膠質瘤在WHO分類上為第四級星狀細胞瘤，是一種位於中樞神經系統(CNS)內的最常見及最具侵略性的腫瘤。目前較普遍的治療方法是利用手術切除配合或學治療與(或)放射性治療來殺死腫瘤細胞，然而預後之存活率的提昇仍有限。核因子κB（NF-κB）是誘導炎症相關細胞因子和趨化因子表達的關鍵轉錄因子，並且和腫瘤細胞的增生、轉移、血管新生及抗細胞凋亡等能力有關。介白素-33( (Interleukin 33, IL-33)則屬於IL-1蛋白超家族之一員，可作為一種IL-1受體相關蛋白ST2的配體，誘導T細胞的極化反應，使T細胞轉變成第二型輔助T細胞(Th2)以調控促發炎反應的發生。相關研究提NF-κB為IL-33/ST2胞內訊息路徑下游分子。到另外，IL-33也能作為一種轉錄因子，在細胞核中扮演負向調控轉錄的功能。本實驗室過去的研究顯示，在高度致瘤性的腦膠質瘤細胞株(大鼠C6-1與人類膠質瘤細胞株)中有大量的IL-33表達，而且我們也證實IL-33在腦腫瘤發展過程中扮演重要角色。然而，NF-κB是否參與IL-33對腦膠質瘤生長的作用並未證實。在這研究中，我們比較控制組與降低IL-33表現量(IL33KD)的大鼠C6腦膠質瘤細胞株內NF-κB總量和其核蛋白量並沒有太大的差異。利用了NF-κB的抑制劑二乙基二硫代氨基甲酸酯（DDTC），研究結果顯示增強了IL33KD對C6細胞群落形成能力的抑制作用。DDTC的抑制細胞群落效應也在IL33KD-U87 MG細胞株觀察到。而另一種NF-κB抑製劑，咖啡酸苯乙酯（CAPE）也同樣的增強了對IL-33KD C6的細胞生長能力的抑製作用。此外，DDTC及CAPE有效降低了IL-33-KD膠質瘤細胞的侵襲能力。透過將IL33KD2 C6腦質瘤細胞植入大鼠腦中並在三天後施打CAPE的動物實驗中，結果顯示施打CAPE的組別所形成的腫瘤有變小的趨勢。此外，我們發現給予外源性IL-33（10ng / ml）的處理IL33KD-C6、IL33KD-U87 MG與IL33KD-U251 MG，僅在一定程度上提高了IL33KD細胞株的集落形成能力。除此之外，提升給予IL-33表現量降低C6細胞株(C6-1)的外源性IL-33蛋白的濃度，對於此C6-1細胞株的群落形成能力的提升並沒有太大的差異。總而言之，抑制NF-κB加成IL33KD抑制腦膠質瘤細胞的生長；基於給予外源性IL-33對於IL33KD腦膠質瘤細胞生長的作用不大，而且，IL-33在C6-1細胞核表現量高，因此我們推測細胞核內的IL-33可能會在在神經膠質瘤細胞生長中發揮調節的作用。

ABSTRACT
Author: Yung-Ning Yang
Advisor: Shun-Fen Tzeng
National Cheng Kung University Institute of life Sciences

SUMMARY
Glioblastoma multiforme (GBM), also known as astrocytoma WHO grade IV is the most common and aggressive form of CNS brain tumors. The conventional treatment for glioma combines surgery with radiation and (or) chemotherapy, but the survival rate of survival is still limited. NF-κB is a crucial transcription factor to induce the expression of inflammatory cytokines and chemokines. Many studies have mentioned that NF-κB proteins play a major role in cancer development by inducing and maintaining a proinflammatory microenvironment, constitutive NF-κB activation appears to promote tumor initiation and progression through mechanisms such as cell proliferation, apoptosis, angiogenesis, and tumor metastasis. IL-33 is a member of IL-1 superfamily and acts as a ligand for ST2 receptor to induce T helper type 2 (Th2) polarization and regulates the initiation of the proinflammatory response. On the other hand, NF-κB is the downstream molecule of the IL-33 / ST2 pathway. In addition, IL-33 can also act as a transcription factor in the nucleus and have a negative regulatory transcription function. Our previous study showed that highly tumorigenic glioma cell lines expressed IL-33 abundantly, and we also demonstrated that IL-33 plays an important role in the development of brain tumors. However, whether NF-κB participates in IL-33 promoting glioma growth has not been confirmed. In this study, we found that adding NF-κB Inhibitor DDTC enhanced the inhibition of the cell viability in IL33KD glioma cell lines (rat C6, human U87 MG), while another NF-κB inhibitor CAPE also enhanced the effect on IL-33KD C6 cells, and both DDTC and CAPE were effective in reducing the invasive ability of IL-33-KD glioma cells. Furthermore, in vivo data showed that treatment of CAPE to C6-IL33KD tumor- bearing rats had a tendency of smaller tumor formation. In addition, we also found that administration of exogenous IL-33 (10 ng/ml) to IL33KD-C6, IL33KD-U87 MG and IL33KD-U251 MG only increased the colony formation capacity to some extent. Then, we increased the exogenous IL-33 concentration to 50 ng/ml, however the colony numbers only slightly increased. Therefore, suppressed the activation of NF-κB in IL33KD glioma cells inhibited the tumor growth. Based on the administration of exogenous IL-33 to IL33KD glioma cell lines partially increase the cell growth significantly, and high expression levels of IL-33 in C6-1 cells, we hypothesized that nuclear IL-33 may play a role in regulation of cell growth in glioma..

