Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder

Itami, Yoshitaka; Miyake, Makito; Ohnishi, Sayuri; Tatsumi, Yoshihiro; Gotoh, Daisuke; Morizawa, Yosuke; Ohnishi, Kenta; Nakai, Yasushi; Inoue, Takeshi; Anai, Satoshi; Tanaka, Nobumichi; Fujii, Tomomi; Shimada, Kaoru; Furuya, Hideki; Khadka, Vedbar S.; Deng, Youping; Fujimoto, Kiyohide

doi:10.3390/diagnostics10010054

Cited by 15 publications

(19 citation statements)

References 35 publications

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“…This is consistent with the observation that mouse bladder wall injection with S. haematobium eggs leads to urothelial hyperplasia, a potentially be pre-cancerous state [17]. Proteins including metalloreductase (STEAP4) [40], platelet-activating factor acetylhydrolase (Pla2g7) [41], disabled homolog 2 (Dab2) [42], peptidyl-prolyl cis-trans isomerase (Fkbp14) [43], stabilin-1 (Stab1) [44,45], lysyl oxidase homolog 2 (Loxl2) [46], U4/U6 small nuclear ribonucleoprotein (Prpf3) [47], latent-transforming growth factor beta-binding protein (Ltbp3) [48], RNA-binding protein (Nob1) [49], isoform 1 of RNA-binding protein (Raly) [50], and probable glutathione peroxidase 8 (Gpx8) [51] are all expressed in many different malignant tissues, including bladder tissue, and are linked with increased cell proliferation, oncogenic properties, and poor cancer prognosis. This is in line with our observations, as all these proteins were more highly expressed in egg-injected mice bladder tissue.…”

Section: Discussionsupporting

confidence: 89%

“…Evidence shows that proteins such as Dab2 play a significant role in aggressive human urothelial carcinoma of the bladder. Dab2 promotes changes to epithelial-mesenchymal transition and increases tumor proliferation, migration, and invasion; inhibiting the protein leads to suppression of these properties and improves prognosis [46]. Similarly, the downregulation of proteins that play a direct or indirect role in tumor suppression including ubiquitin carboxyl-terminal hydrolase 11 ( Usp11 ) [56] [57], growth arrest-specific protein 1 ( Gas1 ) [58, 59], and carbonyl reductase ( Cbr1 ) [60], lambda-crystallin homolog ( Cryl1 ) [61], isoform alpha-2 of guanine nucleotide-binding protein ( Gnao1 ) [62], glyoxylate reductase/hydroxypyruvate reductase ( Grhpr ) [63], protein phosphatase 1 regulatory subunit 14A ( Ppp1r14a ) [64], and homeodomain-only protein ( Hopx ) [65] have been linked to cancer-associated pathways in several tissues, including the bladder.…”

Section: Discussionmentioning

confidence: 99%

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Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Osakunor

Ishida

Lamanna

et al. 2021

Preprint

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BackgroundUrogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology have not been well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology.MethodsPurified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry.ResultsWe demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection.ConclusionS. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control.Author summaryThe molecular mechanisms underlying the urinary and genital pathology from urogenital schistosomiasis have not been well-defined. This has mainly been due to limited mechanistic studies and the lack of a suitable animal model for S. haematobium infection. We leveraged a mouse model of urogenital schistosomiasis, along with proteomics analysis, to determine the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to define protein pathways that may be involved in morbidity from urogenital schistosomiasis infection. Our results show that S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism are significantly enriched in S. haematobium infection. Our findings highlight important protein indicators of host-parasite interactions in the bladder and their association with tissue changes in urogenital schistosomiasis. The findings presented here will be relevant for development of improved interventions for disease control, and contribute to realizing the 2021-2030 NTD goals by demonstrating evidence on the early events that occur during schistosome infection..

