strepkos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Mariam Markouli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas A Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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36
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Ngo MHT, Peng SW, Kuo YC, Lin CY, Wu MH, Chuang CH, Kao CX, Jeng HY, Lin GW, Ling TY, Chang TS, Huang YH. A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3812. [PMID: 34359714 PMCID: PMC8345119 DOI: 10.3390/cancers13153812] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/12/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. METHOD Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM-LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. RESULTS Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). CONCLUSION A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.
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Affiliation(s)
- Mai-Huong T. Ngo
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (C.-X.K.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (S.-W.P.); (G.-W.L.)
| | - Sue-Wei Peng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (S.-W.P.); (G.-W.L.)
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.K.); (H.-Y.J.)
| | - Yung-Che Kuo
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.K.); (H.-Y.J.)
| | - Chun-Yen Lin
- Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan; (C.-Y.L.); (C.-H.C.)
| | - Ming-Heng Wu
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Chia-Hsien Chuang
- Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan; (C.-Y.L.); (C.-H.C.)
| | - Cheng-Xiang Kao
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (C.-X.K.)
| | - Han-Yin Jeng
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.K.); (H.-Y.J.)
| | - Gee-Way Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (S.-W.P.); (G.-W.L.)
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 100, Taiwan;
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Yen-Hua Huang
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (C.-X.K.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (S.-W.P.); (G.-W.L.)
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.K.); (H.-Y.J.)
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center of Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Zindel D, Mensat P, Vol C, Homayed Z, Charrier-Savournin F, Trinquet E, Banères JL, Pin JP, Pannequin J, Roux T, Dupuis E, Prézeau L. G protein-coupled receptors can control the Hippo/YAP pathway through Gq signaling. FASEB J 2021; 35:e21668. [PMID: 34114695 DOI: 10.1096/fj.202002159r] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 04/21/2021] [Accepted: 04/30/2021] [Indexed: 11/11/2022]
Abstract
The Hippo pathway is an evolutionarily conserved kinase cascade involved in the control of tissue homeostasis, cellular differentiation, proliferation, and organ size, and is regulated by cell-cell contact, apical cell polarity, and mechanical signals. Miss-regulation of this pathway can lead to cancer. The Hippo pathway acts through the inhibition of the transcriptional coactivators YAP and TAZ through phosphorylation. Among the various signaling mechanisms controlling the hippo pathway, activation of G12/13 by G protein-coupled receptors (GPCR) recently emerged. Here we show that a GPCR, the ghrelin receptor, that activates several types of G proteins, including G12/13, Gi/o, and Gq, can activate YAP through Gq/11 exclusively, independently of G12/13. We revealed that a strong basal YAP activation results from the high constitutive activity of this receptor, which can be further increased upon agonist activation. Thus, acting on ghrelin receptor allowed to modulate up-and-down YAP activity, as activating the receptor increased YAP activity and blocking constitutive activity reduced YAP activity. Our results demonstrate that GPCRs can be used as molecular switches to finely up- or down-regulate YAP activity through a pure Gq pathway.
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Affiliation(s)
- Diana Zindel
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Claire Vol
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | - Zeinab Homayed
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | | | | | - Jean-Louis Banères
- Institut des Biomolécules Max Mousseron, Univ. Montpellier, CNRS, Montpellier, France
| | - Jean-Philippe Pin
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | - Julie Pannequin
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | | | | | - Laurent Prézeau
- Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM, Montpellier, France
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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13143437. [PMID: 34298652 PMCID: PMC8308039 DOI: 10.3390/cancers13143437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary Hyperactivation of the canonical Wnt and inactivation of the Hippo pathway are well-known genetic backgrounds for familial adenomatosis polyposis (FAP) and colorectal cancer (CRC), although the reciprocal regulation between those pathways is not yet clear. In this study, we found that Axin2, a bona fide downstream target of canonical Wnt, activates the Hippo pathway in APC-mutated CRC, limiting the therapeutic potential of niclosamide on advanced CRC through the inactivation of the Hippo pathway. To overcome the limitation, we combined niclosamide with AMPK activator metformin to activate Hippo and found that this combination synergistically suppressed canonical Wnt and activated Hippo in APC-mutated CRC. Using patient-derived cancer organoid and an APC-MIN mice model, we found the combinatory approach to be effective for APC-mutated CRC. Our results provide not only the reciprocal link between Wnt and Hippo in APC-mutated CRC, but they also provide an effective therapeutic approach with clinically available drugs for FAP and CRC patients. Abstract The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.
