2020-04-082024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/653627摘要：癌細胞的遠端轉移與抗藥性的產生是造成癌症治療無效的重要原因。在眾多造成癌轉移與抗藥性的機制之中，癌細胞上皮－間質轉化 (epithelial-mesenchymal transition, EMT) 是非常重要的機轉之一，癌細胞藉由經過上皮－間質轉化 (EMT) 的過程，由比較不具侵襲性的上皮表現型 (epithelial)轉化為較具侵襲性的間質表現型 (mesenchymal)。這些較具侵襲性的間質表現型 (mesenchymal)癌細胞，大大提升轉移至遠端器官的能力，許多在血液循環中的循環癌細胞 (circulating tumor cells, CTC)，都具有此種間質表現型；或是轉化為所謂的癌幹細胞 (cancer stem cell)，躲藏在一些特殊的利基維環境 (microenvironment niche) 中，也因為這些細胞本身具有一些特殊蛋白質的表現，造成對於化學、放射、標靶治療甚至免疫治療的抵抗性，造成根除癌細胞的困難。本計畫旨在釐清一個上皮細胞特有的轉錄因子GRHL2在卵巢癌細胞轉移時，調控上皮－間質轉化光譜挪移的機轉。<br> Abstract: Majority of the ovarian cancer (OC) patients are diagnosed at advanced stages when distant metastasis results into significant disease burden. Among the various mechanisms contributing to cancer metastasis, epithelial-mesenchymal transition (EMT) was proposed, heavily challenged, and recently confirmed in vivo. During the multiple steps of OC metastasis, EMT is required for the initial dissemination to shed off the OC cells into the ascitic fluid resulted from the activation of angiogenesis. EMT is also required for these shed OC cells to survive inside the ascites via overcoming anoikis. Ultimately, these metastatic cells adhere and implant onto secondary sites (peritoneum, serosal surfaces, omentum) to establish distant metastases and undergo the reversal of EMT, mesenchymal-epithelial transition (MET). Previously, we demonstrated that there is heterogeneity in EMT phenotypes and proposed the concept of EMT Spectrum. It is now widely appreciated that the plasticity of EMT/MET switches occurs in a step-wise fashion via multiple intermediate hybrid states. A transcription factor grainyhead-like 2 (GRHL2) has been identified to have functional roles in maintaining the epithelial state of OC by our group. The loss of GRHL2 results in the step-wise transition of EMT phases in OC and governs the stability of hybrid E/M phenotype. We have also demonstrated that GRHL2 binding sites are prone to be epigenetically regulated by histone modifications and/or methylation at CpG sites. In this proposal, we hypothesize that GRHL2 is pivotal in governing the genome response to EMT/MET transition phases via controlling the chromatin landscape during OC early dissemination. We will utilize the established EMT-Spectrum characterized OC cell lines and inducible systems to re-express GRHL2 to further explore how the alteration of GRHL2 expression contributes to the various transition states of EMT and affects the metastatic potential and aggressiveness of OC.上皮－間質轉化卵巢癌EMTovarian cancer