Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
Laboratory of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei 430030, People's Republic of China.
Endocrinology. 2022 Apr 1;163(4). doi: 10.1210/endocr/bqac022.
Papillary thyroid cancer (PTC) remains the most common endocrine malignancy, despite marked achieves in recent decades, and the mechanisms underlying the pathogenesis and progression for PTC are incompletely elucidated. Accumulating evidence show that γ-glutamylcyclotransferase (GGCT), an enzyme participating in glutathione homeostasis and is elevated in multiple types of tumors, represents an attractive therapeutic target. Using bioinformatics, immunohistochemistry, qRT-PCR, and Western blot assays, we found that GGCT expression was upregulated in PTC and correlated with more aggressive clinicopathological characteristics and worse prognosis. GGCT knockdown inhibited the growth and metastasis ability of PTC cells both in vitro and in vivo and reduced the expression of mesenchymal markers (N-cadherin, CD44, MMP2, and MMP9) while increasing epithelial marker (E-cadherin) in PTC cells. We confirmed binding of microRNA-205-5p (miR-205-5p) on the 3'-UTR regions of GGCT by dual-luciferase reporter assay and RNA-RNA pull-down assay. Delivery of miR-205-5p reversed the pro-malignant capacity of GGCT both in vitro and in vivo. Lastly, we found that GGCT interacted with and stabilized CD44 in PTC cells by co-immunoprecipitation and immunohistochemistry assays. Our findings illustrate a novel signaling pathway, miR-205-5p/GGCT/CD44, that involves in the carcinogenesis and progression of PTC. Development of miR-205-mimics or GGCT inhibitors as potential therapeutics for PTC may have remarkable applications.
甲状腺乳头状癌 (PTC) 仍然是最常见的内分泌恶性肿瘤，尽管近几十年来取得了显著成就，但 PTC 的发病机制和进展的机制仍不完全清楚。越来越多的证据表明，γ-谷氨酰环转移酶 (GGCT) 参与谷胱甘肽稳态，在多种类型的肿瘤中升高，是一个有吸引力的治疗靶点。通过生物信息学、免疫组织化学、qRT-PCR 和 Western blot 检测，我们发现 GGCT 在 PTC 中表达上调，与侵袭性更强的临床病理特征和更差的预后相关。GGCT 敲低抑制 PTC 细胞的体外和体内生长和转移能力，并降低 PTC 细胞中间充质标志物 (N-钙黏蛋白、CD44、MMP2 和 MMP9) 的表达，同时增加上皮标志物 (E-钙黏蛋白)。我们通过双荧光素酶报告基因检测和 RNA-RNA 下拉实验证实了 microRNA-205-5p (miR-205-5p) 在 GGCT 3'-UTR 区域的结合。miR-205-5p 的递送在体外和体内逆转了 GGCT 的促恶性能力。最后，我们通过共免疫沉淀和免疫组织化学检测发现 GGCT 在 PTC 细胞中与 CD44 相互作用并稳定 CD44。我们的研究结果说明了一种新的信号通路，即 miR-205-5p/GGCT/CD44，它参与了 PTC 的发生和发展。开发 miR-205-5p 模拟物或 GGCT 抑制剂作为 PTC 的潜在治疗方法可能具有显著的应用前景。