Introduction
Glioblastoma multiforme (GBM), also known as astrocytoma WHO grade IV, is the most common and aggressive form of CNS brain tumors, accounting for 50% of brain tumors. The conventional treatment for glioma combines surgery with radiation and chemotherapy. Although this treatment includes the use of anti-angiogenic agents to inhibit cancer cell division/ invasion or to induce cancer cell death, the survival time for most patients is short because the efficacy of this approach to high grade glioma is limited. Our previous study has shown that interleukin-33 (IL-33), a member of IL-1 super family, expressed abundantly in tumorigenic rat glioma cell line C6, and its function was to enhance tumor growth. IL-33 can suffer post-translational modifications resulting in two different forms: the full-length protein (proIL-33) and the processed or “mature” form (mIL-33). mIL-33 is formed after proIL-33 cleavage in its N-terminal domain by caspase 1. In the extracellular space, IL-33 binds to its membrane receptor ST2 activating the MyD88-dependent pathway, which is involved in cytokine secretion, cell activation, and differentiation. Recently, it has been highlighted that the two forms of IL-33 (proIL-33 and mIL-33) are biologically active and they can trigger different immune responses. In our previous study, through lentivirus-mediated IL-33 gene knockdown (IL-33-KD) approach, we have reported that IL-33-KD can reduce the proliferation of C6 glioma cells in vitro and in vivo, as well as the cell growth of human U87MG. In the other hand, Nuclear factor κB (NF-κB) protein is one of the downstream of IL-33/ST2 pathway. NF-κB is a critical transcription factor to induce the expression of inflammation-associated cytokines and chemokines. Many reports have documented that NF-κB proteins are involved in the control of many cellular and physiological processes, including immune and inflammatory responses, developmental processes, cellular growth, and apoptosis. Recently, NF-kB has been shown to play a major role in cancer development by inducing and maintaining a proinflammatory microenvironment, constitutive NF-kB activation appears to promote tumor initiation and progression through mechanisms such as cell proliferation, apoptosis, angiogenesis, tumor metastasis, and reprogramming of metabolism. Furthermore, constitutive activation of NF-kB has been shown to promote glioblastoma cells growth and survival. Thus, we would like to determine the effect of glioma cell growth by interleukin-33 gene knockdown in combination with NF-kB inhibitors, and further investigate the role of proIL-33 and mIL-33 in glioma cells.

Materials and methods
Tumorigenic rat glioma cell line (C6) and human glioma cell lines (U87 andU251) were used in this study to determine the functional role of IL-33 in nucleus and cytosol and the effect of tumor progression treatment with NF-kB inhibitors. Lentivirs-mediated gene knockdown approach was conducted to inhibit the expression of IL-33 in the C6, U87 and U251 cells. Quantitative reverse transcription polymerase chain reaction (Q-PCR) was used to measure mRNA expression of IL-33 in above two cells. MTT assay for C6 cells treated with different concentration of DDTC or CAPE was to detect the C6 cells viability after treatment with DDTC or CAPE. Colony formation assay was presented to examine the colony formation ability of glioma cells treated with NF-kB inhibitors or IL-33. Invasion assay was used to investigate glioma cells invasion ability after treated with NF-kB inhibitors. Rat brain stereotactic injection was used to investigate the rate and size of tumor growth. H&E staining and Aidscans were used to examine the tumor volume.

Results
Through Western Blot analysis, we found that in C6-1 rat glioma cells, IL-33 was mainly expressed in nucleus. Thus, to examine whether nuclear and cytoplasmic IL-33 will involve in glioma cell growth, we add exogenous IL-33 to glioma cell cultures and test the colony formation ability. We used lentivirus-mediated approach to knockdown the expression of IL-33 in rat (C6) and human (U87 and U251) glioma cells. The results showed administration of exogenous IL-33 (10 ng/ml) to IL33KD-C6, IL33KD-U87 MG and IL33KD-U251 MG only increased the colony formation capacity to some extent. Interestingly, we increased the exogenous IL-33 concentration to 50 ng/ml, however the colony numbers only slightly increased. On the other hand, we observed that there’s no significant difference in NF-kB protein levels between C6-1 scramble and IL33KD C6-1 rat glioma cells. Thus, we used NF-kB inhibitor (DDTC and CAPE) to suppressed NF-kB activation. By treating with NF-kB inhibitor DDTC, the results showed further inhibition effect of colony formation ability in IL33KD C6-1 and U87 cells, while another NF-κB inhibitor CAPE also enhanced the inhibitory effect on C6-1 glioma cells. To examine whether adding NF-kB inhibitors will also enhanced the inhibition of cell invasion ability, we used the transwell invasion assay. The results demonstrated that both DDTC and CAPE obviously decreased the invasion ability of IL33KD C6-1 glioma cells. Furthermore, the transplantation of IL33KD C6-1 glioma cells into rat brain was carried out to compare the tumorigenicity with or without treatment of CAPE. In vivo data showed that IL33KD C6-1 tumor formation in rat brain has the tendency to be suppressed by administration of CAPE compare to vehicle group.

Conclusions
In this study, we determined that inhibit the activation of NF-κB in IL33KD glioma cells can suppress tumor growth. In combination with IL-33 mainly expressed in nucleus and administration of exogenous IL-33 only partially increased the IL33KD glioma cell colony formation capacity, we hypothesized nuclear IL-33 plays a role in regulation of glioma cell growth.
Key word: Glioblastoma, IL-33, NF-κB

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