Diaphanous-related formin 1 as a target for tumor therapy

Lin, Yuan-Na; Windhorst, Sabine

doi:10.1042/bst20160120

Cited by 15 publications

(14 citation statements)

References 32 publications

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“…5a), together with the fact that it was listed as a putative target of miR-10b. Its potential disease-relevance was substantiated by its recent association with colon carcinoma, and its potential role in actin-organization and microtubule stabilization [35][36][37]. When re-analyzing normalized RNA-seq data generated by Cho et al, retrieved from GEOrepository (GSE111582), both, DIAPH2 and HOXD10, showed lower expression in RDEB-cSCC versus RDEB-skin tissue [8], ( Supplementary Fig.…”

Section: Diaph2 Is Deregulated In Rdeb-cscc and Predicted To Be A Tarmentioning

confidence: 95%

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

et al. 2020

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Background: Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. Methods: MiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knockout of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Samplematched transcriptome data was generated to support the identification of disease relevant miRNA targets. Results: Several miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin-and tubulin cytoskeleton-associated protein DIAPH2. Conclusion: The discovery that miR-10b mediates an aspect of cancer stemnessthat of enhanced tumor cell adhesion, known to facilitate metastatic colonizationprovides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.

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Section: Diaph2 Is Deregulated In Rdeb-cscc and Predicted To Be A Tarmentioning

confidence: 95%

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

et al. 2020

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“…We nominated diaphanous related formin 2 ( DIAPH2) for further evaluation based on significant differences in Kaplan Meier survival curves (p < 0.05, log-rank test, Figure 5A), together with the fact that it was listed as a putative target of miR-10b. Its potential disease-relevance was substantiated by its recent association with colon carcinoma, and its potential role in actin-organization and microtubule stabilization (35-37). When re-analyzing normalized RNA-seq data generated by Cho et al , retrieved from GEO-repository (GSE111582), both, DIAPH2 and HOXD10 , showed lower expression in RDEB-SCC versus RDEB-skin tissue (8, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

MiRNA-10b marks aggressive squamous cell carcinomas, and confers a cancer stem cell-like phenotype

Wimmer

Zauner

Ablinger

et al. 2020

Preprint

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AbstractBackgroundCutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa, which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by an impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined.MethodsMiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression of a dysregulated miRNA was assessed in migration and 3D spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets.ResultsSeveral miRNAs were identified as dysregulated in cSCCs as compared to controls. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes, and impaired their mobility. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2.ConclusionThe discovery that miR-10b confers an aspect of cancer stemness – that of enhanced tumor cell adhesion, known to facilitate metastatic colonization - provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.

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“…We also found that DIAPH3, as a substrate of RNF216, also plays a central role in promoting the growth and metastasis of cholangiocarcinoma. Although DIAPH3 has been reported to be involved in the growth and metastasis of a variety of tumors (34,35,(39)(40)(41), its role in cholangiocarcinoma is not explicit. We elaborated the regulatory upstream of DIAPH3.…”

Section: Dicussionmentioning

confidence: 99%

RNF216 Promotes Occurrence and Progression of Cholangiocarcinoma via Regulation of the DIAPH3 Ubiquitination

Chen

Meng

et al. 2020

Preprint

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BackgroundCholangiocarcinoma is a relatively uncommon malignant tumor with high mortality. However, the molecular underpinnings behind malignant progression of cholangiocarcinoma are incompletely understood. Here we demonstrate that RNF216 plays a suppressive role in cholangiocarcinoma occurrence and metastasis.MethodsIHC and Western blot analysis were performed to examine the expression pattern of RNF216 and DIAPH3 in the clinical CRC cholangiocarcinoma. The relationship between RNF216 and DIAPH3 was then validated using in western blot analysis. The mechanism of RNF216-mediated ubiquitination modification of DIAPH3 was analyzed via Co-IP analysis. Gain- or loss-of-function approaches were manipulated to evaluate the modulatory effects of RNF216 and DIAPH3 on cell growth and metastasis. The mediatory effects of RNF216 and DIAPH3 on cancerogenesis were validated in vivo.ResultsClinical data indicated that expression levels of RNF216 were associated with favorable clinical outcomes. RNF216 was downregulated in cholangiocarcinoma and inhibited cell proliferation and colony formation in vitro and xenograft tumorigenicity in vivo. Moreover, RNF216 suppressed Invasion and migration of cholangiocarcinoma. Mechanistic investigations further showed that RNF216 was involved in the ubiquitination of DIAPH3, a member of formin family related to assembly of actin cytoskeleton. RNF216 elicits tumor suppressor role by promoting degradation of DIAPH3. Importantly, expression of DIAPH3 rescued RNF216-mediated suppression of proliferation, cell migration, and invasion. ConclusionOur findings uncover a suppressive role for RNF216 in cholangiocarcinoma proliferation and metastatic progression and provide novel insight into that RNF216 is a potential biomarker or serves as a therapeutic target for cholangiocarcinoma.

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Diaphanous-related formin 1 as a target for tumor therapy

Cited by 15 publications

References 32 publications

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas

MiRNA-10b marks aggressive squamous cell carcinomas, and confers a cancer stem cell-like phenotype

RNF216 Promotes Occurrence and Progression of Cholangiocarcinoma via Regulation of the DIAPH3 Ubiquitination

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