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Zhao X, Fu J, Hu B, Chen L, Wang J, Fang J, Ge C, Lin H, Pan K, Fu L, Wang L, Du J, Xu W. Serine Metabolism Regulates YAP Activity Through USP7 in Colon Cancer. Front Cell Dev Biol 2021; 9:639111. [PMID: 34055773 PMCID: PMC8152669 DOI: 10.3389/fcell.2021.639111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
Metabolic reprogramming is a vital factor in the development of many types of cancer, including colon cancer. Serine metabolic reprogramming is a major feature of tumor metabolism. Yes-associated protein (YAP) participates in organ size control and tumorigenesis. However, the relationship between YAP and serine metabolism in colon cancer is unclear. In this study, RNA sequencing and metabolomics analyses indicated significant enrichment of the glycine, serine, and threonine metabolism pathways in serine starvation-resistant cells. Short-term serine deficiency inhibited YAP activation, whereas a prolonged response dephosphorylated YAP and promoted its activity. Mechanistically, USP7 increases YAP stability under increased serine conditions by regulating deubiquitination. Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression. Clinically, YAP was significantly activated in colon tumor tissues and positively correlated with the expression of phosphoglycerate dehydrogenase (PHGDH) and USP7. Generally, our study uncovered the mechanism by which serine metabolism regulates YAP via USP7 and identified the crucial role of YAP in the regulation of cell proliferation and tumor growth; thus, VP may be a new treatment for colon cancer.
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Affiliation(s)
- Xiaoya Zhao
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.,Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Bin Hu
- Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Lin Chen
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jinyong Fang
- Department of Science and Education, Jinhua Guangfu Oncology Hospital, Huancheng, Jinhua, China
| | - Chenyang Ge
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haiping Lin
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Kailing Pan
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Liang Fu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.,Department of Nursing, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Lude Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jinlin Du
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Merritt N, Garcia K, Rajendran D, Lin ZY, Zhang X, Mitchell KA, Borcherding N, Fullenkamp C, Chimenti MS, Gingras AC, Harvey KF, Tanas MR. TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex. eLife 2021; 10:62857. [PMID: 33913810 PMCID: PMC8143797 DOI: 10.7554/elife.62857] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers. The proliferation of human cells is tightly regulated to ensure that enough cells are made to build and repair organs and tissues, while at the same time stopping cells from dividing uncontrollably and damaging the body. To get the right balance, cells rely on physical and chemical cues from their environment that trigger the biochemical signals that regulate two proteins called TAZ and YAP. These proteins control gene activity by regulating the rate at which genes are copied to produce proteins. If this process becomes dysregulated, cells can grow uncontrollably, causing cancer. In cancer cells, it is common to find TAZ and YAP fused to other proteins. In epithelioid hemangioendothelioma, a rare cancer that grows in the blood vessels, cancerous growth can be driven by a version of TAZ fused to the protein CAMTA1, or a version of YAP fused to the protein TFE3. While the role of TAZ and YAP in promoting gene activity is known, it is unclear how CAMTA1 and TFE3 contribute to cell growth becoming dysregulated. Merritt, Garcia et al. studied sarcoma cell lines to show that these two fusion proteins, TAZ-CAMTA1 and YAP-TFE3, change the pattern of gene activity seen in the cells compared to TAZ or YAP alone. An analysis of molecules that interact with the two fusion proteins identified a complex called ATAC as the cause of these changes. This complex adds chemical markers to DNA-packaging proteins, which control which genes are available for activation. The fusion proteins combine the ability of TAZ and YAP to control gene activity and the ability of CAMTA1 and TFE3 to make DNA more accessible, allowing the fusion proteins to drive uncontrolled cancerous growth. Similar TAZ and YAP fusion proteins have been found in other cancers, which can activate genes and potentially alter DNA packaging. Targeting drug development efforts at the proteins that complex with TAZ and YAP fusion proteins may lead to new therapies.
