胸腺位於胸部的前縱膈腔，是身體中細胞免疫體系最重要的來源。胸腺中的胸腺表皮細胞不僅與胸腺的發育及T淋巴球的形成有關，異常功能及生長將引發重症肌無力及胸腺腫瘤的形成。胸腺本身可生成及分泌很多細胞激素，而胸腺表皮細胞是這些激素分泌的主要來源。這些激素不僅對於附近的細胞有paracrine的作用，有些更對分泌細胞本身有autocrine的作用。在本研究中，我們探索胸腺表皮細胞分泌的激素及其下游產物訊號傳導與轉錄激活因子3 (STAT3) 在正常胸腺及胸腺表皮細胞瘤中的角色。
我們首先利用臨床資料及病理結果探討胸腺癌的手術成果及預後因子，結果顯示胸腺癌病患的預後不佳，而患有無法完全切除或侵犯縱膈腔大血管的胸腺癌的病患預後最差；進一步我們研究在多種癌症被證實是致癌因子的蛋白質STAT3 在胸腺的成長及胸腺瘤的臨床表現所扮演的角色，我們首次證實STAT3可以在胸腺及胸腺瘤表現，而STAT3在胸腺表皮細胞的持續表現與胸腺組織的維持及重症肌無力的存在有顯著的相關性，表現STAT3的胸腺瘤 （type C除外）有較低的侵襲性及較高的可切除性，而表現STAT3的胸腺癌（type C胸腺瘤）卻有較高的侵襲性與較低的可切除性，顯示STAT3在兩者之訊息傳遞途徑不同。為瞭解那些激素參與其中的變化，我們利用胸腺及胸腺瘤的組織進行體外胸腺表皮細胞的培養，同時以human cytokine antibody array證實IL-6, IL-8, MCP-1 (Monocyte chemoattractive protein-1), GRO (growth related oncogene) 與GRO-α是胸腺表皮細胞在體外培養狀況下分泌較多的激素。接著利用西方墨點法證實IL-6/STAT3訊息傳遞的確存在於正常胸腺表皮細胞。我們首次發現人類胸腺表皮細胞可分泌GRO-α，也發現在無血清培養下IL-6 及GRO-α在胸腺表皮細胞有autocrine的現象，並發現IL-6的分泌早於GRO-α的表現，於是進一步研究IL-6/Jak-2訊息傳遞與GRO-α分泌的相關性，利用anti-IL-6 抗體及Jak-2 抑制劑，我們證實GRO-α的分泌可以被IL-6/Jak-2這訊息傳遞所調控。GRO-α在文獻上被認為是很多癌症中具有致癌因子特性的趨化激素，在胸腺中的角色尚未被報導，為進一步釐清GRO-α在胸腺瘤中的角色，我們利用胸腺及胸腺瘤組織蠟塊經免疫組織染色研究發現，在正常胸腺組織之表皮細胞並無GRO-α的表現，而在胸腺瘤的表皮細胞中，隨著組織型態的惡性度越高GRO-α的表現越顯著，暗示GRO-α在胸腺表皮細胞癌化的過程可能扮演重要的角色。
本研究的重要性在於可以瞭解GRO-α與IL-6/STAT3對於胸腺及胸腺瘤生成及預後的影響，以做為未來研究免疫系統及胸腺瘤治療的基礎。

Thymus is the most important organ for cellular immunity. Thymic epithelial cells (TECs) maintain the thymic architecture and associate with T-cell development, myasthenia gravis and formation of thymic epithelial tumors. A lot of cytokines could be secreted in the thymus and TECs are the main producers. These cytokines could have paracrine and autocrine effects to the surrounding cells or the secreted cells themselves. In this study, we investigated the relationships between cytokines and their general downstream transcription factors signal transducers and activator of transcription 3 (STAT3) in thymus and patients with thymoma and thymic carcinoma.
First, we investigated the surgical results and prognostic factors of thymic carcinoma from clinicopathological parameters. Results showed patients with thymic carcinoma had poor prognosis. Unable to complete resection of the tumor and invasion of the great vessels in the mediastinum are the indicators of poor prognosis. We further investigated that the roles of STAT3, an oncogene in several cancers, in thymus and thymic epithelial tumors. Our data provide the first evidence that constitutive STAT3 activation is seen in both benign and neoplastic thymic tissue and is associated with the persistence of thymic tissue and the presence of myasthenia gravis. Thymoma (exclude type C thymoma) with activated STAT3 tended to have less aggressive behavior. In contrast, thymic carcinoma (type C thymoma) with STAT3 expression had higher rates of unresectability and vascular invasion. It is likely STAT3 to be induced by different factors in thymoma and thymic carcinoma. To identify the involvement of cytokines, we made an in vitro system for primary culture of TECs. By using human cytokine antibody array to detect the main cytokines secreted from primary thymic epithelial cells culture of normal thymus and thymic epithelial tumors, we further documented that IL-6, IL-8, MCP-1, GRO (growth related oncogene), and GRO-α were the main cytokines produced by TECs in vitro. The IL-6/STAT3 signaling pathway in the normal TECs was documented by Western blotting. We also provided the first evidence that GRO and GRO-α could be secreted by TECs. With or without serum supplement in vitro, both IL-6 and GRO-α autocrine in TECs were found. We further investigated the inter-regulation between IL-6/Janus kinase 2 (Jak2) and GRO-α. Neutralizing IL-6 significantly reduced GRO-α production. Inhibiting Jak2 spontaneously blocked GRO-α production with or without IL-6 stimulation. We conclude that human thymic epithelial cells produce GRO-α and that its expression is regulated primarily by IL-6/Jak2 signaling. The roles of GRO-α, an oncogene in several cancers, in thymic epithelial tumors are further investigating. Immunohistochemical staining from paraffin block showed TECs in the normal thymus did not expressed GRO-α. In thymoma, the expression of GRO-α is in TECs and is more frequently expressed in the tumors with histologically high grade malignancy (such as type B3 and type C thymoma). These data implicate GRO-α may play a role in the tumorigenesis of thymic epithelial tumors.
The importance of this study is that we provide evidence to understand the influence of GRO-α and IL-6/STAT3 in the thymus development and tumorigenesis and prognosis of thymic epithelial tumors. These results could be as a basis for further study of the cellular immunity and therapy for thymic epithelial tumors.

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