Dataset Information

Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models.

ABSTRACT: BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) has had little improvement in mortality rates in decades. A clearer understanding of the HNSCC tumor microenvironment will aid in finding more effective targeted therapies for this disease. Tumor-associated fibroblasts (TAFs) are the largest stromal cellular components of the tumor microenvironment in HNSCC. METHODS:We isolated TAFs from clinical HNSCC cases and propagated in vitro. The effects of TAF-secreted paracrine factors on in vitro HNSCC migration, invasion, and proliferation was assessed. The effect of TAFs on HNSCC growth and metastases was determined in an orthotopic floor-of-the-mouth tumor model. RESULTS:TAF-conditioned media increased HNSCC cell migration, invasion, and proliferation. TAFs increased HNSCC tumor growth and metastases in vivo. CONCLUSION:TAFs play a major role in increasing tumor growth and metastasis in HNSCC. Targeting the tumor stroma may be important to reduce the rate of HNSCC metastasis.

SUBMITTER: Wheeler SE

PROVIDER: S-EPMC4111913 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models.

Wheeler Sarah Elizabeth SE Shi Huifang H Lin Fangchen F Dasari Sumana S Bednash Joseph J Thorne Stephen S Watkins Simon S Joshi Radhika R Thomas Sufi Mary SM

Head & neck 20130601 3

<h4>Background</h4>Head and neck squamous cell carcinoma (HNSCC) has had little improvement in mortality rates in decades. A clearer understanding of the HNSCC tumor microenvironment will aid in finding more effective targeted therapies for this disease. Tumor-associated fibroblasts (TAFs) are the largest stromal cellular components of the tumor microenvironment in HNSCC.<h4>Methods</h4>We isolated TAFs from clinical HNSCC cases and propagated in vitro. The effects of TAF-secreted paracrine fact ...[more]

PMID: 23728942

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Project description:While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-? stimulation.siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

Project description:BackgroundLocal or distant metastasis remains the main course of death in head and neck squamous cell carcinoma (HNSCC) patients. MicroRNAs (miRNAs) have been implicated in metastasis of HNSCC, but the mechanisms of their action are mainly undocumented. Through public head and neck cancer miRNA expression datasets, we found that miR-876-5p was a novel potential tumor suppressor targeting HNSCC metastasis.MethodsClinical significance and mechanism of miR-876-5P was systematically analyzed in HNSCC. Quantitative RT-PCR was used to evaluate miR-876-5p levels in HNSCC cell lines and in 20 pairs of HNSCC with associated regional nodal metastases and HNSCC without metastatic primary tumors. Scratch and invasion assays were evaluated to determine the role of miR-876-5p in the regulation of HNSCC cell migration and invasion, respectively. Western blotting was used to investigate the mechanism by which miR-876-5p suppresses HNSCC cell invasion and migration. Luciferase assays were performed to assess miR-876-5p binding to the vimentin gene. The animal model was used to support the in vitro experimental findings.ResultsMiR-876-5p mimics inhibited HNSCC cell migration and invasion. Vimentin protein and mRNA levels were decreased in the miR-876-5p mimics group but increased in the miR-876-5p inhibitors group, which demonstrated that miR-876-5p inhibits vimentin expression in HNSCC cells. By directly targeting the vimentin 3'-UTR, we used dual-luciferase reporter assays to verify that vimentin is a functional downstream target of miR-876-5p. Importantly, increased vimentin expression promoted cell migration and invasion, and co-transfection with miR-876-5p mimics and vimentin restored cell aggressiveness to the original level. Moreover, miR-876-5p overexpression significantly downregulated vimentin expression level and inhibited the distal metastasis of HNSCC cells in vivo.ConclusionsmiR-876-5p, which functions as a tumor suppressor in HNSCC, inhibits metastasis by targeting vimentin and provides a novel therapeutic target for HNSCC treatment.

Dataset Information

Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models.

Publications

Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models.

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