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Affiliation(s)
- Nicole Merritt
- Department of Pathology, University of Iowa, Iowa City, United States
| | - Keith Garcia
- Department of Pathology, University of Iowa, Iowa City, United States.,Cancer Biology Graduate Program, University of Iowa, Iowa City, United States
| | - Dushyandi Rajendran
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States
| | - Zhen-Yuan Lin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States
| | | | - Katrina A Mitchell
- Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, United States
| | | | - Michael S Chimenti
- Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, United States
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United States
| | - Kieran F Harvey
- Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Anatomy and Developmental Biology and Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Munir R Tanas
- Department of Pathology, University of Iowa, Iowa City, United States.,Cancer Biology Graduate Program, University of Iowa, Iowa City, United States.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, United States.,Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Iowa City, United States
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41
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Gaza A, Fritz V, Malek L, Wormser L, Treiber N, Danner J, Kremer AE, Thasler WE, Siebler J, Meister G, Neurath MF, Hellerbrand C, Bosserhoff AK, Dietrich P. Identification of novel targets of miR-622 in hepatocellular carcinoma reveals common regulation of cooperating genes and outlines the oncogenic role of zinc finger CCHC-type containing 11. Neoplasia 2021; 23:502-514. [PMID: 33901943 PMCID: PMC8099721 DOI: 10.1016/j.neo.2021.04.001] [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: 12/22/2020] [Revised: 04/01/2021] [Accepted: 04/06/2021] [Indexed: 12/26/2022] Open
Abstract
The poor prognosis of advanced hepatocellular carcinoma (HCC) is driven by diverse features including dysregulated microRNAs inducing drug resistance and stemness. Lin-28 homolog A (LIN28A) and its partner zinc finger CCHC-type containing 11 (ZCCHC11) cooperate in binding, oligouridylation and subsequent degradation of tumorsuppressive let-7 precursor microRNAs. Functionally, activation of LIN28A was recently shown to promote stemness and chemoresistance in HCC. However, the expression and regulation of LIN28A in HCC had been unclear. Moreover, the expression, regulation and function of ZCCHC11 in liver cancer remained elusive. In contrast to "one-microRNA-one-target" interactions, we identified common binding sites for miR-622 in both LIN28A and ZCCHC11, suggesting miR-622 to function as a superior pathway regulator. Applying comprehensive microRNA database screening, human hepatocytes and HCC cell lines, patient-derived tissue samples as well as "The Cancer Genome Atlas" (TCGA) patient cohorts, we demonstrated that loss of tumorsuppressive miR-622 mediates derepression and overexpression of LIN28A in HCC. Moreover, the cooperator of LIN28A, ZCCHC11, was newly identified as a prognostic and therapeutic target of miR-622 in liver cancer. Together, identification of novel miR-622 target genes revealed common regulation of cooperating genes and outlines the previously unknown oncogenic role of ZCCHC11 in liver cancer.
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Affiliation(s)
- Anne Gaza
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | - Valerie Fritz
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Lara Malek
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Laura Wormser
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Nora Treiber
- Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, Germany
| | - Johannes Danner
- Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, Germany
| | - Andreas E Kremer
- Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | - Wolfgang E Thasler
- Department of General and Visceral Surgery, Red Cross Hospital of Munich, Germany
| | - Jürgen Siebler
- Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | - Gunter Meister
- Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, Germany
| | - Markus F Neurath
- Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany; Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
| | - Anja K Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.
