探討尿苷二磷酸半乳糖運輸蛋白SLC35A2在胃癌中的表現及功能

Abstract

胃癌仍然是全球癌症相關死亡的主要原因之一，尤其在東亞地區的發病率居高不下。儘管診斷和治療技術有所進步，但預後仍然不佳，特別是對於晚期疾病患者而言，其高轉移率和治療抗性導致死亡率居高不下。因此，迫切需要鑑定新的生物標誌物和治療標靶來改善患者的預後。異常糖基化是癌症的一個標誌，並在腫瘤進展中發揮關鍵作用，包括轉移、免疫逃逸和化療抗性。SLC35A2 是一種負責糖基生物合成的 UDP-半乳糖轉運蛋白，已被發現參與調控糖基化過程，但其在胃腺癌中的作用尚不清楚。 在本研究中，我們通過分析公共數據庫及臨床組織，發現 SLC35A2 表達在胃癌中顯著降低，且低表達與臨床預後不良相關，包括晚期 TNM 分期、血管侵犯和遠端轉移。Kaplan-Meier 生存分析進一步確認，低 SLC35A2 表達是較差生存率的重要預測因子。功能性研究表明，SLC35A2 的基因調降或敲除會促進胃癌細胞的遷移及侵襲性行為，並在動物實驗中促進腫瘤生長及轉移。 蛋白組學分析顯示，SLC35A2 調控整合素及參與細胞外基質相互作用、血管生成和鐵死亡相關通路蛋白的半乳糖基化。RNA-seq 則進一步揭示了 SLC35A2 在調控低氧反應、代謝重編程和免疫調節基因中的關鍵作用。此外，表觀遺傳調控因子可恢復 SLC35A2 的表達，突顯其作為治療標靶的潛力。 綜合來看，我們的研究確立了 SLC35A2 作為胃癌進展的關鍵調節因子，並強調其作為生物標誌物的重要性，以及透過靶定 SLC35A2 關聯的分子機制來解決胃癌臨床需求的潛力。

Gastric cancer remains a leading cause of cancer-related mortality worldwide, with a high prevalence in East Asia. Despite advances in diagnosis and treatment, its prognosis remains poor, especially for patients with advanced-stage disease, due to high rates of metastasis and therapeutic resistance. There is an urgent need to identify novel biomarkers and therapeutic targets to improve patient outcomes. Aberrant glycosylation is a hallmark of cancer and plays a pivotal role in tumor progression, including metastasis, immune evasion, and chemoresistance. SLC35A2, a UDP-galactose transporter essential for glycan biosynthesis, has been implicated in regulating glycosylation processes; however, its role in gastric adenocarcinoma remains unclear. In this study, we analyzed public databases and patient tissues, revealing that SLC35A2 expression is significantly downregulated in gastric cancer and low SLC35A2 expression correlates with poor clinical outcomes, including advanced TNM stage, vascular invasion, and distant metastasis. Kaplan-Meier survival analysis confirmed that low SLC35A2 expression is a strong predictor of worse overall survival. Functional studies demonstrated that SLC35A2 knockdown or knockout enhances migratory and invasive behaviors of gastric cancer cells in vitro and promotes metastasis and tumor growth in vivo. Proteomic profiling revealed that SLC35A2 modulates galactosylation of integrins and proteins involved in ECM interactions, angiogenesis, and ferroptosis pathways. RNA-seq further highlighted SLC35A2-dependent regulation of hypoxia response, metabolic reprogramming, and immune modulation genes. Finally, epigenetic modulators restored SLC35A2 expression, underscoring its potential as a therapeutic target. Collectively, our findings establish SLC35A2 as a critical regulator of gastric cancer progression and emphasize its value as a biomarker, as well as its relevance for addressing the unmet clinical need by targeting SLC35A2-associated molecular processes.