2017-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/671867摘要：KH-type splicing regulatory protein (KSRP)為一RNA 結合蛋白，過去研究已知KSRP 可與核醣核酸酶Drosha/Dicer 一同調控miRNA 的生合成，此外KSRP 尚可與mRNA 3’UTR 上的AU-rich element(ARE)結合進而調控mRNA 降解。由於AREs 常被發現在oncogenes、growth factors 以及cytokines 等mRNA 序列上，因此這些可與ARE 結合的蛋白 (ARE-BP)所調控之訊息途徑常與細胞凋亡、腫瘤發生以及進展有關。過去文獻指出ARE-BP 可藉由與c-myc/ c-jun mRNA 結合調控甲狀腺癌細胞增生與細胞週期，進而影響甲狀腺癌的進程。然而目前對於甲狀腺癌的了解以及ARE-BP 所扮演之角色尚未清楚，我們十分有興趣進一步探討KSRP 在甲狀腺癌中的角色為何。初步實驗結果顯示KSRP 於甲狀腺癌病患腫瘤組織的表現高於周圍正常甲狀腺組織，而在in vitro 實驗中也發現KSRP 蛋白表現量與甲狀腺癌細胞遷移以及侵襲能力成一正相關性，同時動物實驗結果也證實將KSRP knockdown 後可降低甲狀腺癌轉移的能力。此外經由細胞以及動物實驗結果，我們也發現KSRP 蛋白表現高低可能與癌幹細胞之族群以及能力相關。我們計畫從mRNA 降解以及miRNA 生合成角度探討KSRP 於甲狀腺癌的分子標的及相關機制以確立KSRP 在甲狀腺癌的角色並釐清可能的臨床運用價值。本研究的完成除了能對KSRP 在甲狀腺癌細胞中的角色有所了解，對於其下游作用標的miRNA/mRNA、特殊機制及影響功能也可進一步探究，也可對KSRP 作為腫瘤標記或是標靶治療做一完整的評估。<br> Abstract: KH-type splicing regulatory protein (KSRP) is a RNA binding protein, which cooperate withDrosha/Dicer complex to promote miRNA biogenesis. KSRP is one of regulatory protein which is able tobind to the landmark cis element AREs (AU-rich element). Besides, AREs are responsible for rapid mRNAdecay in mammalian cells and can be found in 3’ untranslated regions (UTRs) of many short-livedtranscripts encoding cytokines, cell-cycle regulators, cell type-specific transcription factors, andproto-oncogenes. Previous study had shown that ARE binding proteins (ARE-BPs) may interact withmRNA encoding c-myc and c-jun to regulate thyroid carcinoma cell cycle and proliferation which reportedto be crucial for thyroid carcinoma progression. However, the role of this kind of ARE-BP in thyroid cancerprogression is unknown, we are interesting in investigating the role of KSRP in the process of thyroid cancerdevelopment. In our preliminary data, we found that the expression of KSRP in tumor part isolated fromthyroid cancer patients were higher than normal thyroid tissue. We also observed positive correlationsbetween KSRP protein expression and cell invasiveness of thyroid cancer cell lines while in vivoexperiments showed that KSRP-depleted cells significantly suppressed their metastatic abilities.Furthermore, we have also explored that KSRP protein expression was correlated with cancer stemness byour in vitro/in vivo analysis. In this proposed project, we will perform different functional assay to examinethe involvement of KSRP in thyroid cancer development. The underlying molecular mechanisms by whichKSRP execute its effects in mRNA decay and miRNA biogenesis will also be extensively studied. Throughthese experimental evaluations, we will able to obtain a comprehensive point of view about the role ofKSRP in thyroid cancer and provide novel diagnostic and therapeutic targets for thyroid cancer.KSRPmRNA 降解miRNA 生合成細胞浸襲癌幹細胞甲狀腺癌KSRPmRNA decaymiRNA biogenesiscell invasioncancer stem cellthyroid cancer