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Desai C, Thomason J, Kohlmeyer JL, Reisetter AC, Ahirwar P, Jahanseir K, Leidinger M, Ofori-Amanfo G, Fritchie K, Velu SE, Breheny P, Quelle DE, Tanas MR. Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas. Oncotarget 2021; 12:740-755. [PMID: 33889298 PMCID: PMC8057271 DOI: 10.18632/oncotarget.27928] [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: 02/12/2021] [Accepted: 03/15/2021] [Indexed: 01/26/2023] Open
Abstract
Additional prognostic and therapeutic biomarkers effective across different histological types of sarcoma are needed. Herein we evaluate expression of TAZ and YAP, the p53-MDM2 axis, and RABL6A, a novel oncoprotein with potential ties to both pathways, in sarcomas of different histological types. Immunohistochemical staining of a tissue microarray including 163 sarcomas and correlation with clinical data showed that elevated YAP and TAZ independently predict worse overall and progression-free survival, respectively. In the absence of p53 expression, combined TAZ and YAP expression adversely affect overall, progression free, and metastasis free survival more than TAZ or YAP activation alone. RABL6A independently predicted shorter time to metastasis and was positively correlated with p53, MDM2 and YAP expression, supporting a possible functional relationship between the biomarkers. Network analysis further showed that TAZ is positively correlated with MDM2 expression. The data implicate all five proteins as clinically relevant downstream players in the Hippo pathway. Finally, a novel inhibitor of MDM2 (MA242), effectively suppressed the survival of sarcoma cell lines from different histological types regardless of p53 status. These findings suggest both independent and cooperative roles for all five biomarkers across different histological types of sarcoma in predicting patient outcomes and potentially guiding future therapeutic approaches.
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Affiliation(s)
- Chandni Desai
- Department of Pathology, University of Iowa, Iowa City, IA, USA.,Carver College of Medicine, University of Iowa, Iowa City, IA, USA.,These authors contributed equally to this work
| | - Jon Thomason
- Department of Pathology, University of Iowa, Iowa City, IA, USA.,These authors contributed equally to this work
| | - Jordan L Kohlmeyer
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA.,Molecular Medicine Graduate Program, University of Iowa, Iowa City, IA, USA
| | - Anna C Reisetter
- Department of Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Parmanand Ahirwar
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Khadijeh Jahanseir
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Karen Fritchie
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Sadanandan E Velu
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Patrick Breheny
- Department of Biostatistics, University of Iowa, Iowa City, IA, USA
| | - Dawn E Quelle
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA.,Molecular Medicine Graduate Program, University of Iowa, Iowa City, IA, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Munir R Tanas
- Department of Pathology, University of Iowa, Iowa City, IA, USA.,Molecular Medicine Graduate Program, University of Iowa, Iowa City, IA, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
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Wang M, Xu T, Feng W, Liu J, Wang Z. Advances in Understanding the LncRNA-Mediated Regulation of the Hippo Pathway in Cancer. Onco Targets Ther 2021; 14:2397-2415. [PMID: 33854336 PMCID: PMC8039192 DOI: 10.2147/ott.s283157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 03/08/2021] [Indexed: 12/24/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and cannot encode proteins. Over the past decade, lncRNAs have been defined as regulatory elements of multiple biological processes, and their aberrant expression contributes to the development and progression of various malignancies. Recent studies have shown that lncRNAs are involved in key cancer-related signaling pathways, including the Hippo signaling pathway, which plays a prominent role in controlling organ size and tissue homeostasis by regulating cell proliferation, apoptosis, and differentiation. However, dysregulation of this pathway is associated with pathological conditions, especially cancer. Accumulating evidence has revealed that lncRNAs can modulate the Hippo signaling pathway in cancer. In this review, we elaborate on the role of the Hippo signaling pathway and the advances in the understanding of its lncRNA-mediated regulation in cancer. This review provides additional insight into carcinogenesis and will be of great clinical value for developing novel early detection and treatment strategies for this deadly disease.
