探討膜聯蛋白A1對胃癌侵襲性之影響

Abstract

胃癌在世界癌症死因之中位居第二，而在台灣癌症死因中排名第六。即使近年癌症治療學的進步，晚期胃癌的治療預後依然不佳。最近利用雷射顯微細胞組織擷取術合併cDNA微陣列分析來進行基因表現的研究，發現膜聯蛋白A1基因在胃癌中因為有好的再現性，可望作為一癌症指標。膜聯蛋白A1已廣為人知是一受到腎上腺醣皮質素調控的抗發炎蛋白，可以藉由抑制細胞質內磷酸酶A2α來阻礙花生四烯酸的釋出以及下游產物類花生酸的形成。最近愈來愈多的證據暗示膜聯蛋白A1有著更多的細胞功能，諸如膜間聚集效應、胞噬作用、細胞增生、細胞凋亡、甚至腫瘤生成。過去已有多篇研究顯示，在肝癌、食道腺癌、大腸癌、胰癌中可見到膜聯蛋白A1之表現增加，在乳癌、攝護腺癌以及食道鱗狀上皮細胞癌中卻看到膜聯蛋白A1之表現減少。這些研究意喻著膜聯蛋白A1在腫瘤生成的過程中，有隨著腫瘤種類不同而表現形態不同的專一特性。然而目前膜聯蛋白A1在胃癌的角色上仍未有定論，而相對應的調控機制也不清楚。本篇研究發現在胃癌中膜聯蛋白A1的高度表現會和腹膜腔轉移(p值0.009)以及漿膜層侵犯(p值0.044)有顯著的相關性。寇克斯多變量分析顯示胃癌病患之膜聯蛋白A1的高度表現，對於總存活率是一項獨立的危險因子(p值0.037)。細胞實驗中，膜聯蛋白A1的表現量與胃癌細胞的侵襲性呈現正相關。此外，在小鼠的生體實驗中，利用皮下植入以及腹膜腔內注入模型，同樣可見膜聯蛋白A1的表現會增加胃癌細胞的侵襲性。在調控機制的研究方面，本研究發現膜聯蛋白A1會透過FPRs/ERK/ITGB1BP1途徑來調控胃癌的侵襲性，而所有已知的三種甲醯肽受器FPR(包括FPR1-3)都對調控過程有所影響。此研究結果暗示膜聯蛋白A1的表現可以作為預測胃癌病人預後之用。本研究也發現藉由甲醯肽受器FPR、ERK1/2、以及ITGB1BP1這些分子，有一膜聯蛋白A1用以調控胃癌侵襲性的新機制。

Gastric cancer is the second leading cause of cancer-related death in the world and the sixth leading cause of cancer-related death in Taiwan. The prognosis of advanced gastric cancer remains poor despite the improvement in therapeutic options. In the recent studies of gene expression profiling of gastric cancer cells by cDNA microarray with laser capture microdissection, annexin A1 (ANXA1) gene was identified to be a potential marker in gastric carcinogenesis with good reproducibility. AnxA1 has been well-known as a glucocorticoid-regulated anti-inflammatory protein in blocking the release of arachidonic acid and its subsequent conversion to eicosanoids by inhibition of cytosolic phospholipase A2α. More and more evidence suggests that AnxA1 has a wide variety of cellular functions, such as membrane aggregation, phagocytosis, proliferation, apoptosis and even tumorigenesis. Previous studies have shown increased AnxA1 expression in patients with hepatocellular carcinoma, adenocarcinomas of the esophagus, colon and pancreas, but reduced in adenocarcinoma of the breast and prostate, as well as in squamous cell carcinoma of the esophagus and head and neck. These studies suggest AnxA1 to be implicated in tumorigenesis in a tumor type-specific pattern. However, the role of AnxA1 in gastric cancer is indeterminate, and the underlying mechanism is not clear. In this study, we found that high AnxA1 expression was significantly associated with peritoneal metastasis (p=0.009) and serosal invasion (p=0.044) in gastric cancer. Cox multivariate analysis showed that high AnxA1 expression was an independent risk factor for poor overall survival in gastric cancer patients (p=0.037). AnxA1 expression positively correlated with invasiveness of human gastric cancer cells in vitro. Besides, we applied both subcutaneous implantation and intraperitoneal inoculation models in mice and found that AnxA1 would potentiate gastric cancer cell invasiveness in vivo. For the mechanistic evaluation, our study showed that AnxA1 could regulate the gastric cancer cell invasiveness through the formyl peptide receptors (FPRs)/ERK/ITGB1BP1 pathway; and all three FPRs (FPR1-3) were involved in the regulation process. These data suggested that AnxA1 expression may be used to predict patient outcome in gastric cancer. Furthermore, the current study demonstrated a novel mechanism involving FPRs, ERK1/2, and ITGB1BP1 by which AnxA1 regulated gastric cancer cell invasiveness.