Sonic Hedgehog訊息路徑在血液惡性疾病的角色; The Role of Sonic Hedgehog Signaling Pathway in Hematological Malignancy

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題名:	Sonic Hedgehog訊息路徑在血液惡性疾病的角色;The Role of Sonic Hedgehog Signaling Pathway in Hematological Malignancy
作者:	白禮源;Li-Yuan Bai
貢獻者:	中國醫藥大學：醫學研究所碩士班
關鍵詞:	Sonic Hedgehog;血液惡性疾病;白血病;骨髓瘤;hematological malignancy;leukemia;myeloma
日期:	2007-07-13
上傳時間:	2009-08-13 14:50:36 (UTC+8)
摘要:	Sonic hedgehog蛋白（Shh）的主要功能是藉由Patched（Ptc）接受器與鄰近細胞達到細胞與細胞間的聯繫。目前研究已知它們在正常細胞長大、以及脊椎動物與無脊椎動物早期胚胎的分化型態上，扮演重要角色。它們甚至也和人類的腫瘤有重要關聯，包括皮膚基底細胞癌、medulloblastoma、小細胞肺癌、胃癌、食道癌、胰臟癌、膽管癌、及攝護腺癌。Shh蛋白，Ptc 與下游訊息分子Smoothened （Smo），會表現在原始的CD34+CD38+Lin-細胞株上，在成熟的CD19+, CD33+與CD3+細胞株上也可見。許多研究顯示，在早期淋巴球細胞的生長與分化上，以及對於週邊CD4+ T細胞的細胞激素之產生，與細胞週期的進展，Shh訊息傳遞途徑都佔有重要的功能。雖然已知Shh訊息傳遞途徑與造血功能和免疫功能相關，但目前仍沒有證據顯示它與血液腫瘤的關係。在本實驗中，我們試圖探討Shh訊息傳遞途徑在各種血液惡性腫瘤的表現。首先，我們用組織免疫染色來看Shh和Gli1這兩個蛋白在病人的表現。發現骨髓性白血病，包括急性前骨髓性白血病，有最高的比例會表現此兩種蛋白。約有三分之一的多發性骨髓瘤也會染色陽性，但是淋巴球性血液腫瘤病人卻不會。同樣地，在骨髓性細胞株和骨髓瘤細胞株，也可看到不等的表現。之後，我們選取HL-60細胞株做細胞生長和細胞週期的實驗。合成的Shh蛋白，不管是否有沒有加入生長激素，都無法促進HL-60細胞的生長。相反地，Smo的拮抗物，cyclopamine，卻可以時間性和濃度性相關的方式來抑制細胞生長。合成的Shh蛋白無法改變HL-60細胞周期的分佈，但是cyclopamine卻可以使較多的細胞停留在G0/G1週期。總結來說，我們發現Shh路徑會表現在某些血液惡性腫瘤細胞上，尤其是骨髓性細胞和骨髓瘤性細胞。調控Shh訊息傳遞途徑，至少可以部分的改變HL-60細胞生長速率和細胞週期分佈。至於Shh訊息傳遞途徑對血液惡性腫瘤的致癌性和病人預後的影響，則需進一步研究。 Sonic hedgehog (Shh) proteins play an important role in cell-to-cell contact through Patched (Ptc) receptors expressed on adjacent cells. Previous reports showed that they are critical in normal cellular expansion and in the patterning of the early embryo of vertebrates and invertebrates. They were also implicated in human cancers, including basal cell carcinoma, medulloblastoma, small cell lung cancer, and cancers of stomach, esophagus, pancreas, biliary tract and prostate gland. Shh, its receptors Ptc, and downstream signal Smoothened (Smo) are expressed in primitive and mature CD34+CD38+Lin- and mature CD19+, CD33+ and CD3+ cell populations. Several studies have demonstrated an important role of Shh pathway in early lymphoid cell development, lymphoid cells differentiation, as well as in cytokine production and cell cycle progression in activated peripheral CD4+ T lymphocytes. Although Shh pathway is shown to be involved in the hematopoiesis and immune system, there is little evidence demonstrates its relation to hematopoietic malignancy. In present study, we try to investigate the implication of Shh pathway in variable hematological malignancies. Initially, we demonstrated the Shh and Gli1 expression in peoples with hematological malignancies by immunohistochemistry. Patients with myeloid leukemia, including acute promyelocytic leukemia, have the highest possibility of expression of these two proteins. About one third of myeloma cells from patients with multiple myeloma are stained positively, but none from patients with lymphoid malignancies. We also perform the immunohistochemical study in six cell lines. Variable expressions of these two proteins are noted in myeloid and myeloma cell lines. By the results, we select one myeloid cell lines, HL-60, for cell growth and cell cycle studies. Recombinant Shh, either alone or in combination with granulocyte colony stimulating factor, does not stimulate HL-60 cell growth. In contrast, cyclopamine, an antagonist of Smo, can inhibit HL-60 cell growth rate in a time- and concentration-dependent manner. Recombinant Shh can not alter the proportion of cells in different cell cycles, but cyclopamine will make more HL-60 cells in the G0/G1 phase. In conclusion, our study finds Shh pathway expression in some hematological malignancies, especially myeloid leukemia and multiple myeloma. Manipulation of Shh pathway, at least in part, can alter the HL-60 cell growth and cell cycle phase. The tumorigenesis and prognosis prediction of Shh pathway in hematological malignancies should be further examined.
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