Hedgehog 哈奇霍格蛋白於結腸癌患者組織及急性炎症患者血清、血球中的活化表現

Hedgehog activation in colon cancer and acute inflammation

康珮慈(Pei-Cih Kang)

指導教授 ： 張菡馨

中山醫學大學/健康管理學院/營養學研究所/碩士(2008年)

摘要

Hedgehog訊息傳遞路徑是目前研究較為深入且與細胞分化密切相關的訊息傳遞路徑，當在異常活化下，參與了結腸癌化機制。本實驗將結腸癌其腫瘤分類成分化良好型、中間型及分化不良型等三種型態，以免疫組織化學染色法，觀察Hedgehog訊息傳遞路徑及偵測結腸癌幹細胞之標記抗體CD44和CD133，在結腸癌組織上扮演何種角色並觀察當（1）Hh與Gli1、（2）Hh與CD44、（3）Hh與CD133、（4）Gli1與CD44、（5）Gli1與CD133分組間兩兩比較之表現量上，是否與結腸癌組織之三種型態皆有密切關聯性，結果顯示:在結腸癌組織三種型態分類這些訊息的表現量之間具有高度顯著差異性(p＜ 0.01)，可見Hedgehog訊息傳遞路徑與結腸細胞癌化過程有強烈相關性。且CD44與CD133這兩種標記抗體的表現情形，分別與Hh也呈現高度顯著差異性(p＜ 0.01)，說明Hh與CD44及CD133在結腸癌演變上，先後大量表現，亦有加乘作用。因此未來可將Hh訊息傳遞路徑及與結腸癌偵測之標記抗體CD44和CD133合併列入結腸癌分類的潛在因素。另外，根據文獻記載，Hedgehog在造血幹細胞的發育過程中扮演重要調控角色，因此本實驗亦觀察周邊血液在急性炎症上之Hedgehog的活性，結果發現，當急性發炎時白血球增多的免疫反應中，血球確實大量表現Hedgehog，爰依上述結果得知，Hedgehog的失衡除了會在組織上引起病變，同時也發現發炎反應會導致其在週邊血液中大量表現。由此可證實Hedgehog之異常變化與導致急性炎症及結腸癌之間息息相關，預期對此兩種疾病之預防與診斷有重要貢獻。

關鍵字

hedgehog ； 結腸癌 ； 急性炎症 ； Gli1 ； CD44 ； CD133

並列摘要

Hedgehog(Hh) signaling pathway has been proved strongly related to the cell differentiation. In particular, its overexpression has been suggested to be involved in the progress in colon cancer.In this study, we collected tissues from colon cancer patients, and defined the specimen according to their pathological features into three categories. They were classified as well-differentiated, moderate and poor-differentiated levels. Using immunohistochemical staining techniques, we observed the expression status of Hh signaling pathway including Hh per se, and its transcription factor Gli1, and two crucial markers of colon cancer stem cells, CD44 and CD133. We examined expression level and location of all markers, and correlate the relation between Hh signaling pathway and colon cancer stem markers. When we compared the expression status between (1) Hh and Gli1, (2) Hh and CD44, (3) Hh and CD133, (4) Gli1 and CD44,and (5) Gli1 and CD133, the results demonstrated clearly that in each group they were all highly significantly different between well, moderate, and poor-differentiated tumor cells (p<0.01). This suggested that Hh signaling pathway may intrigue with CD44 and CD133 and both play important roles in colon tumorigenesis. Our results may contribute for colon cancer prevention and treatments. Hh signaling pathway is also interacting with hemopoietic stem cell process, therefore in the second part of this study, we examined the relationship between the activation of Hh signaling pathway during acute inflammation. We discovered that during acute inflammation, Hh was highly activated in the peripheral blood cells. Our findings provide the linkage between acute inflammation and abundant expression of Hh pathway in the blood cells.

並列關鍵字

hedgehog ； colon cancer ； acute inflammation ； Gli1 ； CD44 ； CD133

參考文獻

邱錫雄(2006)大腸直腸癌深入報導

Xuan-Fu Xu, Ze-Yu Zhang, Jun Lin, Wen-Juan Yang, Chuan-Yong Guo. (2007) Expression of Smoothened Protein and Its Relationship with Angiogenesis in Human Colon Cancer. Journal of Tongji University (Medical Science). 5(28), 48-50.

Bai LY, Chiu CF, Lin CW, Hsu NY, Lin CL, Lo WJ and Kao MC. (2008) Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia.1-3.

Beachy PA, Karhadkar SS and Berman DM.(2004) Tissue repair and stem cell renewal in carcinogensis. Nature.432 (7015), 324-331.

Berman DM, Karhadkar SS, Maitra A, Montes Dr Ora R, Gerstenblith MR, Briggs K, Perker AR, Shimada Y, Eshleman JR, Watkins DN and Beachy PA.(2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature.425(6960), 846-851.