Abstract
Abstract Background: Accumulating studies suggest that the existence of cancer initiating cells (CICs) may explain the results of chemoresistant and radioresistant from cancer treatment and the incidence of metastasis and recurrence. Previously, we demonstrate that Tid1 plays a crucial role as a tumor suppressor during head and neck cancer tumorigenesis. In addition, the protein level of Tid1 is negatively correlated to the overall stage, survival and recurrence of both head and neck cancer and breast cancer patients. Moreover, we also observe that glucose regulatory protein 78 (GRP78), one of the Tid1-interacting protein, mediates the stemness properties of head and neck cancer-initiating cells (HN-CICs) in our recent studies. Nevertheless, the role of Tid1 in CICs properties remains elusive. Methods: We have identified the HN-CICs from head and neck squamous cell carcinoma (HNSCC) and established HNSCC xenograft-derived cell lines by sphere formation assay. To further investigate whether Tid1 mediates the stemness properties of HN-CICs, we will overexpress or knockdown the Tid1 expression to determine the sphere formation ability and the expression of stemness markers, GRP78, Oct-4 and Nanog, of HN-CICs. The oncogenic ability of the HN-CICs mediated by Tid1 expression will also be examined by both in vitro and in vivo assays. Further, we have successfully established mice with epithelial specific ablation of Tid1 by crossing Tid1flx/flx mice with transgenic K5-Cre mice. Consequently, the mutant and control mice have been subject to carcinogen 4-NQO (4-Nitroquinoline 1-oxide) treatment within drinking water for monitoring head and neck cancer progression. Immunohistochemistry staining was applied to examine the expression profile of stemness/differentiation markers within tumors formed in mutant and wild type mice. Results: Up to date, we discovered that mutant mice treated with 4-NQO displayed faster incident of neoplasia in oral cavity and reduction of body weight in comparison to control mice under same administration. In addition, the histopathological analyses showed that the tumors formed in mutant mice were squamous cell carcinoma whereas tumors formed in wild type mice were benign squamous papilloma. Further, we observed that the expression of Tid1 protein was down regulated in the HN-CICs and SAS xenograft-derived cell lines comparing to the HNSCCs by microarray gene expression analysis and immunoblotting assay. Conclusion: Deficient of Tid1 can accelerate the incident of tumorigenesis and tumor progression mediated by 4-NQO treated mice model. We also found that Tid1 expression was negative correlated to the stemness properties. Therefore, Tid1 may play an important role of controlling stemness properties. However, the molecular mechanisms mediated by Tid1 to regulate the progression of HNSCC remain elusive. Further research effort is needed in this area. Citation Format: Li-Hao Cheng, Jeng-Fan Lo. Tid1 mediating cancer initiating properties of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2015-2067
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