探討細胞介素-33在癌症進程中所扮演的角色

Abstract

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。

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.