Al-Abdallah Abeer, Jahanbani Iman, Al-Shammari Bashayer
Pathology Department, College of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
Research Core Facility, Health Sciences Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
Int J Mol Sci. 2025 Jun 17;26(12):5813. doi: 10.3390/ijms26125813.
Thyroid carcinogenesis has multiple hallmarks, including evasion of tumor suppressors. Reactivation of wild-type p53 function is the ultimate goal in cancer therapy, which requires an understanding of the p53 suppression mechanism specific to the cancer type. MiR-7-5p and IPO7 are implicated in the pathogenesis of several human diseases. This work aims to investigate the role of miR-7-5p and IPO7 in p53 regulation in papillary thyroid cancer (PTC) cells. Primary cultured thyroid cells and FFPE thyroid tissues from PTC and benign cases were used. Functional experiments were performed by transfection with IPO7 siRNA or miR-7-5p mimic/inhibitor, followed by apoptosis and luciferase reporter assays, immunoblot assays, and RT-PCR. The expression and subcellular localization of IPO7, p53, MDM2, and ribosomal proteins (RPL11 and RPL5) were studied by immunofluorescence staining and confocal microscopy. The results show that IPO7 is overexpressed in PTC and regulated by miR-7-5p. Modulation of IPO7 expression in cultured thyroid cells altered the nucleocytoplasmic shuttling of p53, MDM2, RPL11, and RPL5, in addition to the p53 protein level and activity. The expression pattern of IPO7, p53, and MDM2 in cultured thyroid cells and clinical thyroid tissue specimens confirmed the association between IPO7 overexpression and reduced p53 stability in PTC. In conclusion, the data here show that p53 level and activity are differentially controlled in malignant and benign thyroid cells through miR-7-5P/IPO7-mediated regulation of RP-MDM2-p53 nucleocytoplasmic trafficking. In PTC, downregulation of miR-7-5p with consequent overexpression of IPO7 might be a protective mechanism used by cancer cells to evade p53 growth suppression during carcinogenesis.
甲状腺癌发生具有多个特征，包括逃避肿瘤抑制因子。野生型p53功能的重新激活是癌症治疗的最终目标，这需要了解特定癌症类型的p53抑制机制。MiR-7-5p和IPO7与几种人类疾病的发病机制有关。本研究旨在探讨miR-7-5p和IPO7在甲状腺乳头状癌（PTC）细胞中对p53调控的作用。使用了来自PTC和良性病例的原代培养甲状腺细胞以及福尔马林固定石蜡包埋（FFPE）甲状腺组织。通过转染IPO7 siRNA或miR-7-5p模拟物/抑制剂进行功能实验，随后进行凋亡和荧光素酶报告基因检测、免疫印迹检测及逆转录聚合酶链反应（RT-PCR）。通过免疫荧光染色和共聚焦显微镜研究了IPO7、p53、MDM2和核糖体蛋白（RPL11和RPL5）的表达及亚细胞定位。结果表明，IPO7在PTC中过表达且受miR-7-5p调控。在培养的甲状腺细胞中调节IPO7表达，除了改变p53蛋白水平和活性外，还改变了p53、MDM2、RPL11和RPL5的核质穿梭。培养的甲状腺细胞和临床甲状腺组织标本中IPO7、p53和MDM2的表达模式证实了PTC中IPO7过表达与p53稳定性降低之间的关联。总之，这里的数据表明，通过miR-7-5P/IPO7介导的RP-MDM2-p53核质转运调控，恶性和良性甲状腺细胞中p53水平和活性受到不同控制。在PTC中，miR-7-5p下调并随之导致IPO7过表达，这可能是癌细胞在致癌过程中逃避p53生长抑制的一种保护机制。
