乳癌為女性最常見的癌症，同時也是世界上癌症造成相關死亡的第二位。三陰性乳癌(TNBC)佔所有乳癌的15-30%，其定義為同時缺乏動情激素受體(ER)、黃體激素受體(PR)和人類表皮因子受體2(HER2)的乳癌，三陰性乳癌患者相較於其他乳癌亞型，具有不良預後且高風險復發率。缺氧是實質固態瘤的共同特徵，增加了癌症的侵襲性和轉移潛力，並與大多數類型癌症的不良結果有關。缺氧誘導因子1α(HIF-1α)在缺氧而觸發的細胞機制中扮演關鍵角色；轉錄調節因子YAP受Hippo訊息路徑的負調控，對於發育、生理和腫瘤發生有著至關重要的作用。在本研究中，我們聚焦於缺氧對於三陰性乳癌細胞之HIF-1α和YAP信號傳導的影響。我們透過處理CoCl2或者1% O2缺氧槽培養細胞來執行細胞之缺氧條件，半定量共軛焦顯微造影用於評估缺氧下HIF-1α和YAP核易位的表達和比例。我們發現在高細胞密度下，缺氧會誘導YAP核易位；接下來，我們使用transwell檢視細胞功能，在CoCl2誘導的缺氧條件下會顯著增加間質三陰性乳癌細胞的遷移。此外，我們證明了使用了熟知的YAP抑制劑Verteporfin(VP)處理細胞可以顯著減少缺氧狀態下的細胞遷移，這表明YAP可能參與缺氧誘導的細胞遷移。另外，以2維空間單細胞遷移實驗證明，在缺氧環境下之間質三陰性乳癌細胞中具有更大的淨距離細胞遷移，而有趣的是VP作用顯著減少了此細胞遷移的距離。這些數據支持YAP是缺氧條件下促進間質三陰性乳癌細胞遷移所必需。長期以來，黏著斑被認為在調節細胞遷移中扮演一個重要角色，因為它們是位於細胞基底的大型蛋白質複合體，構成細胞外基質與細胞骨架之間的物理聯繫。透過全內反射螢光(TIRF)顯微鏡術顯示，在缺氧條件下僅有間質三陰性乳癌細胞之細胞膜周圍上的黏著斑顯著增加。更進一步，我們還證明了在缺氧條件下，細胞處理VP將會降低細胞前緣黏著斑的表達，這個結果高度支持先前的發現，即缺氧會增加細胞遷移。總結來說，我們的數據指出缺氧或HIF-1α過度表達，接續誘導YAP核易位並調節間質三陰性乳癌細胞的遷移。最後，如上述研究提供有力證據表明YAP可能與缺氧條件下的細胞遷移呈正相關，未來進一步探索在缺氧條件下操作YAP可能有助於克服或預防三陰性乳癌的進展。

Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths in the world. Triple-negative breast cancer (TNBC) occupies 15-30% of all types of breast cancer and it is defined by the lack of three receptors including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC patients are associated with a poor prognosis and the risk of recurrence is higher than that of other types of breast cancer. Hypoxia is a common characteristic of solid tumors and related to poor outcomes in most cancer types, increasing the aggressiveness and metastatic potential of a cancer. Hypoxia-inducible factor 1α (HIF-1α) plays a key role in cellular mechanisms triggered in response to hypoxia. The transcriptional regulator yes-associated protein (YAP) plays a vital role in development, physiology, and tumorigenesis that is negatively regulated by Hippo pathway. In this study, we focus on the effect of hypoxia on HIF-1α and YAP signaling in TNBC. We performed hypoxia conditions by treatment CoCl2 or 1% O2 hypoxia chamber incubation for the cell. Semi-quantification confocal imaging of the nuclear translocation of HIF-1α and YAP has been used to evaluate their expression and proportion under hypoxia. We found hypoxia-induced YAP nuclear translocation in a high cell density. Next, we examined the cell function and discovered a significantly increased cell migration in mesenchymal TNBC cell under CoCl2 mediated hypoxia based on transwell assay. Furthermore, we demonstrated that treatment the cell with Verteporfin (VP), a well-known YAP inhibitor, could strongly decrease cell migration under hypoxia, suggesting that YAP might be involved in hypoxia-induced cell migration. In addition, 2D-single cell migration demonstrated the cell migration with greater net distance to be observed in mesenchymal TNBC cells under hypoxia. Interestingly, VP markedly reduced the distance of cell migration. These data suggest that YAP is required for mesenchymal TNBC cells migration under hypoxia conditions. It has long been proposed that focal adhesions play an important role in regulating cell migration because they are large protein complexes that are organized at the basal surface of cells and physically connect the extracellular matrix to the cytoskeleton. In keeping with this, the immunofluorescence images revealed that the focal adhesion was significantly enhanced on the peripheral membrane, which was only observed in mesenchymal TNBC cells under hypoxia based on total internal reflection fluorescence (TIRF) microscopy. Moreover, we also demonstrated that cell-treated VP reduced expression of focal adhesion on the leading edge in hypoxia conditions. This finding is highly supported by previous findings that hypoxia increases cell migration. Collectively, our data indicated that hypoxia or HIF-1α overexpressed, which consequently imports YAP nuclear translocation to mediate cell migration in mesenchymal TNBC. Lastly, the above studies strengthen the evidence that YAP might be positively related to cell migration under hypoxia. Further exploration of YAP under hypoxia might help overcome or prevent the progression of TNBC.

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