腸胃道間質瘤是人體胃腸道最常見的間質細胞瘤，其致病機轉大部份是由於Cajal間質細胞的KIT基因突變，造成其蛋白質產物，即酪胺酸激酶受體KIT受體，在不需配體結合的情況下持續產生激酶區的活化，引發細胞不受控制的增殖或反細胞凋亡而形成腫瘤。CD44為一個含有20 exon的CD44基因編碼細胞膜蛋白質產物，除具有細胞黏著分子的功能外，也和許多細胞生理及病態生理活動有關。我們的研究顯示，腸胃道間質瘤CD44的低表現與臨床上較差的預後有關。然而CD44表現的增減在不同甚至相同人類腫瘤的預後影響並不一致，推測造成CD44表現改變的機轉，包括CD44裂解，可能是更重要的影響因素。CD44如同一些跨膜蛋白，會經由本身蛋白質細胞外區域的裂解來調控細胞的功能。我們研究發現腸胃道間質瘤腫瘤組織，相較於正常組織，有不同程度的CD44的蛋白質裂解產物之表現，較高的CD44裂解表現和不良臨床預後、腫瘤大小以及腫瘤細胞分裂數有明顯相關。本研究的目的便是要探討腸胃道間質瘤之CD44裂解對細胞增殖的影響以及造成兩者之間變化的分子機轉。
我們利用腫瘤庫之腸胃道間質瘤腫瘤及正常組織，分析兩者的CD44裂解產物與細胞增殖相關分子的表現以及臨床病理意義。我們也利用腸胃道間質瘤腫瘤組織及腫瘤細胞來探討和CD44有密切相關性的osteopontin（OPN）在腸胃道間質瘤以及CD44裂解中的角色及影響。另外我們也研究OPN及其與CD44之交互作用對腸胃道間質瘤之細胞增生與細胞凋亡的影響。實驗結果發現腫瘤組織相對於正常組織，在細胞周期中的Cyclin D1以及其重要調控分子β-catenin，如同CD44裂解在腸胃道間質瘤的表現一般，有明顯的腫瘤專一性及過度表現的情形。而Cyclin D1與β-catenin兩者之間除了具有明顯的相關性外，兩者分別與CD44裂解增加也呈現正相關，顯示Cyclin D1與β-catenin在CD44裂解活動可能引發的細胞分裂增加的效應之重要角色。此外腸胃道間質瘤的OPN的表現除了是不良預後的重要因子外，和CD44以及CD44裂解也有顯著的相關，在組織及細胞上也發現和CD44產生交互作用，並和腫瘤組織細胞分裂增加有顯著相關，並同時促進腫瘤細胞之增生，以及經由β-catenin以及抗細胞凋亡Mcl-1的過度表現來促進腫瘤細胞的抗細胞凋亡作用。
我們因此認為在腸胃道間質瘤中，透過osteopontin與CD44的交互作用所引發的CD44的裂解，可促使β-catenin以及其所調控之細胞周期蛋白Cyclin D1及Mcl-1的過度表現，分別造成腫瘤細胞的異常分裂增殖及抗細胞凋亡作用而影響臨床預後。

Gastrointestinal stromal tumors (GISTs) originate from the interstitial cell of Cajal (ICC) in the muscular layer of the gut. The pathogenesis of GIST is gain-of-function mutations in KIT gene in ICC with consequent uncontrolled cell proliferation and anti-apoptosis. Being associated with variable cellular functions, CD44 belongs to the type I transmembrane glycoprotein that is encoded by a 20-exon CD44 gene. We previously found that loss of CD44 expression is related to poor prognosis in GIST. However, the significance of CD44 expression has been controversial. It is thus likely that the mechanism underlying the change in CD44 expression may be more important than the expression of CD44 itself in human cancer. The proteolytic cleavage of membrane proteins, including CD44, has been considered an important mechanism for the regulation of cellular functions. Our study showed that CD44 cleavage is specifically overexpressed in the majority of GIST tumor samples. In the clinicopathologic factors associated with CD44 cleavage, increased mitosis was the most significant one. The aim of this study is to evaluate the possible mechanism underlying the association between increased CD44 cleavage and increased mitosis in GIST. We also aim to investigate the significance and effects of osteopontin (OPN), a multifunctional secreted glycophosphoprotein functionally related to CD44, in relation to tumor proliferation as well as apoptosis.
In GIST tumor samples and their normal counterpart tissues, we analyzed the expression of specific cell cycle proteins in relation to CD44 cleavage activity. We also evaluated the expression and the significance of osteopontin (OPN), a molecule closely related to CD44. Cyclin D1 and its important regulator, β-catenin, showed similar tumor-specificity and overexpression as did CD44 cleavage activity in GIST. Cyclin D1 and β-catenin, in addition to their significant correlation, were also associated with CD44 cleavage, indicating a potential role of these two molecules in the mitotic effect of CD44 cleavage in GIST. OPN, being associated with CD44 and CD44 cleavage, was also found to be an independent prognostic factor clinically, and its interaction with CD44 most significantly correlated with increased mitosis. Further in vitro studies revealed the significant proliferation-promoting and anti-apoptotic effects of OPN and its interaction with CD44 with respect to CD44 cleavage in GIST.
In conclusion, we identified the significant mitotic effect of CD44 cleavage in relation to OPN/CD44 interaction and dysregulated cell cycle in GIST. Increased OPN expression was an independent poor prognostic factor and its interaction with CD44 significantly correlated with increased mitosis as well as in vitro proliferation-promoting and anti-apoptotic effects through upregulation of cyclin D1 and Mcl-1 expression, respectively, in GIST.

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