Department of Endocrinology, The Third Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Department of Pathology, The Second Xiang-Ya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Endocr Relat Cancer. 2019 May;26(5):525-538. doi: 10.1530/ERC-19-0008.
Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.
在缺氧条件下，肿瘤来源的外泌体中含有与癌症和癌旁细胞相互作用相关的信息丰富的 miRNA，从而有助于肿瘤微环境 (TME) 的组织重塑。与从正常甲状腺滤泡细胞系 (Nthy-ori-3-1)、正常氧 BCPAP 或 KTC-1 细胞中分离的外泌体相比，从缺氧的甲状腺乳头癌细胞 (BCPAP 细胞)、BCPAP 细胞和 KTC-1 细胞中分离的外泌体增强了人脐静脉内皮细胞 (HUVEC) 的血管生成能力，无论是在体外还是体内。在缺氧条件下，甲状腺乳头癌细胞 BCPAP 细胞中的外泌体中 miR-21-5p 显著上调，而用 miR-21-5p 敲低的缺氧 BCPAP 细胞中分离的外泌体减弱了血管生成的促进作用。此外，我们的实验表明，miR-21-5p 直接靶向并抑制 TGFBI 和 COL4A1，从而增加内皮管形成。此外，在甲状腺乳头癌患者的血清中发现了高水平的外泌体 miR-21-5p，其促进了 HUVEC 的血管生成。总之，我们的研究揭示了缺氧甲状腺乳头癌细胞与内皮细胞之间的细胞相互作用，阐明了缺氧甲状腺乳头癌细胞通过外泌体 miR-21-5p/TGFBI 和 miR-21-5p/COL4A1 调节途径增加血管生成的新机制。
