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Two opposite effects of desmoglein 3 on the growth of oral squamous cell carcinoma between anchorage -dependent and -independent conditions

ABSTRACT: Desmoglein 3 (Dsg3) is one of the desmosomal cadherins. Recent studies have reported that Dsg3 is abnormally expressed in oral squamous cell carcinoma (OSCC) and associated with tumor growth and poor survival. A role of Dsg3 in the progression of OSCC remains controversial, since both positive and negative effect on the cancer progression have been reported. Previously we have demonstrated that OSCC cells from the metastatic lymph nodes showed significantly higher DSG3 expression compared to those from the primary tumor of the same patients. Here we investigated the effect of Dsg3 expression on the growth of OSCC between anchorage-dependent (AD) and -independent (AID) conditions. Cell lines established from the primary tumor (P) and metastatic lymph nodes (LY) of three OSCC patients and two commercial OSCC cell lines were used for the experiments. Under AD conditions, Dsg3-low cell lines (Dsg3-low) had higher cell proliferation and migration ability than Dsg3-high cell lines (Dsg3-high) of the same patients. After transferred into AID conditions, all the cell lines except Dsg3-negative 7P showed increased Dsg3 expression by up to 50-fold, compared with AD conditions. Under AID conditions, all the patients showed higher cell proliferation ability in the Dsg3-high compared with Dsg3-low, which was marked contrast to AD conditions. Dsg3 knockdown under AD conditions increased the cell proliferation rate of all the cell lines except Dsg3-negative line. On the other hand, cell growth was not affected under AID conditions. These results suggested that Dsg3 may have two opposite effects on the growth of OSCC cells between AD and AID conditions, and that the involvement of molecules other than Dsg3 may also be important. Therefore, we investigated DEGs by Dsg3 knockdown under AD and AID conditions and their functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275776 | GEO | 2024/12/24

REPOSITORIES: GEO

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Project description:Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines, generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression OSCC cell lines, including CRR cell lines, and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell types. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific siRNA treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.

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Two opposite effects of desmoglein 3 on the growth of oral squamous cell carcinoma between anchorage -dependent and -independent conditions

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