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Affiliation(s)
- Mengwei Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Tianwei Xu
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Wenyan Feng
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Junxia Liu
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Zhaoxia Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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44
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Yang S, Gao S, Liu T, Liu J, Zheng X, Li Z. Circular RNA SMARCA5 functions as an anti-tumor candidate in colon cancer by sponging microRNA-552. Cell Cycle 2021; 20:689-701. [PMID: 33749508 DOI: 10.1080/15384101.2021.1899519] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
It was reported that circular RNA (circRNA) circSMARCA5, as a tumor-related molecule, could modulate development of cancers, including prostatic cancer and cervical cancer. Nevertheless, the essential function of circSMARCA5 in colon cancer has not yet been confirmed. We aimed to investigate the role of circSMARCA5 in colon cancer. CircSMARCA5 expression in tumor cells was detected using RT-qPCR. CCK-8, colony formation, flow cytometry and Transwell assays evaluated the influences of circSMARCA5 in colon cancer cells. RT-qPCR, prediction database and luciferase report assay were accomplished for revealing the correlation between circSMARCA5 and miR-552. After transfection with miR-552 mimic, colon cancer cell behaviors were re-evaluated. Wnt and YAP1 pathways were explored by western blot. Our data presented that circSMARCA5 was under-expressed in colon cancer tissues. Transfection with overexpressing circSMARCA5 plasmid restrained growth, migration and invasion of colon cancer cells. Besides, circSMARCA5 directly sponged to miR-552 and miR-552 up-regulation offset the effects of circSMARCA5 on SW480 and SW620 cells. Furthermore, circSMARCA5 inactivated Wnt and YAP1 pathways by inhibiting miR-552. Anti-tumor role of sircSMARCA5 was showed in colon cancer cells as sponging miR-552 and blocking Wnt and YAP1 pathways.
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Affiliation(s)
- Shiwei Yang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong, China.,Key Laboratory of Metabolism and Gastrointestinal Tumor, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Shandong Medicine and Health Key Laboratory of General Surgery, Jinan 250014, Shandong, China
| | - Shanyu Gao
- Department of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China
| | - Tongming Liu
- Department of Anorectal Surgery, Feicheng People's Hospital, Taian 271600, Shandong, China
| | - Junning Liu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong, China.,Key Laboratory of Metabolism and Gastrointestinal Tumor, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Shandong Medicine and Health Key Laboratory of General Surgery, Jinan 250014, Shandong, China
| | - Xia Zheng
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong, China.,Key Laboratory of Metabolism and Gastrointestinal Tumor, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Shandong Medicine and Health Key Laboratory of General Surgery, Jinan 250014, Shandong, China
| | - Zhi Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong, China.,Key Laboratory of Metabolism and Gastrointestinal Tumor, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.,Shandong Medicine and Health Key Laboratory of General Surgery, Jinan 250014, Shandong, China
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45
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Wei Y, Jiang Z, Lu J. USP22 promotes melanoma and BRAF inhibitor resistance via YAP stabilization. Oncol Lett 2021; 21:394. [PMID: 33777217 PMCID: PMC7988733 DOI: 10.3892/ol.2021.12655] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 02/03/2021] [Indexed: 12/23/2022] Open
Abstract
Yes-associated protein (YAP) is a conserved transcriptional coactivator that plays key roles in controlling organ size, tumorigenesis and drug resistance. Emerging evidence shows that YAP is overexpressed and associated with resistance to BRAF inhibitor treatment in melanoma. However, the mechanism accounting for YAP-overexpression in melanoma is largely unknown. The present study characterized ubiquitin-specific peptidase 22 (USP22) as a deubiquitinase controlling YAP abundance and biological functions in melanoma. Using western blotting and immunohistochemical staining, it was found that the expression of USP22 and YAP was associated in melanoma cell lines and patient samples. Moreover, USP22 interacted with and deubiquitinated YAP to prevent YAP turnover. Depletion of USP22 decreased YAP expression, which in turn suppressed cell proliferation and tumorigenesis. Furthermore, overexpression of USP22 conferred vemurafenib resistance in a YAP-dependent manner. Overall, the present study revealed the important role of the USP22/YAP axis in melanoma and BRAF inhibitor resistance, and provides a rationale to target USP22/YAP for melanoma treatment.
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Affiliation(s)
- Ying Wei
- Department of Plastic and Reconstructive Surgery, Changxing People's Hospital, Huzhou, Zhejiang 313100, P.R. China
| | - Ziyun Jiang
- Research Department, Shanghai Zhuole Biotechnology Center, Shanghai 201499, P.R. China
| | - Jianfeng Lu
- Department of Plastic and Reconstructive Surgery, Changxing People's Hospital, Huzhou, Zhejiang 313100, P.R. China
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46
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Ma H, Wang J, Zhao X, Wu T, Huang Z, Chen D, Liu Y, Ouyang G. Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation. Cell Rep 2021; 30:793-806.e6. [PMID: 31968254 DOI: 10.1016/j.celrep.2019.12.075] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/09/2019] [Accepted: 12/18/2019] [Indexed: 01/14/2023] Open
Abstract
Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.
