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EMILIN1 suppresses cell proliferation by inactivating Aurora Kinase and cell cycle regulator in head and neck squamous cell carcinoma

ABSTRACT: The extracellular matrix (ECM) proteins play an important role in the physiological and pathological processes of tumor development and progression. EMILIN1 (Elastic Microfibril Interface Located ProteIN-1), a homotrimeric ECM glycoprotein, has been reported to be associated with cell adhesion and migration. We previously identified downregulated-EMILIN1 as a prognostic biomarker for secondary primary malignancy in head and neck squamous cell carcinoma (HNSCC). We hypothesized that EMILIN1 functions as a tumor suppressor in HNSCC. In this study, we overexpressed exogenous EMILIN1 expression in the FaDu and CAL27 cell lines and knockdown EMILIN1 expression in both HNSCC Cancer-Associated Fibroblast (CAF) and normal fibroblast cells. Our results showed that EMILIN1 overexpression decreased cell proliferation, cell migration, and cell invasion in FaDu and CAL27 cells. Knockdown EMILIN1 in CAFs also induced cell proliferation and migration. RNA-sequencing analysis revealed the cell cycle and Aurora kinase signaling as the most significant enrichment pathways, and we then confirmed this finding at the protein level. Furthermore, we studied the effect of EMILIN1 on tumor development in vivo using chick chorioallantoic membrane (CAM) assay. EMILIN1overexpression reduced tumor area, Ki67-positive cells, and increased cleaved caspase-3 apoptotic cells. These findings suggest the tumor suppressing role of EMILIN1 in HNSCC through the inactivation of cell cycle pathway and Aurora kinase signaling. To the best of our knowledge, this is the first study to show that Aurora kinases are the key players in EMILIN1 tumor suppressive functions in head and neck cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253677 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Distant metastasis is a major factor associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC), but little is known of its molecular mechanisms. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we identified neurotensin, highly expressed in HNSCCs in comparison with normal tissues, as an invasion-promoting factor in HNSCC by using microarray analysis of clinical samples. Indeed, neurotensin overexpression associated with lymph node metastasis of neck, and tumors exhibiting neurotensin overexpression had a poor distant metastasis-free survival rate. In HNSCC cells which expressed neurotensin receptor 1 (NTSR1), neurotensin promoted cellular invasion, migration, and induction of matrix metalloproteinases transcripts. Disruption of NTSR1 signaling by silencing RNA caused the reversion of the invasion of HNSCC cells. By further microarray analysis using neurotensin-treated cells, neurotensin caused increased expression of genes implicated in tumor progression and metastasis including cell growth, migration, invasion, adhesion, angiogenesis, and apoptosis. Our findings have revealed a critical role of neurotensin/NTSR1 for invasion and migration in the metastatic process of HNSCC. This study raises the possibility that neurotensin/NTSR1 could be used as a possible predictive marker and a molecular therapeutic target in the antimetastatic strategies of HNSCC. Keywords: Identification of a novel therapeutic target for head and neck squamous cell carcinomas A total of 21 primary HNSCC samples were obtained from patients who underwent tumor resection at Chiba University Hospital (Chiba, Japan). 21 samples of normal-appearing mucosa at the margin of the surgical resection several centimeters from the tumor were also collected and designated histologically normal mucosa. 21 HNSCCs and paired normal tissues were used for microarray experiment. The clinicopathological grade was classified according to the criteria of the Japan Society for Head and Neck Cancer. The Ethics Committee of Chiba University approved our study, and informed consent was obtained from all patients for use of their tissue samples and clinical data. Tissue samples were immediately snap frozen in liquid nitrogen and stored at -80Â°C until use.

Project description:To study of differential effect on cancer-associated fibroblasts of HNSCC, we have employed microarray expression profiling. The critical effect of the tumor microenvironment to caner progression is well recognized. Recent research suggests that the cancer-promoting properties of the tumor stroma may attributed to fibroblasts. However, little is known about fibroblasts that inhibit cancer progression. From the immunohistochemical analysis of cancer tissues from head and neck squamous cell carcinoma (HNSCC) patients, we divided cancer-associated fibroblast (CAF) into two groups depending on whether the boundary between epithelial cancer cells and the surrounding extracellular matrix (ECM) is clear and smooth or not. Therefore, we tried to evaluate whether there is a difference between these two CAFs in HNSCC progression. CAF was primary cultured, followed by co-culture with HNSCC cell to observe the effect on Matrigel invasion. The mRNA expression patterns between these two CAF groups were compared by DNA microarray analysis. FaDu cell and primary CAF from each group was co-transplanted into the oral mucosa of mice, and the tumorigenesis was compared. The CAF group (CAF-Promote, CAF-P) from cancer tissues which have unclear boundary between ECM and epithelial cancer cells showed a tendency to stimulate in vitro Matrigel invasion of HNSCC cell. On the contrary, the CAF group (CAF-Defense, CAF-D) from cancer tissues, which have clear boundary with epithelial cancer cell caused no remarkable increase of Matrigel invasion. In addition, CAF-D reduced the tumorigenicity of FaDu compared to CAF-P in the in vivo mice model. In DNA microarray analysis, COL3A1, COL6A6, COL25A1, and COL26A1 were particularly highly expressed in CAF-D group. In this study, these collagen proteins derived from cancer stroma were found to have a function of inhibiting the progression of HNSCC. It is expected to provide important information for predicting the prognosis of HNSCC and development of drug target in the future.

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EMILIN1 suppresses cell proliferation by inactivating Aurora Kinase and cell cycle regulator in head and neck squamous cell carcinoma

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