Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis

Darido, Charbel; Georgy, Smitha Rose; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema; Finlay, Moira; Papenfuss, Anthony T.; Pandolfi, Pier Paolo; Pearson, Richard B.; Jane, Stephen M.

doi:10.1016/j.ccr.2011.10.014

Cited by 213 publications

(304 citation statements)

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“…Deletion of Grhl3 at P1 does not lead to barrier defect nor to death from dehydration. This suggests that although Grhl3 is essential for barrier establishment, it is not required for crucial maintenance of the epithelium [48]. Recent data indicated that another Grhl gene, Grhl1, is compensating for the loss of Grhl3 in adulthood, accounting for the ability of these conditional KO (cKO) mice to maintain an intact skin barrier [49].…”

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

“…Furthermore, the mitotic cells that usually reside towards the basal epidermal layer, where the HF and IFE SCs as well as the TA cells are found, become increasingly prominent in the suprabasal layers, promoting a tumourigenic environment [48]. Pseudo-tumours form from these supra-basal cells when cultured in vitro, demonstrating their potential to become carcinogenic given the right microenvironment [48].…”

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

“…Pseudo-tumours form from these supra-basal cells when cultured in vitro, demonstrating their potential to become carcinogenic given the right microenvironment [48].…”

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

“…Grhl3-deficient embryos exhibit keratinocyte hyperproliferation [48], in addition to aberrant wound healing [42] and fragile skin [50], suggesting that loss of Grhl3 interferes with the normal differentiation program, leading to an excess of cellular proliferation. Altered cellular differentiation and proliferation is a common characteristic of cancers whereby malignant cells, in addition to increased survival, also demonstrate dysregulated cell cycle progression [51,52].…”

Section: The Role Of Grhl3 In Skin Hyperplasiamentioning

confidence: 99%

“…C57Bl/6 mice are well known for their high resistance to chemically induced tumourigenesis, therefore their capacity to form tumours following administration of the well-characterised DMBA/TPA carcinogenesis protocol is low [48]. Grhl3 ∆/-/K14Cre+ mice generated on a C57Bl/6 background readily develop multiple papillomas, keratocanthomas (KAs) and SCCs.…”

Section: Grhl3 Functions As a Tumour Suppressor Against Sccmentioning

confidence: 99%

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Long-Lived Epidermal Cancer-Initiating Cells

Youssef

Cuddihy

Darido

2017

Preprint

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Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population as well as an economic load to the health care system, yet treatments of these preventable cancers remain ineffective. Although primary prevention is possible through minimising sunlight exposure, the World Health Organisation estimates that between 2 and 3 million new cases of NMSCs are diagnosed each year, accounting for 1 in 3 of all newly diagnosed cancers.Furthermore, studies have estimated there has been a 2-fold increase in the incidence of NMSCs between 1960s and 1980s. The increase in cases of NMSCs as well as the lack of effective treatments makes the need for novel therapeutic approaches all the more necessary.To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgent. NMSCs are generally thought to arise from specific types of stem cells that become the source of clonal expansion of tumourigenic cells. Previous research on SCC has alluded to these stem cells being localised in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers. More recent research has Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

“…Pseudo-tumours form from these supra-basal cells when cultured in vitro, demonstrating their potential to become carcinogenic given the right microenvironment [48].…”

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

Section: The Role Of Grhl3 In Skin Hyperplasiamentioning

confidence: 99%

Section: Grhl3 Functions As a Tumour Suppressor Against Sccmentioning

confidence: 99%

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Long-Lived Epidermal Cancer-Initiating Cells

Youssef

Cuddihy

Darido

2017

Preprint

Self Cite

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Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Lammert,

Pannhausen,

Noetzel

et al. 2024

Molecular Oncology

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The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

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Circular RNA profiles and the potential involvement of down‐expression of hsa_circ_0001360 in cutaneous squamous cell carcinogenesis

Chen

Huang

et al. 2021

FEBS Open Bio

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Circular RNAs (circRNAs) act as sponges of non-coding RNAs (ncRNAs) and have been implicated in many pathophysiological processes, including tumor development and progression. However, their roles in cutaneous squamous cell carcinoma (cSCC) are not yet well understood. The present study aimed to identify differentially expressed circRNAs and their potential functions in cutaneous squamous cell carcinogenesis. The expression profiles of circRNAs in 3 paired cSCC and adjacent This article is protected by copyright. All rights reserved Accepted Article 4 non-tumorous tissues were detected with RNA sequencing and bioinformatics analysis. The candidate circRNAs were validated by PCR, Sanger sequencing, and qRT-PCR in another 5 matched samples. The biological functions of circRNAs in SCL-1 cells were assessed using circRNA silencing and overexpression, MTS, flow cytometry, transwell and colony formation assays. In addition, the circRNA-miRNA-mRNA interaction networks were predicted by bioinformatics. In summary, 1115 circRNAs, including 457 up-and 658 down-regulated circRNAs (fold change ≥ 2 and p < 0.05), were differentially expressed in cSCC compared with adjacent non-tumorous tissues. Of 4 selected circRNAs, 2 circRNAs (hsa_circ_0000932 and hsa_circ_0001360) were confirmed to be significantly decreased in cSCC using PCR, Sanger sequencing, and qRT-PCR. Furthermore, hsa_circ_0001360 silencing was found to result in a significant increase of the proliferation, migration and invasion but a significant decrease of apoptosis in SCL-1 cells in vitro, whereas hsa_circ_0001360 overexpression showed the opposite regulatory effects. Hsa_circ_0001360 was predicted to interact with 5 miRNAs and their corresponding genes. In conclusion, circRNA dysregulation may play a critical role in carcinogenesis of cSCC, and hsa_circ_0001360 may have potential as a biomarker for cSCC.

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Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis

Cited by 213 publications

References 71 publications

Long-Lived Epidermal Cancer-Initiating Cells

Long-Lived Epidermal Cancer-Initiating Cells

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes

Circular RNA profiles and the potential involvement of down‐expression of hsa_circ_0001360 in cutaneous squamous cell carcinogenesis

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