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Affiliation(s)
- Handong Ma
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China
| | - Jing Wang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Xueli Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Tiantian Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Zhengjie Huang
- Department of Surgical Oncology, First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Dafan Chen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Yingfu Liu
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.
| | - Gaoliang Ouyang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China; Cancer Research Center of Xiamen University, Xiamen 361102, China.
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47
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Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13051183. [PMID: 33803354 PMCID: PMC7967205 DOI: 10.3390/cancers13051183] [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: 02/18/2021] [Revised: 03/03/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022] Open
Abstract
Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.
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48
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Park H, Lee Y, Lee K, Lee H, Yoo JE, Ahn S, Park YN, Kim H. The Clinicopathological Significance of YAP/TAZ Expression in Hepatocellular Carcinoma with Relation to Hypoxia and Stemness. Pathol Oncol Res 2021; 27:604600. [PMID: 34257565 PMCID: PMC8262240 DOI: 10.3389/pore.2021.604600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/12/2021] [Indexed: 12/30/2022]
Abstract
Background/Aims: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) activation has been implicated in hepatocarcinogenesis and hepatic progenitor cell differentiation, and hypoxia has been shown to induce nuclear translocation of YAP in cancer cells. Here, we aimed to investigate the relationship between hypoxia, YAP and TAZ expression and stemness-related marker expression in human hepatocellular carcinomas (HCCs) and its clinical implications. Methods: Immunohistochemical stains were performed on tissue microarrays from 305 surgically resected HCCs, and the expression status of YAP and TAZ were correlated with CAIX, stemness markers (K19, EpCAM) and epithelial-mesenchymal transition (EMT)-related markers (uPAR, ezrin). The clinicopathological significance of YAP/TAZ expression was analyzed with relation to CAIX expression status. Results: YAP and TAZ expression were seen in 13.4 and 4.3% of HCCs, respectively. YAP/TAZ-positive HCCs frequently demonstrated higher serum AFP levels, microvascular invasion, advanced tumor stage, increased proliferative activity and expression of stemness- and EMT-related markers, CAIX, p53 and Smad2/3 (p < 0.05, all). Interestingly, YAP/TAZ-positivity was associated with microvascular invasion, higher serum AFP levels, stemness and EMT-related marker expression only in tumors expressing CAIX (p < 0.05, all), while these associations were not seen in CAIX-negative HCCs. Conclusions: YAP/TAZ expression is associated with vascular invasion, stemness and EMT in HCCs with hypoxia marker expression. The effect of Hippo signaling pathway deregulation in HCC may depend on the presence or absence of a hypoxic microenvironment, and hypoxia marker expression status should be taken into account when considering the use of YAP/TAZ as markers of aggressive biologic behavior in HCC.
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Affiliation(s)
- Hyunjin Park
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yangkyu Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kiryang Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Hyejung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
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Cha YJ, Bae SJ, Kim D, Ahn SG, Jeong J, Koo JS, Yoo TK, Park WC, Lee A, Yoon CI. High Nuclear Expression of Yes-Associated Protein 1 Correlates With Metastasis in Patients With Breast Cancer. Front Oncol 2021; 11:609743. [PMID: 33718163 PMCID: PMC7947190 DOI: 10.3389/fonc.2021.609743] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. However, the role of YAP1 in breast cancer remains controversial. Here, we investigated the impact of different levels of nuclear YAP1 expression on the clinical characteristics and survival outcome in patients with breast cancer. PATIENTS AND METHODS Retrospectively obtained 455 breast tumor samples at Gangnam Severance Hospital were examined for YAP1 expression by immunohistochemistry, and the clinical data were analyzed. External validation was performed using a retrospective cohort and tissues in 482 patients from Severance Hospital. RESULTS High nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS, hazard ratio [HR] 2.271, 95% confidence intervals [CIs] 1.109-4.650, P = 0.0249), and also confirmed inferior disease free survival (HR 3.208, 95% CIs 1.313-7.833, P = 0.0105) in external validation cohort. In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor DMFS (HR 2.384, 95% CIs 1.055-5.386, P = 0.0367). CONCLUSION Our findings suggest that nuclear YAP1 expression is a biomarker of adverse prognosis and a potential therapeutic target in patients with breast cancer, especially in TNBC.
