ESM1 mediates NGFR-induced invasion and metastasis in murine oral squamous cell carcinoma
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Chen Chen1,2,4, June Ho Shin1,2, Joshua T. Eggold2,3, Man Ki Chung1,2,5, Luhua H. Zhang1,2, Jeremy Lee1,2, John B. Sunwoo1,2,3
1Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305, USA
2Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
3Graduate Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
4Department of Otolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China
5Department of Otorhinolaryngology, Head & Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Sungkyunkwan, Korea
John B. Sunwoo, email: firstname.lastname@example.org
Keywords: nerve growth factor receptor, CD271, HNSCC, metastasis, endocan
Received: April 26, 2016 Accepted: September 02, 2016 Published: September 23, 2016
Oral squamous cell carcinoma (OSCC) is a highly invasive and metastatic malignancy. The nerve growth factor receptor (NGFR) has been observed to be expressed on a subset of cells in OSCC, and NGFR+ cells have greater tumor-initiating capacity in vivo. Further, inhibition of NGFR reduces tumor growth, indicating a functional role of this receptor; however, the mechanisms by which NGFR confers enhanced tumor formation are not known. Here, we used an established murine model of OSCC and gene expression array analysis to identify ESM1 as a downstream target gene of NGFR, critical for tumor invasion and metastasis. ESM1 encodes a protein called endocan, which has the property of regulating proliferation, differentiation, migration, and adhesion of different cell types. Incubation of NGFR+ murine OSCC cells with nerve growth factor resulted in increased expression of ESM1. Importantly, ESM1 overexpression conferred an enhanced migratory, invasive, and metastatic phenotype, similar to what has been correlated with NGFR expression. Conversely, shRNA knockdown of ESM1 in NGFR overexpressing OSCC cells abrogated the tumor growth kinetics and the invasive and metastatic properties associated with NGFR. Together, our data indicate that NGFR plays an important role in the pathogenesis and progression of OSCC via regulation of ESM1.
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