在腫瘤轉移期間，表皮細胞可以藉由表皮-間質轉化 (Epithelial-mesenchymal transition) 重新編輯細胞特性，形成具備動態能力的間質細胞。因表皮-間質轉化 (EMT) 時常發生於幹細胞分化期間，因此這種轉換機制也被認為具備幹細胞特性。然而，當人類腫瘤發生轉移時，觀察到具侵襲性的間質癌細胞出現生長停滯，但已轉移的癌細胞則顯示了快速增殖，並且回復到表皮性狀。根據此提出理論：逆轉表皮-間質轉化 (EMT)，也就是間質-表皮轉化 (MET) 對於腫瘤細胞到達轉移位時的定殖是必須的。藉由間質-表皮轉化使侵襲性細胞轉化回表皮細胞，表皮癌細胞能固定在轉移位點並且大量增殖以達成癌症轉移的目的。雖然許多研究都指出這種表皮與間質型態之間切換 (EMT-MET switches) 對於癌症轉移的重要性，但目前只有少數研究驗證。因此，間質-表皮轉化 (MET) 的機制仍有待闡明。
在這項研究中，我們提出14-3-3θ誘導間質-表皮轉化 (MET) 的機制，其增加了增殖速率並降低了間質相關基因的表達。相反的，我們使用了CRISPR-Cas9基因剪輯技術在肺癌細胞中敲除14-3-3θ基因的表達，發現癌細胞增殖速率降低。此外，在缺乏14-3-3θ的情況下，激酶Erk和Akt的磷酸化被激活，表皮狀相關基因在14-3-3θ-缺失的細胞中被下調。有趣的是，我們也觀察到跟表皮-間質轉化 (EMT) 信號傳導有關的Stat3被磷酸化激活，臨床數據更顯示Stat3磷酸化在癌轉移部位的相反調節，表明表皮與間質型態之間切換的發生。總之，我們認為14-3-3θ通過Stat3途徑逆轉表皮-間質轉化 (EMT)，以允許腫瘤在轉移部位的生長和定殖

During the cancer metastasis, epithelial cells can transform to mesenchymal cells through EMT (Epithelial-mesenchymal transition), leading to cell reprogramming (de-differentiation). Due to EMT often occurs in organogenesis, this switching mechanism is thought to be a feature of stem cell. However, metastases of human cancers often show a re-differentiation in the sense of a mesenchymal-epithelial transition (MET), with invasive cancer cells shown growth arrested, and proliferation detected in re-differentiated (MET) metastasis. This brings about the proposal that EMT must be reversed in order to allow the tumor to grow and colonize towards the secondary site. Although many clinical reports foster the concept of the switches of transient EMT-MET in metastasis, there are only a few experimental proofs found. Therefore, the mechanism of MET remains to be elucidated. In this study, we describe a mechanism that 14-3-3θ induces MET, which increases the proliferation rate and decreases the expression of EMT-related genes. On the contrary, the cell proliferation rate was found reduced in 14-3-3θ-knockout cells by CRISPR-Cas9 technology. In addition, phosphorylation of Erk and Akt was activated under the absence of 14-3-3θ. Furthermore, Stat3 were more activated and the expression of EMT-related genes was increased in 14-3-3θ-knockout cells. Clinical data also showed the opposite regulation of Stat3 phosphorylation at cancer metastatic site, indicating the occurrence of the switches of EMT-MET. In summary, we conclude that 14-3-3θ reverses epithelial-mesenchymal transition to allow the tumor to grow and colonize to the metastatic site to the metastatic site via Stat3 pathway.

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