中文摘要
過量表現突變蛋白或病毒蛋白可誘導內質網壓力，幾個路徑可被內質網分佈不均所活化來維持細胞內的平衡，最近有三個主要的分子ATF-6、IRE1、PERK可被內質網壓力來活化。在這個報告，我們發現內質網壓力所活化的路徑可以誘導環氧化酶酵素-2並且可能致癌的機制。Tunicamycin和brefeidin A 為內質網壓力誘導物，可再ML-1及MCF-7下胞株裡增加環氧化酶酵素-2的表現。在內質網壓力下我們也可觀察到NF-kB的入核及pp38 MAP kinase的活化。同時利用染色體免疫沉澱法來分析內質網壓力時可增NF-kB結合在環氧化酶酵素-2啟始端，而這結合可以被p38抑制物所減弱。當使用IkBa-kinase抑制劑Bay 11-7082或IkBa-kinase dominant negative mutant可有效抑制環氧化酶酵素-2的表現。PP38 MAP kinase SB-203580或eIF2a磷酸化抑制物2-aminopurine減緩NF-B結合能力及環氧化酶酵素-2的表現，PP38 MAP kinase抑制物可以降低NF-kB ser276位置的磷酸化。在tunicamycin合併bay11-7082處理時，ERK、JNK及p38的磷酸化可觀察到類似tunicamycin單獨處理，然而在tunicamycin合併Evodiamine處理時，ERK、JNK及p38的磷酸化可觀察到些微的被降低。當表現突變型B型肝炎表面抗原時，可在ML-1及HuH-7細胞株裡誘導環氧化酶酵素-2的表現。以轉殖鼠有表現突變型B型肝炎表面抗原的組織肝及腎臟也有較高的環氧化酶酵素-2的表現。類似的，在人類含有突變型B型肝炎表面抗原肝腫瘤細胞也可觀察到有較高環氧化酶酵素-2信息合醣核酸的表現。表現有突變型B型肝炎表面抗原ML-1可增強anchorage-independent生長的能力，而這個增強生長優勢可被環氧化酶酵素-2抑制物所破壞。因此，由突變型B型肝炎表面抗原或藥物可透過NF-kB及pp38 MAP kinase路徑來刺激環氧化酶酵素-2表現。我們的結果提供一個重要的結論-細胞內致癌性跟潛伏的內質網壓力有關。

Abstract
Overexpression of mutant proteins or viral infection can induce endoplasmic reticulum stress (ER stress). Several pathways that maintain cellular homeostasis are activated in response to these ER disturbances. Three major molecular, ATF-6 / IRE1 / PERK, are activated by ER stress. In this report, we investigated which of these ER stress-activated pathways induce COX-2, and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-kB and activation of pp38 MAP kinase were observed during ER stress. Increased nuclear NF-kB binding activity on COX-2 promoter during was analyzed by CHIP assay and this binding activity attenuated by p38 inhibitor. IkBa-kinase inhibitor Bay 11-7082 or IkBa kinase dominant negative mutant significantly inhibited the induction of COX-2. PP38 MAP kinase inhibitor SB-203580 or eIF2a phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-kB DNA binding activity and COX-2 induction. PP38 MAP kinase inhibitor can decrease NF-kB phosphorylation on ser276 site. In tunicamycin combined bay11-7082 treatment, phosphorylation of ERK, JNK, and p38 was similar to tunicamycin treatment. However, in tunicamycin combined with Evodiamine treatment, Evodiamine had minor decrease phosphorylation of ERK, JNK, and p38. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through NF-kB and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

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