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Osakunor

Ishida

Lamanna

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…haematobium eggs leads to urothelial hyperplasia, a potentially pre-cancerous state [ 18 ]. Proteins including metalloreductase ( STEAP4 ) [ 41 ], platelet-activating factor acetylhydrolase ( Pla2g7 ) [ 42 ], disabled homolog 2 ( Dab2 ) [ 43 ], peptidyl-prolyl cis-trans isomerase ( Fkbp14 ) [ 44 ], stabilin-1 ( Stab1 ) [ 45 , 46 ], lysyl oxidase homolog 2 ( Loxl2 ) [ 47 ], U4/U6 small nuclear ribonucleoprotein ( Prpf3 ) [ 48 ], latent-transforming growth factor beta-binding protein ( Ltbp3 ) [ 49 ], RNA-binding protein ( Nob1 ) [ 50 ], isoform 1 of RNA-binding protein ( Raly ) [ 51 ], and probable glutathione peroxidase 8 ( Gpx8 ) [ 52 ] are all expressed in many different malignant tissues, including bladder tissue, and are linked with increased cell proliferation, oncogenic properties, and poor cancer prognosis. This is in line with our observations, as all these proteins were more highly expressed in egg-injected mice bladder tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence shows that proteins such as Dab2 play a significant role in aggressive human urothelial carcinoma of the bladder. Dab2 promotes changes to epithelial-mesenchymal transition and increases tumor proliferation, migration, and invasion; inhibiting the protein leads to suppression of these properties and improves prognosis [ 43 ]. Similarly, the downregulation of proteins that play a direct or indirect role in tumor suppression including ubiquitin carboxyl-terminal hydrolase 11 ( Usp11 ) [ 53 ] [ 54 ], growth arrest-specific protein 1 ( Gas1 ) [ 55 , 56 ], and carbonyl reductase ( Cbr1 ) [ 57 ], lambda-crystallin homolog ( Cryl1 ) [ 58 ], isoform alpha-2 of guanine nucleotide-binding protein ( Gnao1 ) [ 59 ], glyoxylate reductase/hydroxypyruvate reductase ( Grhpr ) [ 60 ], protein phosphatase 1 regulatory subunit 14A ( Ppp1r14a ) [ 61 ], and homeodomain-only protein ( Hopx ) [ 62 ] have been linked to cancer-associated pathways in several tissues, including the bladder.…”

Section: Discussionmentioning

confidence: 99%

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

et al. 2022

View full text Add to dashboard Cite

Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology are not well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. We demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control.

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“…We are the first group to our knowledge, to commercialize containers with multiple horizontal connections. HTCP has been reported in several studies [19,20]. However, the migration characteristics of substances secreted by HTCP cells have not yet been reported.…”

mentioning

confidence: 99%

Novel Platform for Regulation of Extracellular Vesicles and Metabolites Secretion from Cells Using a Multi-Linkable Horizontal Co-Culture Plate

et al. 2021

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Microfluidics is applied in biotechnology research via the creation of microfluidic channels and reaction vessels. Filters are considered to be able to simulate microfluidics. A typical example is the cell culture insert, which comprises two vessels connected by a filter. Cell culture inserts have been used for years to study cell-to-cell communication. These systems generally have a bucket-in-bucket structure and are hereafter referred to as a vertical-type co-culture plate (VTCP). However, VTCPs have several disadvantages, such as the inability to simultaneously observe samples in both containers and the inability of cell-to-cell communication through the filters at high cell densities. In this study, we developed a novel horizontal-type co-culture plate (HTCP) to overcome these disadvantages and confirm its performance. In addition, we clarified the migration characteristics of substances secreted from cells in horizontal co-culture vessels. It is generally assumed that less material is exchanged between the horizontal vessels. However, the extracellular vesicle (EV) transfer was found to be twice as high when using HTCP. Other merits include control of the degree of co-culture via the placement of cells. We believe that this novel HTCP container will facilitate research on cell-to-cell communication in various fields.

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Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder

Cited by 15 publications

References 35 publications

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Novel Platform for Regulation of Extracellular Vesicles and Metabolites Secretion from Cells Using a Multi-Linkable Horizontal Co-Culture Plate

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