婦癌中新蛋白標的與相關代謝調節及免疫調控功能

Abstract

婦科惡性腫瘤包卵巢癌、子宮癌、子宮頸癌、外陰癌等數種分佈於女性生殖器官，其中卵巢癌的診斷通常在晚期且具有高復發率，而子宮癌雖多為早期，但一旦診斷為末期或是復發則無良好的治療方式。面對這些不易治療的婦癌，新穎的生物標的在早期檢測、預後評估和標靶治療等有其重要的一面。我們研究強調了白血球細胞趨化素2 (Leukocyte cell-derived chemotaxin 2, LECT2) 和己酮糖磷酸激酶 (Ketohexokinase, KHK) 作為這些惡性腫瘤的潛在生物標的的重要性。我們實驗證實在上皮性卵巢癌中，血清 LECT2 的濃度降低與疾病進展和腫瘤免疫抑制微環境相關， 我們利用細胞與小鼠上皮性卵巢癌模型驗證LECT2除了會透過調節 c-Met 路徑，另一方面也會通過調節腫瘤細胞與免疫細胞的腫瘤微環境來促進卵巢癌進展，這種調節會影響免疫檢查點抑制療法的效果，這項發現將可化為補充LECT2 作為協同免疫治療抑制劑。而在子宮內膜癌，我們發現KHK有兩種異構體KHK-A及KHK-C，其中高KHK-A的表達與不良預後和較晚期疾病有關，過表現KHK-A會促使腫瘤細胞增殖、集落形成和幹細胞特性的增強。此外，我們也發現KHK-A 與 TP53 基因突變和拷貝數變異有關，表明其在代謝調節和致癌途徑中可能發揮作用。KHK抑制劑已被運用在糖尿病的治療上，在子宮內膜癌的代謝調控和腫瘤進展中也可能發揮關鍵作用，為新療法提供潛在的治療機會。這些新興的生物標的LECT2 和 KHK-A，為婦科癌症的發病機制提供了新發現，並有望在診斷、預後及治療策略有益。

Gynecologic malignancies, including epithelial ovarian cancer (EOC) and endometrial cancer, present significant challenges due to their often advanced-stage diagnosis, high recurrence rates, and complex tumor microenvironments. Novel biomarkers are critical for early detection, prognostic assessment, and targeted therapy. Recent investigations have highlighted the importance of human leukocyte cell-derived chemotaxin 2 (LECT2) and ketohexokinase (KHK) as promising biomarkers for these malignancies. In EOC, reduced serum LECT2 levels correlate with disease progression and an immunosuppressive microenvironment, suggesting a pivotal role in regulating metastasis via the c-Met pathway. Using the murine EOC model, we discovered that loss of Lect2 promotes EOC progression by modulating both tumor cells and the tumor microenvironment. This modulation impacts the effectiveness of immune checkpoint blockade therapies, emphasizing LECT2's potential as a target for synergistic immunotherapy. For endometrial cancer, KHK has two splicing alternative isoforms, KHK-A and KHK-C, respectively. High KHK-A expression is linked to poor prognosis and advanced stage, driving tumor cell proliferation, colony formation, and stem cell properties. Moreover, KHK-A's association with TP53 mutations and copy number variations indicates a potential role in metabolic regulation and oncogenic pathways. KHK-A may play a vital role in the metabolic regulation and tumor progression of endometrial cancer, offering potential targets for new therapeutic strategies. These emerging biomarkers, LECT2 and KHK-A, offer new insights into the pathogenesis of gynecologic cancers, providing potential avenues for innovative diagnostic, prognostic, and therapeutic strategies.