Down-regulation of ß-catenin and the associated migration ability by Taiwanin C in arecoline and 4-NQO-induced oral cancer cells via GSK-3ß activation.

Cancer is one of the leading causes of death worldwide, and oral squamous cell carcinoma (OSCC) accounts for almost a sixth of all reported cancers. Arecoline, from areca nut is known to enhance carcinogenesis in oral squamous cells. The objective of this study is to determine the effect of Taiwanin C, from Taiwania cryptomerioides Hayata against Arecoline-associated carcinogenesis. An OSCC model was created in C57BL/6J Narl mice by administrating 0.5 mg mL-1 arecoline with 0.2 mg mL-1 4-NQO carcinogen for 8 and 28 wk to mimic the etiology of oral cancer patients in Asia. Mice were sacrificed and two cell lines, T28 from the tumor and N28 cancerous cell line from the surrounding non tumor area, were established. Taiwanin C showed effective anti-tumor activity in nude mice models. Taiwanin C significantly inhibited the cell viability of T28 cells in a dose dependent manner, but did not inflict any effect on N28 normal cells. Taiwanin C treatment inhibited the migration ability of T28 cells in a dose dependent manner as determined by wound healing and migration assays. Taiwanin C also reduced the levels of ß-catenin and its downstream metastatic proteins, Tbx3 and c-Myc. Besides, Taiwanin C inhibited the nuclear accumulation of ß-catenin and induced ß-catenin degradation via proteasome-mediated pathway. Moreover, Taiwanin C enhanced GSK-3ß and reduced the p-ser9 GSK-3ß protein level to inactivate Wnt signaling. Taken together, Taiwanin C blocked the cell migration effects of T28 cells mediated through the activation of GSK-3ß to enhance protein degradation and reduce nuclear accumulation of ß-catenin. © 2016 Wiley Periodicals, Inc.

TSLC1 expression discriminates cutaneous melanomas from dysplastic nevi.

Cutaneous melanoma is a malignant tumor of melanocytes that causes the majority of skin cancer-related deaths. However, sometimes, discrimination between dysplastic nevi and early melanomas is difficult, even for experienced pathologists. Besides histology, the silencing of tumor suppressor genes aids in the diagnosis of melanoma. We have shown previously that tumor suppressor in lung cancer 1 (TSLC1) is a tumor suppressor gene, and its silencing through aberrant promoter methylation is associated with the generation of cutaneous melanoma. To examine TSLC1 expression in melanocytic skin lesions to determine whether it can serve as a diagnostic marker in histologically questionable lesions. Cytoplasmic localization of the expression of the TSLC1 gene was detected by immunohistochemistry; the levels of TSLC1 mRNA and protein were detected by quantitative real-time reverse transcription-PCR and western blot, respectively. Using immunohistochemistry, the average TSLC1 expression levels in cutaneous melanomas decreased approximately 3.6-fold (n=20) as compared with dysplastic nevi (n=30) and 3.7-fold as compared with normal skin (n=25). The average expression levels of TSLC1 mRNA and protein in dysplastic nevi lesions and normal skin were significantly higher than the levels in cutaneous melanomas. No significant changes in TSLC1 mRNA and protein expressions were found between normal skin and dysplastic nevi. Our results show that a loss of TSLC1 frequently occurs in cutaneous melanoma, and indicate that it could serve as a diagnostic marker for cutaneous melanoma in histologically questionable lesions.