Cancer-associated fibroblasts regulate keratinocyte cell–cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer

Cirillo, Nicola; Hassona, Yazan; Celentano, Antonio; Lim, Ka Keat; Manchella, Sankar; Parkinson, Eric Kenneth; Prime, Stephen S.

doi:10.1093/carcin/bgw113

Cited by 41 publications

(25 citation statements)

References 51 publications

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“…It is targeted by miR-141-3p which was downregulated in our data. It is suggested that the ability of OSCC cells to secrete TGF-β2 could contribute to clinical progression by maintaining a microenvironment conducive for tumor growth and proliferation 53 , 54 . In addition to the proteins discussed above we have identified a number of proteins which were overexpressed in smoke exposed cells and inversely correlated to their respective miRNAs, but have not been reported in literature in the context of oral cancer.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke and chewing tobacco alter expression of different sets of miRNAs in oral keratinocytes

Bhat

Advani

Rajagopalan

et al. 2018

Sci Rep

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Carcinogenic effect of tobacco in oral cancer is through chewing and/or smoking. Significant differences exist in development of oral cancer between tobacco users and non-users. However, molecular alterations induced by different forms of tobacco are yet to be fully elucidated. We developed cellular models of chronic exposure to chewing tobacco and cigarette smoke using immortalized oral keratinocytes. Chronic exposure to tobacco resulted in increased cell scattering and invasiveness in immortalized oral keratinocytes. miRNA sequencing using Illumina HiSeq 2500 resulted in the identification of 10 significantly dysregulated miRNAs (4 fold; p ≤ 0.05) in chewing tobacco treated cells and 6 in cigarette smoke exposed cells. We integrated this data with global proteomic data and identified 36 protein targets that showed inverse expression pattern in chewing tobacco treated cells and 16 protein targets that showed inverse expression in smoke exposed cells. In addition, we identified 6 novel miRNAs in chewing tobacco treated cells and 18 novel miRNAs in smoke exposed cells. Integrative analysis of dysregulated miRNAs and their targets indicates that signaling mechanisms leading to oncogenic transformation are distinct between both forms of tobacco. Our study demonstrates alterations in miRNA expression in oral cells in response to two frequently used forms of tobacco.

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Section: Discussionmentioning

confidence: 99%

Cigarette smoke and chewing tobacco alter expression of different sets of miRNAs in oral keratinocytes

Bhat

Advani

Rajagopalan

et al. 2018

Sci Rep

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“…The effects of TGFβ on transcription can be positive or negative depending on the targeted gene and the cellular context [ 27 ]. Cirillo et al [ 28 ] suggested that the TGF-β family of cytokines secreted by cancer-associated fibroblast (CAFs) derived from genetically unstable oral squamous cell carcinomas promote the malignant phenotype by weakening intercellular epithelial adhesion. As shown by authors, members of the TGF-β family of cytokines distinguish CAFs from oral cancer and from normal oral fibroblasts [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cirillo et al [ 28 ] suggested that the TGF-β family of cytokines secreted by cancer-associated fibroblast (CAFs) derived from genetically unstable oral squamous cell carcinomas promote the malignant phenotype by weakening intercellular epithelial adhesion. As shown by authors, members of the TGF-β family of cytokines distinguish CAFs from oral cancer and from normal oral fibroblasts [ 28 ]. In other studies, the researchers investigated the role of TGF-β in the induction of fibrosis in another oral disorder, namely oral submucous fibrosis (OSF) [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

New Gene Markers for Metabolic Processes and Homeostasis in Porcine Buccal Pouch Mucosa during Cells Long Term-Cultivation—A Primary Culture Approach

