白血病是血液型惡性腫瘤的統稱，其中急性白血病好發於成年人且最致命的一種白血病亞型。目前針對急性白血病上有許多不同的治療方式，誘導分化治療法即是一種透過迫使癌細胞走向分化，進而引發癌細胞死亡的治療法。但發現病患會因產生抗藥性而導致療程的失敗。介白素-18是一種促發炎的細胞激素。介白素-18已被發現會大量表現在一些血液型惡性腫瘤中，並且導致較差的癒後。介白素-18雖然已在固態腫瘤中被認為扮演促進腫瘤生成的角色，但是對於介白素-18在血液型惡性腫瘤中的影響及調控機制尚不清楚。在本研究中我們發現介白素-18雖不會對急性白血病細胞株 U937與THP-1細胞的增生造成影響，但具有抑制其細胞凋亡的能力；也發現在U937細胞中，特別是刺激分化後的U937細胞，介白素-18會透過後轉錄調控的機制來增加環氧化酶-2 的表現。兩個RNA結合蛋白 HuR和IMP3 參與在穩定環氧化酶-2 mRNA中，另外也發現介白素-18並不影響 HuR和IMP3 的表現量，但會增加他們從細胞核到細胞質的移動並增加HuR和IMP3結合至環氧化酶-2 mRNA上。於此，我發現介白素-18會活化JNK和ERK1/2路徑，而增加HuR轉移(但不影響IMP-3)到細胞質以及環氧化酶-2 3端UTR報導子的轉錄活性。這些結果顯示介白素-18穩定環氧化酶-2 mRNA的機制可能是透過JNK和/或ERK1/2路徑所調控的HuR出核轉送。因此這研究結果指出介白素-18和環氧化酶-2的抑制劑，可能可以做為一個以誘導分化治療的白血病的合併藥劑。

Leukemia is a broad term covering a spectrum of diseases. The acute myeloid leukemia (AML) is a common subtype occurred in adults and also the majority type of all leukemia patients to result in death. Instead of killing cancer cells through cytotoxicity, forcing malignant cells to undergo differentiation is one of the strategies in AML therapy. However, the patients always failed to complete remission due to drug resistance is still a challenge. IL-18 is a pro-inflammatory cytokine. IL-18 was observed to be overexpressed in some hematologic malignancies and associated with a poor clinical outcome. Importantly, although the protumor effect of IL-18 was suggested in solid tumors, the effects and details remain less to be elucidated in hematopoietic neoplasms. In this study, we found that IL-18 has no effect on the proliferation but showed an antiapoptotic effect on U937 and THP-1 cells. Increase of COX-2 expression is responsive to IL-18 treatment through a post-transcriptional regulation in U937 cells, especially in differentiated U937 cells. Two RNA binding proteins HuR and IMP-3 mediate the stabilization of COX-2 mRNA. IL-18 has no effect on the levels of HuR and IMP-3 but induced their shuttle from nucleus to cytoplasm and interaction. Importantly, IL-18 induces the bindings of HuR and IMP-3 on the 3’UTR of COX-2 mRNA. JNK and ERK1/2 signaling pathways contribute to IL-18-enhanced COX-2 transcripts and the shuttle of HuR, but not IMP-3, from nucleus to cytoplasm in differentiated U937 cells. These results suggested that IL-18 can stabilize COX-2 mRNA through the JNK- and/or ERK1/2-regulated HuR nucleocytoplasmic shuttle. It also implied that the IL-18 and COX-2 inhibitors could represent a potential adjuvant to be combined with differentiation therapy for AML therapy.

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