探討細胞介素-33在癌症進程中所扮演的角色

癌症轉移是指癌細胞從體內原來的地方擴散到另外一個部位，為主要造成癌症病人死亡的主因。找出抑制腫瘤轉移之分子並了解其分子機制，可以做為診斷的參考與治療的標靶。細胞介素-33 (Interleukin-33)為細胞介素-1家族的成員之一，透過與受體ST2L的結合調控下游訊號通路。IL-33在恆定的情況下表現於多種類型的細胞和組織，但在發炎反應的過程中其表現量會增加。有許多研究探討IL-33在免疫細胞與癌細胞中扮演重要的角色，但在癌症進展中的作用仍有爭議需進一步探討。在我們的研究中發現IL-33促進細胞的移動性、癌幹細胞特性、非貼附依存性生長和轉移能力。在癌細胞的機制探討發現，經由IL-33的增加人蝸牛同源物2 (Slug)表現量進而影響細胞上皮-間質轉化(EMT)而有形態學上的改變，同時也促進癌細胞的移行性和浸襲性。進一步探討IL-33如何調控Slug發現，IL-33透過與受體ST2L的結合，促進下游的ERK訊息傳遞，經由c-Jun/Fra-1的調控增加Slug的表現量。此外，過去研究證實缺氧的狀態下會促進癌細胞上皮-間質轉化，進而增加癌細胞浸襲性與腫瘤轉移。在我們的研究顯示當癌細胞面臨缺氧環境時，可能因增加了IL-33調控Slug路徑的活化，促進癌細胞的轉移。另外，我們也發現了IL-33是具有雙重作用的因子，會因其分佈的位置而有不同的作用。全長的IL-33主要在細胞核內降低癌細胞的細胞移行和浸襲能力，但當IL-33釋放到細胞外則促進腫瘤的發展。因此，細胞外的IL-33可做為未來治療癌症轉移之一有潛力的標靶與臨床診斷的評估指標。

關鍵字

細胞介素33 ；上皮到間質轉化；人蝸牛同源物2 ；浸襲；轉移；缺氧

並列摘要

Metastasis is the most important contributor to mortality in cancer patients. Identification of tumor metastasis mediator and elucidation of the molecular mechanism contributes to development of cancer targeted therapies. Interleukin-33 (IL-33), a member of the IL-1 family, was identified as the ligand for IL-1 receptor-related protein ST2L. Although IL-33 is universally expressed in tissues during homeostasis, its expression can be up-regulated in the process of inflammation. Growing evidence suggests that IL-33 plays important roles in immune cells and tumor cells, but the controversial roles of IL-33 in cancer progression remains to be investigated. In this study, we demonstrated that IL-33 promotes cancer cell mobility, sphere formation, anchorage-independent growth, and tumor metastasis. We also found that IL-33 enhances the migratory and invasive capabilities of cancer cells by inducing epithelial-to-mesenchymal transition (EMT) through upregulation of zinc-finger protein Slug. Further evidence has showed that IL-33 may induce Slug expression through ST2L-ERK-c-Jun/Fra-1 signaling in cancer cells. Moreover, hypoxia had been reported to promote the invasion and metastasis of cancer cells via a process of EMT. Our results showed that hypoxia may enhance IL-33/ST2L–mediated ERK-c-Jun/Fra-1-Slug signaling resulting in cancer metastasis. Furthermore, we demonstrated that IL-33 has a dual function depending on the cellular localization. Full-length IL-33 is mainly localized in nucleus, and represses cancer cell migration and invasion. However, extracellular IL-33–driven cancer cell mobility and tumor metastasis, may act as a potential therapeutic target and a biomarker for cancer therapy.

並列關鍵字

IL-33 ； epithelial-mesenchymal transition ； Slug ； invasion ； metastasis ； hypoxia

參考文獻

1. I. J. Fidler, The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453-458 (2003).

2. A. F. Chambers, A. C. Groom, I. C. MacDonald, Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563-572 (2002).

3. I. J. Fidler, The organ microenvironment and cancer metastasis. Differentiation 70, 498-505 (2002).

4. D. F. Quail, J. A. Joyce, Microenvironmental regulation of tumor progression and metastasis. Nat Med 19, 1423-1437 (2013).

6. J. A. Joyce, J. W. Pollard, Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239-252 (2009).

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探討細胞介素-33在癌症進程中所扮演的角色

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