Dyszkiewicz-Konwińska

Nawrocki²,

Huang

et al. 2018

IJMS

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The oral mucosal tissue is a compound structure composed of morphologically and physiologically different cell types. The morphological modification involves genetically determined lifespan, which may be recognized as the balance between cell survival and apoptosis. Although the biochemical processes and pathways in oral mucosa, with special regards to drug transport, delivery, and metabolism, are well known, the cellular physiological homeostasis in this tissue requires further investigation. The porcine buccal pouch mucosal cells (BPMCs) collected from 20 pubertal crossbred Landrace gilts, were used in this study. Immediately after recovery, the oral mucosa was separated micro-surgically, and treated enzymatically. The dispersed cells were transferred into primary in vitro culture systems for a long-term cultivation of 30 days. After each step of in vitro culture (IVC), the cells were collected for isolation of total RNA at 24 h, 7, 15, and 30 days of IVC. While the expression was analyzed for days 7, 15, and 30, the 24th hour was used as a reference for outcome calibration. The gene expression profile was determined using Affymetrix microarray assays and necessary procedures. In results, we observed significant up-regulation of SCARB1, PTGS2, DUSP5, ITGB3, PLK2, CCL2, TGFB1, CCL8, RFC4, LYN, ETS1, REL, LIF, SPP1, and FGER1G genes, belonging to two ontological groups, namely “positive regulation of metabolic process”, and “regulation of homeostatic process” at 7 day of IVC as compared to down-regulation at days 15 and 30. These findings suggest that the metabolic processes and homeostatic regulations are much more intense in porcine mucosal cells at day 7 of IVC. Moreover, the increased expression of marker genes, for both of these ontological groups, may suggest the existence of not only “morphological lifespan” during tissue keratinization, but also “physiological checkpoint” dedicated to metabolic processes in oral mucosa. This knowledge may be useful for preclinical experiments with drugs delivery and metabolism in both animals and humans.

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“…Among different signaling pathways, the Transforming growth factor βs (TGFβs) have profound effects on EMT progression [ 10 , 13 , 41 , 42 ]. Therefore, identification of TGFB2 gene as a target of DDB2 in HNSCC cells is an important observation.…”

Section: Resultsmentioning

confidence: 99%

“…In GBM, TGFβ2 has been shown to play essential role in pathogenesis [ 57 ]. In one study, the paracrine function of TGFb2 has been reported in cancer-associated fibroblasts (CAFs)-induced EMT of oral keratinocytes [ 41 ]. Identification of TGFB2 as a DDB2 target is a new significant observation.…”

Section: Discussionmentioning

confidence: 99%

DDB2 regulates Epithelial-to-Mesenchymal Transition (EMT) in Oral/Head and Neck Squamous Cell Carcinoma

et al. 2018

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DDB2 is a sensor of DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Our previous studies show that DDB2 is involved in the regulation of metastasis in colon adenocarcinoma. Squamous Cell Carcinomas in the Oral/Head & Neck region (HNSCC) are particularly aggressive due to high incidence of recurrence and distant metastasis. In this study, we show that DDB2 expression is downregulated in advanced HNSCCs and loss of DDB2 expression coincides with reduced survival. Recent meta-analysis of gene expression data characterized the mesenchymal-type (EMT-type) as one most aggressive cancer cluster in HNSCC. Here, we report that DDB2 constitutively represses mRNA expression of the EMT- regulatory transcription factors SNAIL, ZEB1, and angiogenic factor VEGF in HNSCC cells. As a result, re-expression of DDB2 in metastatic cells reversed EMT with transcriptional upregulation of epithelial marker E-cadherin, and downregulation of mesenchymal markers N-cadherin, Vimentin, and Fibronectin. Interestingly, in a reverse assay, depletion of DDB2 in non-metastatic cells induced expression of the same EMT-regulatory transcription factors. TGFβs are major regulators of Snail and Zeb1, and we observed that DDB2 transcriptionally regulates expression of TGFB2 in HNSCC cells. Re-expression of DDB2 in mouse embryonic fibroblasts (MEFs) isolated from Ddb2 (−/−) knockout-mice resulted in repression of EMT-regulatory factors Zeb1, Snail and Tgfb2. Taken together, these results support the active role of DDB2 as a candidate suppressor of the EMT-process in HNSCC. Early detection leads to significantly higher survival in HNSCC and DDB2 expression in tumors can be a predictor of EMT progression.

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Cancer-associated fibroblasts regulate keratinocyte cell–cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer

Cited by 41 publications

References 51 publications

Cigarette smoke and chewing tobacco alter expression of different sets of miRNAs in oral keratinocytes

Cigarette smoke and chewing tobacco alter expression of different sets of miRNAs in oral keratinocytes

New Gene Markers for Metabolic Processes and Homeostasis in Porcine Buccal Pouch Mucosa during Cells Long Term-Cultivation—A Primary Culture Approach

DDB2 regulates Epithelial-to-Mesenchymal Transition (EMT) in Oral/Head and Neck Squamous Cell Carcinoma

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