背景：CD44屬於第一型跨膜蛋白，為一個含有20 exon之基因編碼產物。CD44和許多細胞活動有關，包括間質的黏著，細胞遷移，增殖，侵襲與轉移。由於腫瘤的侵襲與轉移起始於腫瘤細胞在細胞外間質的主動遷移，CD44以及它的細胞外蛋白質裂解便可能參與了這些侵襲與轉移之過程。腸胃道間質瘤是人體胃腸道最常見的間葉細胞瘤，它是從位於腸胃道的Cajal間質細胞演生而來。報告指出CD44的表現在某些間質細胞腫瘤是其良好或不佳預後因子。本研究的目的是要探討經由手術切除後的腸胃道間質瘤之CD44表現和它在臨床預後上的意義，以及CD44的細胞外蛋白質裂解情形和CD44裂解活動與CD44的表現之間的相關性。
方法：從1995年1月到2006年3月，研究對象為92位在國立成功大學附設醫院接受手術切除腸胃道間質瘤的病人。為了探討CD44表現的意義，進行了腫瘤檢體的CD44免疫組織染色與病人臨床病理資料的收集。其中11位病人也利用反轉錄聚合酵素鏈鎖反應（RT-PCR）來評估CD44 mRNA的表現以及西方墨點法（Western blot）分析CD44裂解產物。
結果：81位病人中有59位是呈現陽性的CD44免疫組織染色表現。CD44喪失表現和疾病的惡化進展 (P = 0.019)，腫瘤大小 (P = 0.032)，NIH腸胃道間質瘤危險分類標準之高危險群 (P = 0.001)相關。Kaplan-Meier方法分析發現較差的無惡化存活期和CD44喪失表現 (P = 0.034)，疾病的惡化進展 (P < 0.001)，NIH分類標準之高危險群 (P = 0.003)有相關。多變數分析顯示依據NIH分類標準之高危險狀態是唯一預測疾病的惡化進展及無惡化存活期之單一因子 (P = 0.023 及 0.045)。在RT-PCR實驗，三位CD44免疫組織染色喪失表現的病人中有兩位是CD44 mRNA減少或無表現。11位病人中有8位是同時有CD44免疫組織染色及CD44 mRNA陽性表現。其中有六位似有CD44 mRNA過度表現的情形。西方墨點法發現11位病人中有9位的腫瘤組織可發現CD44裂解產物，在三個正常組織則無此CD44裂解產物，顯示在腸胃道間質瘤中CD44裂解普遍存在。
結論：可手術切除之腸胃道間質瘤之CD44喪失表現和較大的腫瘤，疾病的惡化進展，NIH分類標準之高危險狀態，以及較差的存活率相關。根據我們我結果，兩種可能的機制會造成腸胃道間質瘤CD44在蛋白質層級的喪失表現：其中之一為CD44 mRNA的降低表現，另外則是經由CD44的過度表現加上裂解造成的高代謝。這兩種機制的加成作用很可能決定了CD44喪失表現在腸胃道間質瘤臨床上及生物學上的意義。

Background: CD44 is a type I transmembrane protein encoded by a single 20-exon gene and has been implicated in a lot of cellular activities, including cell migration, invasion and metastasis. Since tumor invasion and metastasis initiate as active migration of tumor cells in extracellular matrix, the expression of CD44 and its ectodomain cleavage may be involved in these processes. CD44 has been reported as both a favorable and unfavorable prognostic factor in some mesenchymal tumors. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. It is derived from the interstitial cells of Cajal (ICC) of the gut. The purpose of this study is to investigate the clinical significance of CD44 expression in GIST, the activities of CD44 ectodomain cleavage, as well as the association between CD44 expression and CD44 cleavage.
Methods: Between January 1995 and March 2006, 92 patients undergoing surgical resection for GIST in National Cheng Kung University Hospital were evaluated. To study the significance of CD44 expression, immunohistochemical staining of CD44 in tumor specimen was performed and the clinicopathological data of patients was collected. Eleven of these patients were also subjected to RT-PCR for CD44 mRNA study and Western blot for CD44 cleavage analysis to identify potential mechanisms for CD44 expression.
Results: Fifty-nine of 81 patients (73%) showed positive CD44 IHC expression. Loss of CD44 expression was associated with disease progression (P = 0.019), increased tumor size (P = 0.032), and high risk status (National Institutes of Health Consensus Criteria, P = 0.001). Kaplan-Meier analysis revealed worse progression-free survival among patients with loss of CD44 expression (P = 0.034), disease progression (P < 0.001), and high risk status (P = 0.003). Multivariate analysis demonstrated that high-risk status was the only independent risk factor for disease progression and progression-free survival (P = 0.023 and 0.045, respectively). In the RT-PCR study, two of 3 patients with loss of CD44 IHC expression showed decreased or loss of CD44 mRNA expression. Eight of 11 patients with positive CD44 IHC status were also positive for CD44 mRNA. Six of these 8 patients seemed to express upregulated CD44 mRNA. Western blot analysis revealed CD44 cleavage product in 9 of 11 GIST tumor samples and in none of the 3 normal tissues, suggesting the high prevalence of CD44 cleavage in GIST.
Conclusions: Loss of CD44 expression is associated with increased tumor size, disease progression, high risk status and poor survival in GIST after surgical resection. From our results, two putative mechanisms could contribute to the loss of CD44 expression in GIST at the protein level: one is CD44 mRNA downregulation and the other being upregulated turnover through CD44 ectodomain cleavage. It is likely that the synergic net effects of these mechanisms determine the clinical and biologic significance of CD44 loss in GIST.

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