肺癌是全世界死亡的主要原因。在過去的十年中，男性肺癌患者的生存率略有提高，
但女性肺癌患者的預後仍然很差。了解如何誘導女性肺癌患者預後不良的分子機制
對於製定治療策略很重要。我們初步結果表明，與雄性小鼠相比，雌性 EGFRL858R
誘導的肺癌小鼠的腫瘤負荷更高， 表明雌激素可能促進肺癌的進展。事實上，雌激
素處理的肺癌細胞改變了許多癌症相關基因的表達， 纖維蛋白 (FN) 為一種細胞外基
質糖蛋白，它與細胞粘附、遷移和生長有關。在這項研究中，我們首先發現 17β -雌
二醇 (E2) 處理抑制了 A549 細胞中纖維蛋白的表達。根據我們的初步結果， 假設 E2
抑制的纖維蛋白可能與肺癌女性的不良預後有關。 ， 首先我們通過使用纖維蛋白的
過表達和敲低檢查纖連蛋白在體外肺癌進展中的作用。結果表明纖維蛋白的降低可
能會失去細胞間的相互作用並且促進癌細胞的脫離和遷移。相反地，轉染 E2 處理的
A549 的纖維蛋白會增加細胞遷移。 這些數據表明 E2-A549 細胞在缺失纖維蛋白作為
細胞粘附分子表達的情況下，降低了細胞生長但增加遷移活性。最近，我們已經完
成了雄性和雌性肺腫瘤和卵巢剝奪小鼠中纖維蛋白的數據。有趣的是，從肺癌組織
中提取的樣本顯示，在雌性小鼠中檢測到更高的纖維蛋白，但未在雄性小鼠中檢測
到，這與癌細胞中纖維蛋白的表現不ㄧ致。 纖維蛋白的免疫組織染色(IHC)顯示纖維
蛋白主要來自免疫微環境(TME)而不是癌細胞本身，這意味著 E2 可能負調節肺癌細
胞纖維蛋白表達，但正調節癌症相關的纖維細胞 (CAF)中的纖維蛋白。總之， E2 抑
制肺癌細胞中纖維蛋白的表達，但在肺癌惡化及抗藥情形下會促進纖維細胞中纖維
蛋白的表達，這可能與肺癌女性預後不良有關。了解女性肺癌患者預後不良的原因
將有助於未來的癌症治療。

Lung cancer is the leading cause of death worldwide. In the past decade, the survival rate in men lung cancer patients has been improved slightly, but still poor prognosis in women lung cancer patients. Understanding the molecular mechanism of how to induce poor prognosis in women lung cancer patients is important for developing therapeutic strategies. Our recent preliminary result indicated that a higher tumor burden was found in female EGFRL858R-induced lung cancer mice compared to that in male mice, suggesting that estrogen may promote lung cancer progression. Indeed, estrogen-treated lung cancer cells alter many cancer-related genes expression including fibronectin (FN) as an extracellular matrix glycoprotein, which is related to cellular adhesion, migration, and growth. In this study, at first, we found that 17β-estradiol (E2) treatment inhibited fibronectin expression in A549 cells. Based on our recent preliminary results, we hypothesize that E2-repressed fibronectin may be involved in the poor prognosis of women with lung cancer. In beginning, we examined the role of fibronectin in lung cancer progression in vitro by using overexpression and knockdown of fibronectin. The result indicated that knockdown of fibronectin might lose the interaction between cell to cell, and thereby promotes the detachment and migration of cancer cells. Conversely, FN transfected to E2-treated A549 (E2-A549) increases cell migration. Taken together, these data suggest that E2-A549 cells, with deleted the expression of FN as a cell-adhesion molecule, slightly reduce cell growth but increase migration activity. Recently, we already finished data on the protein level of FN in our male and female lung tumors and ovary-deprived mice. Interestingly, samples extracted from lung cancer tissues showed higher aggressive FN were detected in female mice but not in males, which is different compared to the level in cancer cells. IHC stained biomarkers regarded FN derived from TMEs or peripheral tumors primarily instead of individual carcinoma cells, implying that E2 may negatively regulate FN expression but positively regulate FN in cancer-associated fibroblasts (CAFs). In conclusion, E2 inhibits FN expression in lung cancer cells but promotes FN expression in activated fibroblast in drug-sensitive and even overexpression in resistant condition, which might be associated to poor prognosis of women with lung cancer. Understanding the reason(s) of why poor prognosis happens in women lung cancer patients will be beneficial for cancer therapy in the future.

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