根據統計，男性肺癌的存活率高於女性。在這項研究中，我們發現雌性 EGFRL858R小鼠的腫瘤形成比雄性小鼠更顯著。 透過NGS的分析發現在肺癌細胞中p53 和 Sp1 的基因表現量在雌激素處理後下降。過去研究顯示，與肺癌男性相比，在肺癌晚期而非早期肺癌女性的p53突變率增加，而男性則是沒有差異。此結果表明雌激素抑制 p53 表達與女性肺癌預後不良有關。 EGFRL858R 誘導的p53缺失肺癌小鼠模型不僅改變了肺癌細胞中的基因表達，而且通過CCL5表現量上升 與GDF15表現量下降促進 M2 巨噬細胞的分化。我們研究也發現雌激素會增加DNA-甲基轉移酶1 (DNMT1)的表現並且增加p53啟動子的甲基化，導致p53表現量下降。除此之外，臨床統計結果顯示停經前的女性在肺癌晚期Sp1表現量降低，導致肺癌治療預後不良。在我們的結果表明Sp1 的缺失增加了雌激素抑制的 miR-3194、miR-135-5p、miR-182-5p 和 miR-193-5p的表現，進而增強肺癌細胞中 CD44 的表達，並且促進癌症的惡性發展。綜合以上我們發現的結果，發現女性肺癌患者中雌激素抑制的 p53 和 Sp1 表達不僅會影響癌細胞生長，還會影響腫瘤相關微環境，導致女性的肺癌患者預後不良。

Survival rate of lung cancer is higher in men than in women. We found that tumor formation is significantly larger in female EGFRL858R transgenic mice than in male mice. Expression levels for p53 and Sp1 are downregulated in the estrogen-mediated, gene expression profile of lung cancer cells. In females, the p53 mutation rate is higher with late-stage, not early stage, lung cancer, compared to males with lung cancer, indicating that estrogen-inhibited p53 expression is related to a poor prognosis in females with lung cancer. We found that in mice, the knockout of p53 proteins in an EGFRL858R-induced lung cancer model changed the gene expression of cancer cells and increased the polarization of M2 macrophages by increasing the expression of CCL5 and decreasing the expression of GDF15. In addition, estrogen increased DNA methyltransferase-1 expression, which enhanced methylation in the promoter of TP53, which in turn led to a downregulation of p53. In addition, the expression of Sp1 declined in pre-menopausal women with late-stage lung cancer, resulting in poor cancer prognoses. The loss of Sp1 appeared to increase estrogen-inhibited miR-3194, miR-135-5p, miR-182-5p, and miR-193-5p, all of which enhanced CD44 expression in lung cancer cells and thus promoted cancer malignancy. We conclude that the estrogen-inhibited expression of p53 and Sp1 in females with lung cancer affects both their cancer cells and tumor-associated microenvironments, leading to a poor cancer prognosis in women.

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