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Affiliation(s)
- Yoon Jin Cha
- Department of Pathology, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Soong June Bae
- Department of Surgery, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Dooreh Kim
- Department of Surgery, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Sung Gwe Ahn
- Department of Surgery, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Joon Jeong
- Department of Surgery, Gangnam Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Ja Seung Koo
- Department of Pathology, Severance Hospital, College of Medicine, Yonsei University, Seoul, South Korea
| | - Tae-Kyung Yoo
- Division of Breast Surgery, Department of Surgery, College of Medicine, Seoul St Mary’s Hospital, The Catholic University of Seoul, Seoul, South Korea
| | - Woo-Chan Park
- Division of Breast Surgery, Department of Surgery, College of Medicine, Seoul St Mary’s Hospital, The Catholic University of Seoul, Seoul, South Korea
| | - Ahwon Lee
- Department of Pathology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Seoul, Seoul, South Korea
| | - Chang Ik Yoon
- Division of Breast Surgery, Department of Surgery, College of Medicine, Seoul St Mary’s Hospital, The Catholic University of Seoul, Seoul, South Korea
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50
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Yu D, Liu H, Qin J, Huangfu M, Guan X, Li X, Zhou L, Dou T, Liu Y, Wang L, Fu M, Wang J, Chen X. Curcumol inhibits the viability and invasion of colorectal cancer cells via miR-30a-5p and Hippo signaling pathway. Oncol Lett 2021; 21:299. [PMID: 33732375 PMCID: PMC7905558 DOI: 10.3892/ol.2021.12560] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 01/13/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNA-30a-5p (miR-30a-5p), which functions as a tumor suppressor, has been reported to be downregulated in colorectal cancer (CRC) tissues and to be associated with cancer invasion. However, the detailed regulatory mechanism of curcumol in the malignant progression of CRC remains unknown. MTT, Transwell, scratch, western blotting and reverse transcription-quantitative PCR assays were performed to examine how curcumol inhibited CRC cell viability, invasion and migration, and to detect the role of miR-30a-5p and curcumol in the invasion and Hippo signaling pathways of CRC cells. The present study revealed that miR-30a-5p expression was downregulated in human CRC tissues and cells. The results demonstrated that miR-30a-5p downregulation was accompanied by the inactivation of the Hippo signaling pathway, which was demonstrated to promote CRC cell viability, invasion and migration. Curcumol treatment was identified to increase miR-30a-5p expression and to activate the Hippo signaling pathway, which in turn inhibited the invasion and migration of CRC cells. Overexpression of miR-30a-5p enhanced the effects of curcumol on cell invasion and migration, and the Hippo signaling pathway in CRC cells. Furthermore, downregulation of miR-30a-5p reversed the effects of curcumol on cell invasion and migration, and the Hippo signaling pathway in CRC cells. These findings identified novel signaling pathways associated with miR-30a-5p and revealed the effects of curcumol on miR-30a-5p expression. Therefore, curcumol may serve as a potential therapeutic strategy to delay CRC progression.
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Affiliation(s)
- Dan Yu
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Haiping Liu
- Science and Technology Department, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, P.R. China
| | - Jianli Qin
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Mengjie Huangfu
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Xiao Guan
- Department of Pharmacology, Xiangya School of Medicine of Central South University, Changsha, Hunan 410008, P.R. China
| | - Xumei Li
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Luwei Zhou
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Tong Dou
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Yisa Liu
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Lin Wang
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Minglei Fu
- Department of Dispensary, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Juan Wang
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China.,Department of Pharmacy, China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China.,Department of Pharmacy, Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China.,Department of Pharmacy, Guangxi Key Laboratory of Sphingolipid Metabolism (Incubated), Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
| | - Xu Chen
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, P.R. China
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