研究背景：骨橋蛋白(OPN)是一個多功能性的糖磷酸化蛋白。其在腫瘤細胞的存活及惡化上扮演重要的角色。本研究旨在探討OPN在食道鱗狀細胞癌的化放療抗性以及幽門桿菌導致胃癌前病變的角色。
研究方法：在食道癌的世代追蹤研究，我們收錄了罹患食道鱗狀細胞癌且接受合併化放療的患者。使用ELISA測量患者治療前的血漿OPN濃度，並和健康者做比較。在食道癌患者，進一步分析其血漿OPN濃度和化放療反應及預後的相關性。並利用細胞實驗來驗證抑制OPN表現是否能增加化放療的敏感性以及探討下游的作用機轉。
在慢性胃炎的世代追蹤研究上，我們比較有無幽門桿菌感染，及有無胃癌前病變（腸上皮化生）患者，其胃黏膜及血漿OPN濃度的差異。分析OPN表現強度和胃發炎指數及腸上皮化生的相關性。患者於除菌後接受胃鏡追蹤檢查，以評估OPN的表現的變化。進一步利用細胞實驗來探討幽門桿菌刺激OPN表現的機轉，以及OPN調控腸上皮化生形成的機轉。
結果：食道鱗狀細胞癌患者的血漿OPN濃度明顯比健康者高，其血漿OPN濃度的平均值分別為133.4 ng/mL以及84.6 ng/mL。血漿OPN濃度高的食道癌患者，對化放療的反應以及預後明顯較差。細胞實驗進一步證實，OPN表現量高的食道癌細胞株對放射線較具抗性。抑制這類細胞株的OPN表現，可以增加其對化放療的敏感性；同時會增加G2/M細胞週期；也會減少去氧核醣核酸修復基因(DNA damage response genes)的表現。
在慢性胃炎的世代追蹤研究上，幽門桿菌感染者的胃黏膜比沒有感染者表現較高的OPN (p < 0.001)。在有幽門桿菌感染的患者中，胃黏膜OPN的表現強度和胃黏膜發炎程度(p < 0.001)以及腸上皮化生的形成有正相關(勝算比2.6, 95%信賴區間: 1.15-5.94, p = 0.02)。然而，血漿OPN的濃度在各組間無顯著差異。殺菌後只有正常胃黏膜的OPN表現會下降(P < 0.001)，腸上皮化生部位的OPN表現量則居高不下。免疫螢光染色證實表現OPN的免疫細胞主要是T細胞和巨噬細胞。幽門桿菌刺激monocyte (U937)製造分泌型OPN (sOPN)，而刺激胃上皮細胞(MKN45)製造胞內型OPN (iOPN)。阻斷TLR2可以抑制胃炎菌株引發的iOPN表現，但無法抑制胃癌菌株引發的iOPN表現。幽門桿菌刺激胃上皮細胞表現iOPN必須經由第四型分泌系統注射CagA蛋白來達成。幽門桿菌會促進胃上皮細胞堆積beta-catenin以及分泌IL-8，而抑制iOPN表現則可完全阻斷這些作用。外加OPN (sOPN)到GES-1細胞可以透過AKT-GSK-3beta訊息傳遞路徑促進beta-catenin進入細胞核。
結論：OPN會促進食道癌對化放療的抗性以及腸上皮化生的形成。血漿OPN濃度是一個簡便的腫瘤指標，可以用來預測食道癌對化放療的療效。抑制OPN是極具潛力的治療方式，可以增加食道癌的化放療療效以及預防胃癌的發生。

Background: Osteopontin (OPN) is a multifunctional glycophosphoprotein which play important roles in tumor survival and progression. We investigated the role of OPN in chemoradiation resistance of esophageal squamous cell carcinoma (ESCC) and H. pylori-induced gastric precancer formation.
Methods: In ESCC cohort, the consecutive ESCC patients treated by definitive chemoradiotherapy (CRT) were enrolled. The patients’ baseline plasma OPN levels were determined by ELISA and compared to healthy controls. In ESCC patients, the correlations between OPN level and CRT response, and between OPN level and prognosis were evaluated. The cell culture experiments were performed to investigate the effect of OPN knockdown on enhancing chemoradiosensitivity and the downstream mechanisms. In chronic gastritis cohort, OPN expression levels in gastric mucosa and plasma were compared between patients with and without H. pylori infection and between H. pylori-infected patients with and without gastric precancerous change (intestinal metaplasia, IM). The correlations between OPN expression and gastric inflammation and IM were evaluated. Patients were followed after H. pylori eradication to assess OPN expression change. The cell culture experiments were performed to elucidate the upstream mechanisms of OPN induction by H. pylori, and the downstream pathways involved in IM formation.
Results: Patients with ESCC had significantly elevated plasma OPN levels than healthy controls (mean OPN level: 133.4 vs 84.6 ng/mL, p < 0.001). In ESCC patients, high baseline plasma OPN level correlated with poor CRT response and prognosis. The cell culture experiments confirmed that ESCC cells with high OPN expression were more resistant to irradiation-induced proliferation inhibition. OPN knockdown in high-OPN expression ESCC cells enhanced chemoradiosensitivity, increased G2/M phase of cell cycle, and inhibited expression of DNA damage response genes.
In chronic gastritis cohort, H. pylori-infected patients had higher gastric OPN expression than the non-infected controls (p < 0.001). For the H. pylori-infected patients, an increased gastric OPN expression correlated with more severe chronic gastric inflammation (p < 0.001) and the presence of IM (OR: 2.6, 95% CI: 1.15-5.94, p = 0.02). However, the plasma OPN levels were similar between groups. After H. pylori eradication, the gastric OPN expression could be decreased only in areas without IM (p < 0.001). Double immunofluorescence stain showed T-cell and macrophage were the main OPN expressing immunocytes. H. pylori stimulate secretory OPN (sOPN) from monocytes (U937 cell) and intracellular OPN (iOPN) from gastric epithelial cells (MKN45). TLR2 antagonist abolished iOPN expression in MKN45 induced by gastritis strain, but not by cancer strain of H. pylori. The H. pylori CagA delivered via type IV secretion system is indispensable for iOPN upregulation. H. pylori induced beta-catenin accumulation and interleukin-8 secretion in MKN45, whereas OPN knockdown in MKN45 completely abrogated these effects. Adding recombinant OPN (sOPN) to GES-1 cell also increased beta-catenin nuclear translocation via AKT-GSK-3beta signal transduction pathways.
Conclusion: OPN may contribute to chemoradiation resistance of ESCC and gastric IM formation. Plasma OPN is a potential marker for prediction of CRT response and prognosis of ESCC. Inhibition of OPN may be a promising strategy to improve CRT response of ESCC and prevent formation of gastric cancer.

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