黑色素瘤發生、發展的性別差異化與雌激素水平有著密切聯系。

近年來，越來越多的研究表明，性別在癌癥的發生、發展以及轉移過程中扮演著重要角色。例如不久之前的一篇《自然》論文就發現Y染色體丟失與癌癥風險升高、癌癥加速惡化相關，這也是男性癌癥預后差、更難治療的原因；還有研究表明受腸道菌群影響的中性粒細胞衰老在男性中更嚴重，因此推動了腫瘤的發生。

圖片來源：123RF

另一方面，一些流行病學數據顯示，包括黑色素瘤在內的幾種癌癥，在青春期至更年期之間的女性中更常見。法國國家健康與醫學研究院的Lionel Larue博士指出：“年輕女性尤其是懷孕后，黑色素瘤的發生風險會格外高?！弊罱屯潞献髟凇蹲匀弧冯s志上揭開了其中的謎團：黑色素瘤發生、發展的性別差異化與雌激素水平有著密切聯系。研究發現了一條全新的信號通路，該通路會被雌激素激活，能夠促進癌細胞的生長、遷徙。這一發現不僅解釋了女性特異性癌癥的潛在發生機制，也為相關癌癥治療提供了新的研究方向。

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在新研究中，作者提到了一個關鍵的蛋白——E-鈣粘蛋白。它是一種細胞黏附分子，是維持細胞間連接和組織完整性的關鍵蛋白。E-鈣粘蛋白的缺失或功能障礙與多種癌癥的發生和轉移密切相關，包括乳腺癌、胃癌和甲狀腺癌等。年輕女性的E-鈣粘蛋白的表達水平低于男性和老年女性，這與雌激素一樣同樣具備性別、年齡的差異特點。

為了研究E-鈣粘蛋白在女性特異性黑色素瘤轉移中的作用，研究人員構建了一種條件性敲除E-鈣粘蛋白的小鼠模型。實驗結果顯示，E-鈣粘蛋白缺失本身不會直接誘發黑色素瘤。隨后研究者進一步引入了NRAS基因突變，這一突變會顯著增加黑色素瘤的發生。當黑色素瘤產生后，E-鈣粘蛋白缺失的小鼠展現出了更高的肺轉移率。并且這一情況在雌性小鼠中更為嚴重，它們肺部轉移灶的數量更多、體積也更大。

通過對腫瘤樣本的RNA測序分析，研究人員發現在E-鈣粘蛋白缺失的雌性小鼠中，胃泌素釋放肽受體（GRPR）的表達顯著上調。GRPR是一種G蛋白偶聯受體，其在多種癌癥中均表現出異常表達，并與侵襲性和轉移性表型相關。

不過，從E-鈣粘蛋白缺失到GRPR上調并非簡單的直接調節，而是存在著一條特殊的通路。其中E-鈣粘蛋白缺失會激活β-連環蛋白（β-catenin）信號通路，進而上調雌激素受體α（ESR1）的表達。ESR1的激活進一步促進了GRPR的轉錄。雌激素信號越高，這一通路就越活躍，最終GRPR的信號也越強。這也在一定程度上解釋了為何年輕女性更易患上黑色素瘤，腫瘤也更容易發展。

作者嘗試對實驗雌鼠進行了雌激素受體拮抗劑治療，這一措施能夠顯著抑制GRPR陽性黑色素瘤細胞的侵襲和轉移能力。這一結果表明，雌激素信號不僅在乳腺癌等傳統意義上的激素依賴性癌癥中發揮作用，也可能參與了其他癌癥類型的轉移與發展。這一發現為理解性別差異在癌癥中的作用提供了新的視角，同時為開發針對女性癌癥患者的個性化治療策略提供潛在靶點。

參考資料：

Raymond, J.H., Aktary, Z., Pouteaux, M. et al. Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin. Nature (2025). https://doi.org/10.1038/s41586-025-09111-x